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Sample records for systemic inflammation induced

  1. Amorphous silica nanoparticles impair vascular homeostasis and induce systemic inflammation

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    Nemmar A

    2014-06-01

    Full Text Available Abderrahim Nemmar,1 Sulayma Albarwani,2 Sumaya Beegam,1 Priya Yuvaraju,1 Javed Yasin,3 Samir Attoub,4 Badreldin H Ali5 1Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khod, Sultanate of Oman; 3Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 4Department of Pharmacology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 5Department of Pharmacology, College of Medicine and Health Sciences, Sultan Qaboos University, Al-Khod, Sultanate of Oman Abstract: Amorphous silica nanoparticles (SiNPs are being used in biomedical, pharmaceutical, and many other industrial applications entailing human exposure. However, their potential vascular and systemic pathophysiologic effects are not fully understood. Here, we investigated the acute (24 hours systemic toxicity of intraperitoneally administered 50 nm and 500 nm SiNPs in mice (0.5 mg/kg. Both sizes of SiNPs induced a platelet proaggregatory effect in pial venules and increased plasma concentration of plasminogen activator inhibitor-1. Elevated plasma levels of von Willebrand factor and fibrinogen and a decrease in the number of circulating platelets were only seen following the administration of 50 nm SiNPs. The direct addition of SiNPs to untreated mouse blood significantly induced in vitro platelet aggregation in a dose-dependent fashion, and these effects were more pronounced with 50 nm SiNPs. Both sizes of SiNPs increased lactate dehydrogenase activity and interleukin 1β concentration. However, tumor necrosis factor α concentration was only increased after the administration of 50 nm SiNPs. Nevertheless, plasma markers of oxidative stress, including 8-isoprostane

  2. Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone.

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    Myung-Sunny Kim

    Full Text Available It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D. Salicylates and thiazolidinediones (TZDs both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT and AT macrophages (ATMs, as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi, whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.

  3. Neuroinflammation and oxidative stress in rostral ventrolateral medulla contribute to neurogenic hypertension induced by systemic inflammation

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    Wu Kay LH

    2012-09-01

    Full Text Available Abstract Background In addition to systemic inflammation, neuroinflammation in the brain, which enhances sympathetic drive, plays a significant role in cardiovascular diseases, including hypertension. Oxidative stress in rostral ventrolateral medulla (RVLM that augments sympathetic outflow to blood vessels is involved in neural mechanism of hypertension. We investigated whether neuroinflammation and oxidative stress in RVLM contribute to hypertension following chronic systemic inflammation. Methods In normotensive Sprague-Dawley rats, systemic inflammation was induced by infusion of Escherichia coli lipopolysaccharide (LPS into the peritoneal cavity via an osmotic minipump. Systemic arterial pressure and heart rate were measured under conscious conditions by the non-invasive tail-cuff method. The level of the inflammatory markers in plasma or RVLM was analyzed by ELISA. Protein expression was evaluated by Western blot or immunohistochemistry. Tissue level of superoxide anion (O2·- in RVLM was determined using the oxidation-sensitive fluorescent probe dihydroethidium. Pharmacological agents were delivered either via infusion into the cisterna magna with an osmotic minipump or microinjection bilaterally into RVLM. Results Intraperitoneal infusion of LPS (1.2 mg/kg/day for 14 days promoted sustained hypertension and induced a significant increase in plasma level of C-reactive protein, tumor necrosis factor-α (TNF-α, or interleukin-1β (IL-1β. This LPS-induced systemic inflammation was accompanied by activation of microglia, augmentation of IL-1β, IL-6, or TNF-α protein expression, and O2·- production in RVLM, all of which were blunted by intracisternal infusion of a cycloxygenase-2 (COX-2 inhibitor, NS398; an inhibitor of microglial activation, minocycline; or a cytokine synthesis inhibitor, pentoxifylline. Neuroinflammation in RVLM was also associated with a COX-2-dependent downregulation of endothelial nitric oxide synthase and an

  4. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice.

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    Bercik, Premysl; Verdu, Elena F; Foster, Jane A; Macri, Joseph; Potter, Murray; Huang, Xiaxing; Malinowski, Paul; Jackson, Wendy; Blennerhassett, Patricia; Neufeld, Karen A; Lu, Jun; Khan, Waliul I; Corthesy-Theulaz, Irene; Cherbut, Christine; Bergonzelli, Gabriela E; Collins, Stephen M

    2010-12-01

    Clinical and preclinical studies have associated gastrointestinal inflammation and infection with altered behavior. We investigated whether chronic gut inflammation alters behavior and brain biochemistry and examined underlying mechanisms. AKR mice were infected with the noninvasive parasite Trichuris muris and given etanercept, budesonide, or specific probiotics. Subdiaphragmatic vagotomy was performed in a subgroup of mice before infection. Gastrointestinal inflammation was assessed by histology and quantification of myeloperoxidase activity. Serum proteins were measured by proteomic analysis, circulating cytokines were measured by fluorescence activated cell sorting array, and serum tryptophan and kynurenine were measured by liquid chromatography. Behavior was assessed using light/dark preference and step-down tests. In situ hybridization was used to assess brain-derived neurotrophic factor (BDNF) expression in the brain. T muris caused mild to moderate colonic inflammation and anxiety-like behavior that was associated with decreased hippocampal BDNF messenger RNA (mRNA). Circulating tumor necrosis factor-α and interferon-γ, as well as the kynurenine and kynurenine/tryptophan ratio, were increased. Proteomic analysis showed altered levels of several proteins related to inflammation and neural function. Administration of etanercept, and to a lesser degree of budesonide, normalized behavior, reduced cytokine and kynurenine levels, but did not influence BDNF expression. The probiotic Bifidobacterium longum normalized behavior and BDNF mRNA but did not affect cytokine or kynurenine levels. Anxiety-like behavior was present in infected mice after vagotomy. Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry, which can be normalized by inflammation-dependent and -independent mechanisms, neither of which requires the integrity of the vagus nerve. Copyright © 2010 AGA Institute. Published by Elsevier Inc

  5. Protection against fine particle-induced pulmonary and systemic inflammation by omega-3 polyunsaturated fatty acids.

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    Li, Xiang-Yong; Hao, Lei; Liu, Ying-Hua; Chen, Chih-Yu; Pai, Victor J; Kang, Jing X

    2017-03-01

    Exposure to fine particulate matter, such as through air pollution, has been linked to the increased incidence of chronic diseases. However, few measures have been taken to reduce the health risks associated with fine particle exposure. The identification of safe and effective methods to protect against fine particle exposure-related damage is urgently needed. We used synthetic, non-toxic, fluorescent fine particles to investigate the physical distribution of inhaled fine particles and their effects on pulmonary and systemic inflammation in mice. Tissue levels of omega-3 fatty acids were elevated via dietary supplementation or the fat-1 transgenic mouse model. Markers of pulmonary and systemic inflammation were assessed. We discovered that fine particulate matter not only accumulates in the lungs but can also penetrate the pulmonary barrier and travel into other organs, including the brain, liver, spleen, kidney, and testis. These particles induced both pulmonary and systemic inflammation and increased oxidative stress. We also show that elevating tissue levels of omega-3 fatty acids was effective in reducing fine particle-induced inflammation, whether as a preventive method (prior to exposure) or as an intervention (after exposure). These results advance our understanding of how fine particles contribute to disease development and suggest that increasing tissue omega-3 levels may be a promising nutritional means for reducing the risk of diseases induced by particle exposure. Our findings demonstrate that elevating tissue omega-3 levels can prevent and treat fine particle-induced health problems and thereby present an immediate, practical solution for reducing the disease burden of air pollution. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  6. LPS-induced systemic inflammation is more severe in P2Y12 null mice

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    Liverani, Elisabetta; Rico, Mario C.; Yaratha, Laxmikausthubha; Tsygankov, Alexander Y.; Kilpatrick, Laurie E.; Kunapuli, Satya P.

    2014-01-01

    Thienopyridines are a class of antiplatelet drugs that are metabolized in the liver to several metabolites, of which only one active metabolite can irreversibly antagonize the platelet P2Y12 receptor. Possible effects of these drugs and the role of activated platelets in inflammatory responses have also been investigated in a variety of animal models, demonstrating that thienopyridines could alter inflammation. However, it is not clear whether it is caused only by the P2Y12 antagonism or whether off-target effects of other metabolites also intervene. To address this question, we investigated P2Y12 KO mice during a LPS-induced model of systemic inflammation, and we treated these KO mice with a thienopyridine drug (clopidogrel). Contrary to the reported effects of clopidogrel, numbers of circulating WBCs and plasma levels of cytokines were increased in LPS-exposed KO mice compared with WT in this inflammation model. Moreover, both spleen and bone marrow show an increase in cell content, suggesting a role for P2Y12 in regulation of bone marrow and spleen cellular composition. Finally, the injury was more severe in the lungs of KO mice compared with WT. Interestingly, clopidogrel treatments also exerted protective effects in KO mice, suggesting off-target effects for this drug. In conclusion, the P2Y12 receptor plays an important role during LPS-induced inflammation, and this signaling pathway may be involved in regulating cell content in spleen and bone marrow during LPS systemic inflammation. Furthermore, clopidogrel may have effects that are independent of P2Y12 receptor blockade. PMID:24142066

  7. CELECOXIB ATTENUATES SYSTEMIC LIPOPOLYSACCHARIDE-INDUCED BRAIN INFLAMMATION AND WHITE MATTER INJURY IN THE NEONATAL RATS

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    FAN, L.-W.; KAIZAKI, A.; TIEN, L.-T.; PANG, Y.; TANAKA, S.; NUMAZAWA, S.; BHATT, A. J.; CAI, Z.

    2013-01-01

    Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is associated with inflammatory processes. Cyclooxygenase-2 (COX-2) can be induced by inflammatory stimuli, such as cytokines and pro-inflammatory molecules, suggesting that COX-2 may be considered as the target for anti-inflammation. The objective of the present study was to examine whether celecoxib, a selective COX-2 inhibitor, can reduce systemic LPS-induced brain inflammation and brain damage. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) was performed in postnatal day 5 (P5) of Sprague-Dawley rat pups and celecoxib (20 mg/kg) or vehicle was administered i.p. 5 min after LPS injection. The body weight and wire hanging maneuver test were performed 24 hr after the LPS exposure, and brain injury was examined after these tests. Systemic LPS exposure resulted in an impairment of behavioral performance and acute brain injury, as indicated by apoptotic death of oligodendrocytes (OLs) and loss of OL immunoreactivity in the neonatal rat brain. Treatments with celecoxib significantly reduced systemic LPS-induced neurobehavioral disturbance and brain damage. Celecoxib administration significantly attenuated systemic LPS-induced increments in the number of activated microglia and astrocytes, concentrations of IL-1β and TNFα, and protein levels of phosphorylated-p38 MAPK in the neonatal rat brain. The protection of celecoxib was also associated with a reduction of systemic LPS-induced COX-2+ cells which were double labeled with GFAP+ (astrocyte) cells. The overall results suggest that celecoxib was capable of attenuating the brain injury and neurobehavioral disturbance induced by systemic LPS exposure, and the protective effects are associated with its anti-inflammatory properties. PMID:23485816

  8. Involvement of purinergic system in inflammation and toxicity induced by copper in zebrafish larvae

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    Leite, Carlos Eduardo, E-mail: carlos.leite@pucrs.br [Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Programa de Pós-Graduação em Medicina: Ciências Médicas, Universidade Federal do Rio Grande do Sul, Porto Alegre, CEP 90035-003 (Brazil); Maboni, Lucas de Oliveira [Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Cruz, Fernanda Fernandes [Instituto de Toxicologia e Farmacologia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, CEP 90619-900 (Brazil); Rosemberg, Denis Broock [Programa de Pós-graduação em Ciências Ambientais, Universidade Comunitária da Região de Chapecó, Chapecó, CEP 89809-000 (Brazil); and others

    2013-11-01

    The use of zebrafish (Danio rerio) is increasing as an intermediate preclinical model, to prioritize drug candidates for mammalian testing. As the immune system of the zebrafish is quite similar to that of mammals, models of inflammation are being developed for the screening of new drugs. The characterization of these models is crucial for studies that seek for mechanisms of action and specific pharmacological targets. It is well known that copper is a metal that induces damage and cell migration to hair cells of lateral line of zebrafish. Extracellular nucleotides/nucleosides, as ATP and adenosine (ADO), act as endogenous signaling molecules during tissue damage by exerting effects on inflammatory and immune responses. The present study aimed to characterize the inflammatory status, and to investigate the involvement of the purinergic system in copper-induced inflammation in zebrafish larvae. Fishes of 7 days post-fertilization were exposed to 10 μM of copper for a period of 24 h. The grade of oxidative stress, inflammatory status, copper uptake, the activity and the gene expression of the enzymes responsible for controlling the levels of nucleotides and adenosine were evaluated. Due to the copper accumulation in zebrafish larvae tissues, the damage and oxidative stress were exacerbated over time, resulting in an inflammatory process involving IL-1β, TNF-α, COX-2 and PGE{sub 2}. Within the purinergic system, the mechanisms that control the ADO levels were the most involved, mainly the reactions performed by the isoenzyme ADA 2. In conclusion, our data shed new lights on the mechanisms related to copper-induced inflammation in zebrafish larvae. - Graphical abstract: This scheme provides a chronological proposition for the biochemical events induced by copper in zebrafish larvae. The dashed line shows the absorption of copper over the exposure time. After 1 h of exposure to copper, the release of PGE{sub 2} occurs, followed by an increase of MPO (as a consequence

  9. Involvement of purinergic system in inflammation and toxicity induced by copper in zebrafish larvae

    International Nuclear Information System (INIS)

    Leite, Carlos Eduardo; Maboni, Lucas de Oliveira; Cruz, Fernanda Fernandes; Rosemberg, Denis Broock

    2013-01-01

    The use of zebrafish (Danio rerio) is increasing as an intermediate preclinical model, to prioritize drug candidates for mammalian testing. As the immune system of the zebrafish is quite similar to that of mammals, models of inflammation are being developed for the screening of new drugs. The characterization of these models is crucial for studies that seek for mechanisms of action and specific pharmacological targets. It is well known that copper is a metal that induces damage and cell migration to hair cells of lateral line of zebrafish. Extracellular nucleotides/nucleosides, as ATP and adenosine (ADO), act as endogenous signaling molecules during tissue damage by exerting effects on inflammatory and immune responses. The present study aimed to characterize the inflammatory status, and to investigate the involvement of the purinergic system in copper-induced inflammation in zebrafish larvae. Fishes of 7 days post-fertilization were exposed to 10 μM of copper for a period of 24 h. The grade of oxidative stress, inflammatory status, copper uptake, the activity and the gene expression of the enzymes responsible for controlling the levels of nucleotides and adenosine were evaluated. Due to the copper accumulation in zebrafish larvae tissues, the damage and oxidative stress were exacerbated over time, resulting in an inflammatory process involving IL-1β, TNF-α, COX-2 and PGE 2 . Within the purinergic system, the mechanisms that control the ADO levels were the most involved, mainly the reactions performed by the isoenzyme ADA 2. In conclusion, our data shed new lights on the mechanisms related to copper-induced inflammation in zebrafish larvae. - Graphical abstract: This scheme provides a chronological proposition for the biochemical events induced by copper in zebrafish larvae. The dashed line shows the absorption of copper over the exposure time. After 1 h of exposure to copper, the release of PGE 2 occurs, followed by an increase of MPO (as a consequence of

  10. Dynamic expression of leukocyte innate immune genes in whole blood from horses with lipopolysaccharide-induced acute systemic inflammation

    DEFF Research Database (Denmark)

    Vinther, Anne Mette L.; Skovgaard, Kerstin; Heegaard, Peter M. H.

    2015-01-01

    Background: In horses, insights into the innate immune processes in acute systemic inflammation are limited even though these processes may be highly important for future diagnostic and therapeutic advances in high-mortality disease conditions as the systemic inflammatory response syndrome (SIRS...... expressions in blood leukocytes during equine acute LPS-induced systemic inflammation thoroughly characterized a highly regulated and dynamic innate immune response. These results provide new insights into the molecular mechanisms of equine systemic inflammation.......) and sepsis. Therefore, the aim of this study was to investigate the expression of 31 selected blood leukocyte immune genes in an equine model of acute systemic inflammation to identify significantly regulated genes and to describe their expression dynamics during a 24-h experimental period. Systemic...

  11. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo.

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    Yorifumi Satou

    2011-02-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL, and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (T(reg. Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for T(reg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ, which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ T(reg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased T(reg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ T(reg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of T(reg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.

  12. IL10 Released by a New Inflammation-regulated Lentiviral System Efficiently Attenuates Zymosan-induced Arthritis

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    Garaulet, Guillermo; Alfranca, Arántzazu; Torrente, María; Escolano, Amelia; López-Fontal, Raquel; Hortelano, Sonsoles; Redondo, Juan M; Rodríguez, Antonio

    2013-01-01

    Administration of anti-inflammatory cytokines is a common therapeutic strategy in chronic inflammatory diseases. Gene therapy is an efficient method for delivering therapeutic molecules to target cells. Expression of the cell adhesion molecule E-selectin (ESEL), which is expressed in the early stages of inflammation, is controlled by proinflammatory cytokines, making its promoter a good candidate for the design of inflammation-regulated gene therapy vectors. This study describes an ESEL promoter (ESELp)-based lentiviral vector (LV) that drives localized transgene expression during inflammation. Mouse matrigel plug assays with ESELp-transduced endothelial cells showed that systemic lipopolysaccharide (LPS) administration selectively induces ESELp-controlled luciferase expression in vivo. Inflammation-specific induction was confirmed in a mouse model of arthritis, showing that this LV is repeatedly induced early in acute inflammation episodes and is downregulated during remission. Moreover, the local acute inflammatory response in this animal model was efficiently blocked by expression of the anti-inflammatory cytokine interleukin-10 (IL10) driven by our LV system. This inflammation-regulated expression system has potential application in the design of new strategies for the local treatment of chronic inflammatory diseases such as cardiovascular and autoimmune diseases. PMID:22760540

  13. HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis

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    Runkuan Yang

    2017-01-01

    Full Text Available Severe acute pancreatitis (SAP starts as a local inflammation of pancreatic tissue that induces the development of multiple extrapancreatic organs dysfunction; however, the underlying mechanisms are still not clear. Ischemia-reperfusion, circulating inflammatory cytokines, and possible bile cytokines significantly contribute to gut mucosal injury and intestinal bacterial translocation (BT during SAP. Circulating HMGB1 level is significantly increased in SAP patients and HMGB1 is an important factor that mediates (at least partly gut BT during SAP. Gut BT plays a critical role in triggering/inducing systemic inflammation/sepsis in critical illness, and profound systemic inflammatory response syndrome (SIRS can lead to multiple organ dysfunction syndrome (MODS during SAP, and systemic inflammation with multiorgan dysfunction is the cause of death in experimental SAP. Therefore, HMGB1 is an important factor that links gut BT and systemic inflammation. Furthermore, HMGB1 significantly contributes to multiple organ injuries. The SAP patients also have significantly increased circulating histones and cell-free DNAs levels, which can reflect the disease severity and contribute to multiple organ injuries in SAP. Hepatic Kupffer cells (KCs are the predominant source of circulating inflammatory cytokines in SAP, and new evidence indicates that hepatocyte is another important source of circulating HMGB1 in SAP; therefore, treating the liver injury is important in SAP.

  14. Endotoxin-induced and vaccine-induced systemic inflammation both impair endothelium-dependent vasodilation, but not pulse wave reflection

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    Lind L

    2012-07-01

    Full Text Available Lars Lind,1 Johannes Hulthe,2,3 Annika Johansson,3 Ewa Hedner31Department of Medicine, University Hospital, Uppsala, 2Sahlgrenska Hospital, Gothenburg, 3AstraZeneca Research and Development, Mölndal, SwedenBackground: Inflammation induced by either endotoxin or vaccination has previously been shown to impair endothelium-dependent vasodilation (EDV in healthy young individuals. However, the vascular effects of these two mechanisms of inducing inflammation have not been compared in the same individuals.Methods: Twelve young healthy males were studied at the same time of the day on three occasions in a random order; on one occasion 4 hours following an endotoxin injection (Escherichia coli endotoxin, 20 IU/kg, on another occasion 8 hours following vaccination against Salmonella typhi, and on a third occasion 4 hours following a saline control injection. EDV and endothelium-independent vasodilation (EIDV were evaluated by local infusions of acetylcholine and sodium nitroprusside in the brachial artery, and forearm blood flow was measured with venous occlusion plethysmography. The augmentation index was determined by pulse wave analysis as an index of pulse wave reflection.Results: Both endotoxin and vaccination impaired EDV to a similar degree compared with the saline control (P = 0.005 and P = 0.014, respectively. EIDV was not significantly affected by inflammation. Endotoxin, but not vaccination, increased body temperature and circulating levels of intracellular adhesion molecule-1 and interleukin-6. Augmentation index was not affected by the interventions.Conclusion: Despite the fact that endotoxin induced a more pronounced degree of inflammation than vaccination, both inflammatory challenges impaired EDV to a similar degree, supporting the view that different inflammatory stimuli could induce harmful effects on the vasculature.Keywords: endothelium, endotoxin, vaccination, vasodilation, inflammation

  15. Effect of chronic continual- and intermittent hypoxia-induced systemic inflammation on the cardiovascular system in rats.

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    Xu, Xiao-Mei; Yao, Dan; Cai, Xue-Ding; Ding, Cheng; Lin, Qian-Ding; Wang, Liang-Xing; Huang, Xiao-Ying

    2015-05-01

    Obstructive sleep apnea syndrome (OSAS) has been recognized as an important risk factor for cardiovascular morbidity and mortality. However, the underlying mechanisms are poorly understood. Present study aimed to investigate the role of NF-κB-dependent inflammation pathways in pathophysiological responses of cardiovascular system in OSAS. Thirty male specific pathogen-free (SPF) Sprague-Dawley rats were randomly assigned to normoxia (N) group, continual hypoxia (CH) group, and intermittent hypoxia (IH) group (n = 10) and were exposed to N (21% O2), CH (8% O2), or IH (6-11% O2 for 10 s and 21% O2 for 80 s in every 90 s) for 8 h/day for 35 days. The hemodynamic and pathomorphologic effects of IH and CH exposure were investigated as well as the expression of NF-κB-dependent inflammation factors. Chronic IH or CH significantly increased mean pulmonary arterial pressure (mPAP) in rats, while no significant changes occurred in mean carotid arterial pressure (mCAP). The ratio of right ventricle (RV) to left ventricle (LV) + septum (S) was significantly increased by both IH and CH, suggesting RV hypertrophy was induced by IH or CH. Elastic fiber staining showed an irregular pattern of elastic fiber distribution after hypoxia, and aortic tunica media thickness was increased. Both chronic IH and CH upregulated the expressions of transcription factor NF-κB and related pro-inflammatory cytokines and adhesion molecules. The current study expands our understanding that both IH and CH could activate the expression of NF-κB and related inflammatory factors as well as cause pathophysiologic damage to the cardiovascular system in OSAS. All these results provide further support to an emerging hypothesis that activation of NF-κB-dependent inflammation may play a central role in the pathophysiology of cardiovascular dysfunction in OSAS.

  16. Local and Systemic Inflammation May Mediate Diesel Engine Exhaust-Induced Lung Function Impairment in a Chinese Occupational Cohort.

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    Wang, Haitao; Duan, Huawei; Meng, Tao; Yang, Mo; Cui, Lianhua; Bin, Ping; Dai, Yufei; Niu, Yong; Shen, Meili; Zhang, Liping; Zheng, Yuxin; Leng, Shuguang

    2018-04-01

    Diesel exhaust (DE) as the major source of vehicle-emitted particle matter in ambient air impairs lung function. The objectives were to assess the contribution of local (eg, the fraction of exhaled nitric oxide [FeNO] and serum Club cell secretory protein [CC16]) and systemic (eg, serum C-reaction protein [CRP] and interleukin-6 [IL-6]) inflammation to DE-induced lung function impairment using a unique cohort of diesel engine testers (DETs, n = 137) and non-DETs (n = 127), made up of current and noncurrent smokers. Urinary metabolites, FeNO, serum markers, and spirometry were assessed. A 19% reduction in CC16 and a 94% increase in CRP were identified in DETs compared with non-DETs (all p values regulatory risk assessment. Local and systemic inflammation may be key processes that contribute to the subsequent development of obstructive lung disease in DE-exposed populations.

  17. Differences in systemic inflammation between cigarette and biomass smoke-induced COPD

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    Golpe R

    2017-09-01

    Full Text Available Rafael Golpe,1 Irene Martín-Robles,1 Pilar Sanjuán-López,1 Luis Pérez-de-Llano,1 Carlos González-Juanatey,2 José L López-Campos,3,4 Elena Arellano-Orden4 1Respiratory Medicine Service, 2Cardiology Service, University Hospital Lucus Augusti, Lugo, 3Medical-Surgical Unit of Respiratory Diseases, University Hospital Virgen del Rocío, Sevilla, 4Center for Biomedical Research in Respiratory Diseases Network, Carlos III Health Institute, Madrid, Spain Background and objective: It is known that biomarkers of systemic inflammation are raised in COPD caused by tobacco (T-COPD compared with healthy controls, but there is less information on the inflammatory status of subjects with COPD caused by biomass smoke (B-COPD. In addition, the possible (if any differences in inflammation between both types of the disease are still not well known. The aim of this study was to assess the inflammatory profile in B-COPD and T-COPD.Methods: A total of 20 subjects (15 men and five women with T-COPD were matched one to one for sex, age and forced expiratory volume in 1 s (FEV1 to 20 B-COPD patients. In all, 20 sex-matched healthy subjects with normal lung function without smoking history or biomass exposure were included as controls. The following biomarkers were measured: exhaled nitric oxide, serum IL-6, IL-8, IL-5, IL-13, periostin, surfactant protein-P, TNF-α, IgE, erythrocyte sedimentation rate, C-reactive protein and fibrinogen. Complete blood count was also obtained.Results: The age of the subjects was 70.2±7.9 years and FEV1% was 56.2%±14.6%. Most inflammatory biomarkers were higher in both types of COPD than in healthy controls. IL-6, IL-8 and IL-5 were significantly higher in T-COPD than in B-COPD, without other significant differences.Conclusion: Both types of COPD are associated with high levels of systemic inflammation biomarkers. T-COPD patients have a higher systemic inflammatory status than the patients with B-COPD. Keywords: biomass smoke

  18. Chronic Sleep Disruption Alters Gut Microbiota, Induces Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice.

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    Poroyko, Valeriy A; Carreras, Alba; Khalyfa, Abdelnaby; Khalyfa, Ahamed A; Leone, Vanessa; Peris, Eduard; Almendros, Isaac; Gileles-Hillel, Alex; Qiao, Zhuanhong; Hubert, Nathaniel; Farré, Ramon; Chang, Eugene B; Gozal, David

    2016-10-14

    Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF.

  19. Lidocaine Prevents Oxidative Stress-Induced Endothelial Dysfunction of the Systemic Artery in Rats With Intermittent Periodontal Inflammation.

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    Saito, Takumi; Yamamoto, Yasuhiro; Feng, Guo-Gang; Kazaoka, Yoshiaki; Fujiwara, Yoshihiro; Kinoshita, Hiroyuki

    2017-06-01

    Periodontal inflammation causes endothelial dysfunction of the systemic artery. However, it is unknown whether the use of local anesthetics during painful dental procedures alleviates periodontal inflammation and systemic endothelial function. This study was designed to examine whether the gingival or systemic injection of lidocaine prevents oxidative stress-induced endothelial dysfunction of the systemic artery in rats with intermittent periodontal inflammation caused by lipopolysaccharides (LPS). Some rats received 1500 µg LPS injections to the gingiva during a week interval from the age of 8 to 11 weeks (LPS group). Lidocaine (3 mg/kg), LPS + lidocaine (3 mg/kg), LPS + lidocaine (1.5 mg/kg), and LPS + lidocaine (3 mg/kg, IP) groups simultaneously received gingival 1.5 or 3 mg/kg or IP 3 mg/kg injection of lidocaine on the same schedule as the gingival LPS. Isolated aortas or mandibles were subjected to the evaluation of histopathologic change, isometric force recording, reactive oxygen species, and Western immunoblotting. Mean blood pressure and heart rate did not differ among the control, LPS, LPS + lidocaine (3 mg/kg), and lidocaine (3 mg/kg) groups. LPS application reduced acetylcholine (ACh, 10 to 10 mol/L)-induced relaxation (29% difference at ACh 3 × 10 mol/L, P = .01), which was restored by catalase. Gingival lidocaine (1.5 and 3 mg/kg) dose dependently prevented the endothelial dysfunction caused by LPS application (24.5%-31.1% difference at ACh 3 × 10 mol/L, P = .006 or .001, respectively). Similar to the gingival application, the IP injection of lidocaine (3 mg/kg) restored the ACh-induced dilation of isolated aortas from rats with the LPS application (27.5% difference at ACh 3 × 10 mol/L, P lidocaine (3 mg/kg), or the combination. The LPS induced a 4-fold increase in the protein expression of tumor necrosis factor-α in the periodontal tissue (P lidocaine (3 mg/kg) coadministration partly reduced the levels. Lidocaine application also decreased

  20. Effects of an Encapsulated Fruit and Vegetable Juice Concentrate on Obesity-Induced Systemic Inflammation: A Randomised Controlled Trial

    Directory of Open Access Journals (Sweden)

    Evan J. Williams

    2017-02-01

    Full Text Available Phytochemicals from fruit and vegetables reduce systemic inflammation. This study examined the effects of an encapsulated fruit and vegetable (F&V juice concentrate on systemic inflammation and other risk factors for chronic disease in overweight and obese adults. A double-blinded, parallel, randomized placebo-controlled trial was conducted in 56 adults aged ≥40 years with a body mass index (BMI ≥28 kg/m2. Before and after eight weeks daily treatment with six capsules of F&V juice concentrate or placebo, peripheral blood gene expression (microarray, quantitative polymerase chain reaction (qPCR, plasma tumour necrosis factor (TNFα (enzyme-linked immunosorbent assay (ELISA, body composition (Dual-energy X-ray absorptiometry (DEXA and lipid profiles were assessed. Following consumption of juice concentrate, total cholesterol, low-density lipoprotein (LDL cholesterol and plasma TNFα decreased and total lean mass increased, while there was no change in the placebo group. In subjects with high systemic inflammation at baseline (serum C-reactive protein (CRP ≥3.0 mg/mL who were supplemented with the F&V juice concentrate (n = 16, these effects were greater, with decreased total cholesterol, LDL cholesterol and plasma TNFα and increased total lean mass; plasma CRP was unchanged by the F&V juice concentrate following both analyses. The expression of several genes involved in lipogenesis, the nuclear factor-κB (NF-κB and 5′ adenosine monophosphate-activated protein kinase (AMPK signalling pathways was altered, including phosphomevalonate kinase (PMVK, zinc finger AN1-type containing 5 (ZFAND5 and calcium binding protein 39 (CAB39, respectively. Therefore, F&V juice concentrate improves the metabolic profile, by reducing systemic inflammation and blood lipid profiles and, thus, may be useful in reducing the risk of obesity-induced chronic disease.

  1. Metallothionein reduces central nervous system inflammation, neurodegeneration, and cell death following kainic acid-induced epileptic seizures

    DEFF Research Database (Denmark)

    Penkowa, Milena; Florit, Sergi; Giralt, Mercedes

    2005-01-01

    We examined metallothionein (MT)-induced neuroprotection during kainic acid (KA)-induced excitotoxicity by studying transgenic mice with MT-I overexpression (TgMT mice). KA induces epileptic seizures and hippocampal excitotoxicity, followed by inflammation and delayed brain damage. We show for th...

  2. Interleukin-6 and lung inflammation: evidence for a causative role in inducing respiratory system resistance increments.

    Science.gov (United States)

    Rubini, Alessandro

    2013-10-01

    Interleukin-6 is a multifunctional cytokine that has been shown to be increased in some pathological conditions involving the respiratory system such as those experimentally induced in animals or spontaneously occurring in humans. Experimental data demonstrating that interleukin-6 plays a significant role in commonly occurring respiratory system inflammatory diseases are reviewed here. Those diseases, i.e. asthma and chronic obstructive pulmonary disease, are characterised by mechanical derangements of the respiratory system, for the most part due to increased elastance and airway resistance. Recent findings showing that interleukin-6 has a causative role in determining an increase in airway resistance are reviewed. The end-inflation occlusion method was used to study the mechanical properties of the respiratory system before and after interleukin-6 administration. The cytokine was shown to induce significant, dose-dependent increments in both the resistive pressure dissipation due to frictional forces opposing the airflow in the airway (ohmic resistance) and the additional resistive pressure dissipation due to the visco-elastic properties of the system, i.e. stress relaxation (visco-elastic resistance). There were no alterations in respiratory system elastance. Even when administered to healthy mammals, interleukin-6 determines a significant effect on respiratory system resistance causing an increase in the mechanical work of breathing during inspiration. IL-6 hypothetically plays an active role in the pathogenesis of respiratory system diseases and the mechanisms that may be involved are discussed here.

  3. Comparison of Watermelon and Carbohydrate Beverage on Exercise-Induced Alterations in Systemic Inflammation, Immune Dysfunction, and Plasma Antioxidant Capacity

    Directory of Open Access Journals (Sweden)

    R. Andrew Shanely

    2016-08-01

    Full Text Available Consuming carbohydrate- and antioxidant-rich fruits during exercise as a means of supporting and enhancing both performance and health is of interest to endurance athletes. Watermelon (WM contains carbohydrate, lycopene, l-citrulline, and l-arginine. WM may support exercise performance, augment antioxidant capacity, and act as a countermeasure to exercise-induced inflammation and innate immune changes. Trained cyclists (n = 20, 48 ± 2 years participated in a randomized, placebo controlled, crossover study. Subjects completed two 75 km cycling time trials after either 2 weeks ingestion of 980 mL/day WM puree or no treatment. Subjects drank either WM puree containing 0.2 gm/kg carbohydrate or a 6% carbohydrate beverage every 15 min during the time trials. Blood samples were taken pre-study and pre-, post-, 1 h post-exercise. WM ingestion versus no treatment for 2-weeks increased plasma l-citrulline and l-arginine concentrations (p < 0.0125. Exercise performance did not differ between WM puree or carbohydrate beverage trials (p > 0.05, however, the rating of perceived exertion was greater during the WM trial (p > 0.05. WM puree versus carbohydrate beverage resulted in a similar pattern of increase in blood glucose, and greater increases in post-exercise plasma antioxidant capacity, l-citrulline, l-arginine, and total nitrate (all p < 0.05, but without differences in systemic markers of inflammation or innate immune function. Daily WM puree consumption fully supported the energy demands of exercise, and increased post-exercise blood levels of WM nutritional components (l-citrulline and l-arginine, antioxidant capacity, and total nitrate, but without an influence on post-exercise inflammation and changes in innate immune function.

  4. Low-grade systemic inflammation in overweight children

    NARCIS (Netherlands)

    Visser, M; Bouter, L M; McQuillan, G M; Wener, M H; Harris, T B

    OBJECTIVE: Human adipose tissue expresses and releases the proinflammatory cytokine interleukin-6, potentially inducing low-grade systemic inflammation in persons with excess body fat. To limit potential confounding by inflammation-related diseases and subclinical cardiovascular disease, we tested

  5. Modulation of Brain Dead Induced Inflammation by Vagus Nerve Stimulation

    NARCIS (Netherlands)

    Hoeger, S.; Bergstraesser, C.; Selhorst, J.; Fontana, J.; Birck, R.; Waldherr, R.; Beck, G.; Sticht, C.; Seelen, M. A.; van Son, W. J.; Leuvenink, H.; Ploeg, R.; Schnuelle, P.; Yard, B. A.

    Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability

  6. Neuropsychiatry phenotype in asthma: Psychological stress-induced alterations of the neuroendocrine-immune system in allergic airway inflammation

    Directory of Open Access Journals (Sweden)

    Isao Ohno

    2017-09-01

    Full Text Available Since the recognition of asthma as a syndrome with complex pathophysiological signs and symptoms, recent research has sought to classify asthma phenotypes based on its clinical and molecular pathological features. Psychological stress was first recognized as a potential immune system modulator of asthma at the end of the 19th century. The activation of the central nervous system (CNS upon exposure to psychological stress is integral for the initiation of signal transduction processes. The stress hormones, including glucocorticoids, epinephrine, and norepinephrine, which are secreted following CNS activation, are involved in the immunological alterations involved in psychological stress-induced asthma exacerbation. The mechanisms underlying this process may involve a pathological series of events from the brain to the lungs, which is attracting attention as a conceptually advanced phenotype in asthma pathogenesis. This review presents insights into the critical role of psychological stress in the development and exacerbation of allergic asthma, with a special focus on our own data that emphasizes on the continuity from the central sensing of psychological stress to enhanced eosinophilic airway inflammation.

  7. Neuropsychiatry phenotype in asthma: Psychological stress-induced alterations of the neuroendocrine-immune system in allergic airway inflammation.

    Science.gov (United States)

    Ohno, Isao

    2017-09-01

    Since the recognition of asthma as a syndrome with complex pathophysiological signs and symptoms, recent research has sought to classify asthma phenotypes based on its clinical and molecular pathological features. Psychological stress was first recognized as a potential immune system modulator of asthma at the end of the 19th century. The activation of the central nervous system (CNS) upon exposure to psychological stress is integral for the initiation of signal transduction processes. The stress hormones, including glucocorticoids, epinephrine, and norepinephrine, which are secreted following CNS activation, are involved in the immunological alterations involved in psychological stress-induced asthma exacerbation. The mechanisms underlying this process may involve a pathological series of events from the brain to the lungs, which is attracting attention as a conceptually advanced phenotype in asthma pathogenesis. This review presents insights into the critical role of psychological stress in the development and exacerbation of allergic asthma, with a special focus on our own data that emphasizes on the continuity from the central sensing of psychological stress to enhanced eosinophilic airway inflammation. Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  8. Central Nervous System and Innate Immune Mechanisms for Inflammation- and Cancer-induced Anorexia

    OpenAIRE

    Ruud, Johan

    2012-01-01

    Anyone who has experienced influenza or a bacterial infection knows what it means to be ill. Apart from feeling feverish, experiencing aching joints and muscles, you lose the desire to eat. Anorexia, defined as loss of appetite or persistent satiety leading to reduced energy intake, is a hallmark of acute inflammatory disease. The anorexia is part of the acute phase response, triggered as the result of activation of the innate immune system with concomitant release of inflammatory mediators, ...

  9. BAFF knockout improves systemic inflammation via regulating adipose tissue distribution in high-fat diet-induced obesity.

    Science.gov (United States)

    Kim, Do-Hwan; Do, Myoung-Sool

    2015-01-16

    Obesity is recognized as a chronic low-grade inflammatory state due to adipose tissue expansion being accompanied by an increase in the production of proinflammatory adipokines. Our group is the first to report that B-cell-activating factor (BAFF) is produced from adipocytes and functions as a proinflammatory adipokine. Here, we investigated how loss of BAFF influenced diet-induced obesity in mice by challenging BAFF(-/-) mice with a high-fat diet for 10 weeks. The results demonstrated that weight gain in BAFF(-/-) mice was >30% than in control mice, with a specific increase in the fat mass of the subcutaneous region rather than the abdominal region. Expression of lipogenic genes was examined by quantitative real-time PCR, and increased lipogenesis was observed in the subcutaneous adipose tissue (SAT), whereas lipogenesis in the epididymal adipose tissue (EAT) was reduced. A significant decrease in EAT mass resulted in the downregulation of inflammatory gene expression in EAT, and more importantly, overall levels of inflammatory cytokines in the circulation were reduced in obese BAFF(-/-) mice. We also observed that the macrophages recruited in the enlarged SAT were predominantly M2 macrophages. 3T3-L1 adipocytes were cultured with adipose tissue conditioned media (ATCM), demonstrating that EAT ATCM from BAFF(-/-) mice contains antilipogenic and anti-inflammatory properties. Taken together, BAFF(-/-) improved systemic inflammation by redistributing adipose tissue into subcutaneous regions. Understanding the mechanisms by which BAFF regulates obesity in a tissue-specific manner would provide therapeutic opportunities to target obesity-related chronic diseases.

  10. Adipose Tissue Inflammation Induces B Cell Inflammation and Decreases B Cell Function in Aging

    Directory of Open Access Journals (Sweden)

    Daniela Frasca

    2017-08-01

    Full Text Available Aging is the greatest risk factor for developing chronic diseases. Inflamm-aging, the age-related increase in low-grade chronic inflammation, may be a common link in age-related diseases. This review summarizes recent published data on potential cellular and molecular mechanisms of the age-related increase in inflammation, and how these contribute to decreased humoral immune responses in aged mice and humans. Briefly, we cover how aging and related inflammation decrease antibody responses in mice and humans, and how obesity contributes to the mechanisms for aging through increased inflammation. We also report data in the literature showing adipose tissue infiltration with immune cells and how these cells are recruited and contribute to local and systemic inflammation. We show that several types of immune cells infiltrate the adipose tissue and these include macrophages, neutrophils, NK cells, innate lymphoid cells, eosinophils, T cells, B1, and B2 cells. Our main focus is how the adipose tissue affects immune responses, in particular B cell responses and antibody production. The role of leptin in generating inflammation and decreased B cell responses is also discussed. We report data published by us and by other groups showing that the adipose tissue generates pro-inflammatory B cell subsets which induce pro-inflammatory T cells, promote insulin resistance, and secrete pathogenic autoimmune antibodies.

  11. Nicotine administration and withdrawal affect survival in systemic inflammation models

    OpenAIRE

    Steiner, Alexandre A.; Oliveira, Daniela L.; Roberts, Jennifer L.; Petersen, Scott R.; Romanovsky, Andrej A.

    2008-01-01

    How different regimens of nicotine administration and withdrawal affect systemic inflammation is largely unknown. We studied the effects of chronic and acute nicotine administration and of nicotine withdrawal on the outcome of aseptic and septic systemic inflammation. Male C57BL/6 mice were implanted with subcutaneous osmotic pumps (to deliver nicotine) and intrabrain telemetry probes (to measure temperature). Aseptic inflammation was induced by lipopolysaccharide (40 mg/kg ip); sepsis was in...

  12. Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

    Science.gov (United States)

    Kim, Bo-Young; Son, Yonghae; Eo, Seong-Kug; Park, Young Chul; Kim, Koanhoi

    2016-09-23

    27-Hydroxycholesterol (27OHChol) is a cholesterol oxidation product that induces inflammation. In the current study we investigated the effects of diclofenac on inflammatory responses caused by 27OHChol using human monocyte/macrophage (THP-1) cells. Transcription and secretion of CCL2, CCL3, and CCL4 chemokines enhanced by 27OHChol were significantly attenuated by diclofenac in a concentration dependent manner. Migrations of monocytic cells and CCR5-positive Jurkat T cells were reduced proportionally to the concentrations of diclofenac. Superproduction of CCL2 and monocytic cell migration induced by 27OHChol plus LPS were significantly attenuated by diclofenac. Diclofenac also attenuated transcription of MMP-9 and release of its active gene product. These results indicate that diclofenac inhibits 27OHChol-induced inflammatory responses, thereby suppressing inflammation in a milieu rich in cholesterol oxidation products. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Inflammation-induced lymphangiogenesis and lymphatic dysfunction

    Science.gov (United States)

    Liao, Shan; von der Weid, Pierre-Yves

    2014-01-01

    The lymphatic system is intimately linked to tissue fluid homeostasis and immune cell trafficking. These functions are paramount in the establishment and development of an inflammatory response. In the past decade, an increasing number of reports has revealed that marked changes, such as lymphangiogenesis and lymphatic contractile dysfunction occur in both vascular and nodal parts of the lymphatic system during inflammation, as well as other disease processes. This review provides a critical update on the role of the lymphatic system in disease process such as chronic inflammation and cancer and examines the changes in lymphatic functions the diseases cause and the influence these changes have on the progression of the diseases. PMID:24449090

  14. Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice.

    Science.gov (United States)

    Cruz, Fernanda F; Borg, Zachary D; Goodwin, Meagan; Sokocevic, Dino; Wagner, Darcy E; Coffey, Amy; Antunes, Mariana; Robinson, Kristen L; Mitsialis, S Alex; Kourembanas, Stella; Thane, Kristen; Hoffman, Andrew M; McKenna, David H; Rocco, Patricia R M; Weiss, Daniel J

    2015-11-01

    An increasing number of studies demonstrate that administration of either conditioned media (CM) or extracellular vesicles (EVs) released by mesenchymal stromal cells (MSCs) derived from bone marrow and other sources are as effective as the MSCs themselves in mitigating inflammation and injury. The goal of the current study was to determine whether xenogeneic administration of CM or EVs from human bone marrow-derived MSCs would be effective in a model of mixed Th2/Th17, neutrophilic-mediated allergic airway inflammation, reflective of severe refractory asthma, induced by repeated mucosal exposure to Aspergillus hyphal extract (AHE) in immunocompetent C57Bl/6 mice. Systemic administration of both CM and EVs isolated from human and murine MSCs, but not human lung fibroblasts, at the onset of antigen challenge in previously sensitized mice significantly ameliorated the AHE-provoked increases in airway hyperreactivity (AHR), lung inflammation, and the antigen-specific CD4 T-cell Th2 and Th17 phenotype. Notably, both CM and EVs from human MSCs (hMSCs) were generally more potent than those from mouse MSCs (mMSCs) in most of the outcome measures. The weak cross-linking agent 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride was found to inhibit release of both soluble mediators and EVs, fully negating effects of systemically administered hMSCs but only partly inhibited the ameliorating effects of mMSCs. These results demonstrate potent xenogeneic effects of CM and EVs from hMSCs in an immunocompetent mouse model of allergic airway inflammation and they also show differences in mechanisms of action of hMSCs versus mMSCs to mitigate AHR and lung inflammation in this model. There is a growing experience demonstrating benefit of mesenchymal stromal cell (MSC)-based cell therapies in preclinical models of asthma. In the current study, conditioned media (CM) and, in particular, the extracellular vesicle fraction obtained from the CM were as potent as the MSCs

  15. The involvement of central nervous system histamine receptors in psychological stress-induced exacerbation of allergic airway inflammation in mice.

    Science.gov (United States)

    Miyasaka, Tomomitsu; Okuyama-Dobashi, Kaori; Masuda, Chiaki; Iwami, Shunya; Sato, Miki; Mizoguchi, Hirokazu; Kawano, Tasuku; Ohkawara, Yuichi; Sakurada, Shinobu; Takayanagi, Motoaki; Ohno, Isao

    2016-09-01

    Psychological stress is one of the major risk factors for asthma exacerbation. Although histamine in the brain acts as an excitatory and inhibitory neurotransmitter associated with psychological stress, the contribution of brain histamine to psychological stress-induced exacerbation of asthma remains unclear. The objective of this study was to investigate the role of histamine receptors in the CNS on stress induced asthma aggravation. We monitored the numbers of inflammatory cells and interleukin (IL)-13 levels in bronchoalveolar lavage fluid, airway responsiveness to inhaled methacholine, mucus secretion in airway epithelial cells, and antigen-specific IgE contents in sera in a murine model of stress-induced asthma treated with epinastine (an H1R antagonist), thioperamide (an H3/4R antagonist), or solvent. All indicators of stress-induced asthma exacerbation were significantly reduced in stressed mice treated with epinastine compared with those treated with solvent, whereas treatment with thioperamide did not reduce the numbers of inflammatory cells in the stressed mice. These results suggest that H1R, but not H3/4R, may be involved in stress-induced asthma exacerbations in the central nervous system. Copyright © 2016 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

  16. Lipid profile, hyperglycaemia, systemic inflammation and ...

    African Journals Online (AJOL)

    Lipid profile, hyperglycaemia, systemic inflammation and anthropometry as cardiovascular risk factors and their association with dietary intakes in children from rural Cofimvaba, Eastern Cape, South Africa.

  17. Effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in glial and neuronal cells of the central nervous system.

    Science.gov (United States)

    Ramesh, Geeta; Martinez, Alejandra N; Martin, Dale S; Philipp, Mario T

    2017-02-02

    Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi (Bb), affects both the central and peripheral nervous systems. Previously, we reported that in a model of acute LNB in rhesus monkeys, treatment with the anti-inflammatory drug dexamethasone significantly reduced both pleocytosis and levels of cerebrospinal fluid (CSF) immune mediators that were induced by Bb. Dexamethasone also inhibited the formation of inflammatory, neurodegenerative, and demyelinating lesions in the brain and spinal cord of these animals. In contrast, these signs were evident in the infected animals that were left untreated or in those that were treated with meloxicam, a non-steroidal anti-inflammatory drug. To address the differential anti-inflammatory effects of dexamethasone and meloxicam in the central nervous system (CNS), we evaluated the potential of these drugs to alter the levels of Bb-induced inflammatory mediators in culture supernatants of rhesus frontal cortex (FC) explants, primary rhesus astrocytes and microglia, and human oligodendrocytes. We also ascertained the potential of dexamethasone to modulate Bb-induced apoptosis in rhesus FC explants. As meloxicam is a known COX-2 inhibitor, we evaluated whether meloxicam altered the levels of COX-2 as induced by live Bb in cell lysates of primary rhesus astrocytes and microglia. Dexamethasone but not meloxicam significantly reduced the levels of several Bb-induced immune mediators in culture supernatants of FC explants, astrocytes, microglia, and oligodendrocytes. Dexamethasone also had a protective effect on Bb-induced neuronal and oligodendrocyte apoptosis in rhesus FC explants. Further, meloxicam significantly reduced the levels of Bb-induced COX-2 in microglia, while both Bb and meloxicam were unable to alter the constitutive levels of COX-2 in astrocytes. These data indicate that dexamethasone and meloxicam have differential anti-inflammatory effects on Bb-induced inflammation in glial and neuronal cells

  18. Endurance and Resistance Training Affect High Fat Diet-Induced Increase of Ceramides, Inflammasome Expression, and Systemic Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Cornelia Mardare

    2016-01-01

    Full Text Available The study aimed to investigate the effects of differentiated exercise regimes on high fat-induced metabolic and inflammatory pathways. Mice were fed a standard diet (ST or a high fat diet (HFD and subjected to regular endurance training (ET or resistance training (RT. After 10 weeks body weight, glucose tolerance, fatty acids (FAs, circulating ceramides, cytokines, and immunological mediators were determined. The HFD induced a significant increase in body weight and a disturbed glucose tolerance (p<0.05. An increase of plasma FA, ceramides, and inflammatory mediators in adipose tissue and serum was found (p<0.05. Both endurance and resistance training decreased body weight (p<0.05 and reduced serum ceramides (p<0.005. While RT attenuated the increase of NLRP-3 (RT expression in adipose tissue, ET was effective in reducing TNF-α and IL-18 expression. Furthermore, ET reduced levels of MIP-1γ, while RT decreased levels of IL-18, MIP-1γ, Timp-1, and CD40 in serum (p<0.001, respectively. Although both exercise regimes improved glucose tolerance (p<0.001, ET was more effective than RT. These results suggest that exercise improves HFD-induced complications possibly through a reduction of ceramides, the reduction of inflammasome activation in adipose tissues, and a systemic downregulation of inflammatory cytokines.

  19. Effects of Anthocyanin and Flavanol Compounds on Lipid Metabolism and Adipose Tissue Associated Systemic Inflammation in Diet-Induced Obesity

    Directory of Open Access Journals (Sweden)

    Roel A. van der Heijden

    2016-01-01

    Full Text Available Background. Naturally occurring substances from the flavanol and anthocyanin family of polyphenols have been proposed to exert beneficial effects in the course of obesity. We hypothesized that their effects on attenuating obesity-induced dyslipidemia as well as the associated inflammatory sequelae especially have health-promoting potential. Methods. Male C57BL/6J mice (n=52 received a control low-fat diet (LFD; 10 kcal% fat for 6 weeks followed by 24 weeks of either LFD (n=13 or high-fat diet (HFD; 45 kcal% fat; n=13 or HFD supplemented with 0.1% w/w of the flavanol compound epicatechin (HFD+E; n=13 or an anthocyanin-rich bilberry extract (HFD+B; n=13. Energy substrate utilization was determined by indirect calorimetry in a subset of mice following the dietary switch and at the end of the experiment. Blood samples were collected at baseline and at 3 days and 4, 12, and 20 weeks after dietary switch and analyzed for systemic lipids and proinflammatory cytokines. Adipose tissue (AT histopathology and inflammatory gene expression as well as hepatic lipid content were analyzed after sacrifice. Results. The switch from a LFD to a HFD lowered the respiratory exchange ratio and increased plasma cholesterol and hepatic lipid content. These changes were not attenuated by HFD+E or HFD+B. Furthermore, the polyphenol compounds could not prevent HFD-induced systemic rise of TNF-α levels. Interestingly, a significant reduction in Tnf gene expression in HFD+B mice was observed in the AT. Furthermore, HFD+B, but not HFD+E, significantly prevented the early upregulation of circulating neutrophil chemoattractant mKC. However, no differences in AT histopathology were observed between the HFD types. Conclusion. Supplementation of HFD with an anthocyanin-rich bilberry extract but not with the flavanol epicatechin may exert beneficial effects on the systemic early inflammatory response associated with diet-induced obesity. These systemic effects were transient

  20. Cytokine-induced oxidative stress in cardiac inflammation and heart failure – how the ubiquitin proteasome system targets this vicious cycle

    Directory of Open Access Journals (Sweden)

    Antje eVoigt

    2013-03-01

    Full Text Available The ubiquitin proteasome system (UPS is critical for the regulation of many intracellular processes necessary for cell function and survival. The absolute requirement of the UPS for the maintenance of protein homeostasis and thereby for the regulation of protein quality control is reflected by the fact that deviation of proteasome function from the norm was reported in cardiovascular pathologies. Inflammation is a major factor contributing to cardiac pathology. Herein, cytokines induce protein translation and the production of free radicals, thereby challenging the cellular protein equilibrium. Here, we discuss current knowledge on the mechanisms of UPS-functional adaptation in response to oxidative stress in cardiac inflammation. The increasing pool of oxidant-damaged degradation-prone proteins in cardiac pathology accounts for the need for enhanced protein turnover by the UPS. This process is accomplished by an up-regulation of the ubiquitylation machinery and the induction of immunoproteasomes. Thereby, the inflamed heart muscle is cleared from accumulating misfolded proteins. Current advances on immunoproteasome-specific inhibitors in this field question the impact of the proteasome as a therapeutic target in heart failure.

  1. Chronic systemic inflammation originating from epithelial tissues.

    Science.gov (United States)

    Uluçkan, Özge; Wagner, Erwin F

    2017-02-01

    Chronic systemic inflammation (CSI) has recently been identified as a major contributor to common diseases ranging from cancer to metabolic disorders and neurologic alterations. In the last decade, we and others have generated genetically engineered mouse models for inflammatory diseases, which enable studying the molecular mechanisms of CSI. Recently, organ cross-talk induced by CSI under homeostatic and pathological conditions has begun to be appreciated. In this review, we will revisit whole organism physiology in relation to CSI originating from epithelial tissues, such as the skin and gut. Furthermore, we will discuss the current knowledge regarding the mechanisms, the specific immune cells and molecules responsible for inducing the most common comorbidities, such as cardiovascular, metabolic, and neurological complications, as well as bone loss, in heterogeneous diseases like psoriasis, atopic dermatitis, and inflammatory bowel disease. As it would be impossible to discuss all comorbidities of these diseases as well as all epithelial tissues, we present an overview with a special emphasis on our recent findings linking skin inflammation to bone loss. © 2016 Federation of European Biochemical Societies.

  2. Ferrous sulfate, but not iron polymaltose complex, aggravates local and systemic inflammation and oxidative stress in dextran sodium sulfate-induced colitis in rats

    Directory of Open Access Journals (Sweden)

    Toblli JE

    2015-05-01

    Full Text Available Jorge E Toblli, Gabriel Cao, Margarita Angerosa Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina Background and aims: Iron deficiency is common in inflammatory bowel disease, yet oral iron therapy may worsen the disease symptoms and increase systemic and local oxidative stress. The aim of this study was to compare the effects of oral ferrous sulfate and iron polymaltose complex on inflammatory and oxidative stress markers in colitic rats.Methods: Animals were divided into four groups with ten animals each. Rats of three groups received dextran sodium sulfate to induce colitis and animals of two of these groups received 5 mg iron/kg of body weight a day, as ferrous sulfate or iron polymaltose complex, for 7 days. Gross colon anatomy, histology of colon and liver, stainings of L-ferritin, Prussian blue, hepcidin, tumor necrosis factor-α, and interleukin-6, as well serum levels of liver enzymes, inflammatory markers, and iron markers, were assessed.Results: Body weight, gross anatomy, crypt injury and inflammation scores, inflammatory parameters in liver and colon, as well as serum and liver hepcidin levels were not significantly different between colitic animals without iron treatment and colitic animals treated with iron polymaltose complex. In contrast, ferrous sulfate treatment caused significant worsening of these parameters. As opposed to ferrous sulfate, iron polymaltose complex caused less or no additional oxidative stress in the colon and liver compared to colitic animals without iron treatment.Conclusion: Iron polymaltose complex had negligible effects on colonic tissue erosion, local or systemic oxidative stress, and local or systemic inflammation, even at high therapeutic doses, and may thus represent a valuable oral treatment of iron deficiency in inflammatory bowel disease. Keywords: preclinical, oral iron treatment, tolerability, colonic tissue erosion

  3. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

    NARCIS (Netherlands)

    Jurk, Diana; Wilson, Caroline; Passos, Joao F.; Oakley, Fiona; Correia-Melo, Clara; Greaves, Laura; Saretzki, Gabriele; Fox, Chris; Lawless, Conor; Anderson, Rhys; Hewitt, Graeme; Pender, Sylvia L. F.; Fullard, Nicola; Nelson, Glyn; Mann, Jelena; van de Sluis, Bart; Mann, Derek A.; von Zglinicki, Thomas

    Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-kappa B induces premature ageing in mice. We also show that these mice have reduced

  4. Lamin-B in systemic inflammation, tissue homeostasis, and aging.

    Science.gov (United States)

    Chen, Haiyang; Zheng, Xiaobin; Zheng, Yixian

    2015-01-01

    Gradual loss of tissue function (or homeostasis) is a natural process of aging and is believed to cause many age-associated diseases. In human epidemiology studies, the low-grade and chronic systemic inflammation in elderly has been correlated with the development of aging related pathologies. Although it is suspected that tissue decline is related to systemic inflammation, the cause and consequence of these aging phenomena are poorly understood. By studying the Drosophila fat body and gut, we have uncovered a mechanism by which lamin-B loss in the fat body upon aging induces age-associated systemic inflammation. This chronic inflammation results in the repression of gut local immune response, which in turn leads to the over-proliferation and mis-differentiation of the intestinal stem cells, thereby resulting in gut hyperplasia. Here we discuss the implications and remaining questions in light of our published findings and new observations.

  5. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance

    International Nuclear Information System (INIS)

    Permana, Paska A.; Menge, Christopher; Reaven, Peter D.

    2006-01-01

    Macrophage infiltration into adipose tissue increases with obesity, a condition associated with low-grade inflammation and insulin resistance. We investigated the direct effects of macrophage-secreted factors on adipocyte inflammation and insulin resistance. 3T3-L1 adipocytes incubated with media conditioned by RAW264.7 macrophages (RAW-CM) showed dramatically increased transcription of several inflammation-related genes, greater nuclear factor kappa B (NF-κB) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-κB inhibitor. Adipocytes incubated with RAW-CM also released more non-esterified fatty acids and this increased lipolysis was not suppressed by insulin. In addition, RAW-CM treatment decreased insulin-stimulated glucose uptake in adipocytes. Taken together, these results indicate that macrophage-secreted factors induce inflammatory responses and reduce insulin responsiveness in adipocytes. These effects of macrophage-secreted factors on adipocytes may contribute significantly to the systemic inflammation and insulin resistance associated with obesity

  6. 6-Hydroxydopamine induces brain vascular endothelial inflammation.

    Science.gov (United States)

    Fu, Qizhi; Song, Runluo; Yang, Zhongxi; Shan, Qi; Chen, Wenna

    2017-11-01

    Disruption of the blood-brain barrier associated with endothelial dysfunction is an important hallmark of Parkinson's disease (PD). 6-Hydroxydopamine (6-OHDA) is a synthetic dopamine derivate often used to model PD as it results in retrograde degeneration of striatal dopaminergic (DA) terminals. Presently, the effects of 6-OHDA on endothelial dysfunction remain unknown. Using a 6-OHDA rodent model of PD, we found that administration of 6-OHDA could increase the expression of endothelial adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin. An in vitro study displayed that treatment with 6-OHDA increased the release of these molecules in human brain microvascular endothelial cells in a dose-dependent manner. Correspondingly, 6-OHDA significantly increased attachment of THP-1 monocytes to brain endothelial cells. In addition, real-time polymerase chain reaction and enzyme-linked immunosorbent assay results indicated that 6-OHDA elevated the production of proinflammatory cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Furthermore, 6-OHDA treatment increased the expression of cyclooxygenase-2 and inducible nitric oxide synthase, as well as the production of prostaglandin E2 and nitric oxide. Importantly, 6-OHDA elevated the transcriptional activity of NF-кB by increasing the phosphorylation, degradation, and subsequent nuclear translocation of p65. Mechanistically, the angiotensin II type 1 receptor was found to mediate 6-OHDA-induced endothelial dysfunction. Our findings suggest that 6-OHDA-induced endothelial inflammation may play an important role in the pathogenesis of PD. © 2017 IUBMB Life, 69(11):887-895, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

  7. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

    Energy Technology Data Exchange (ETDEWEB)

    Lovelace, Erica S.; Wagoner, Jessica; MacDonald, James; Bammler, Theo; Bruckner, Jacob; Brownell, Jessica; Beyer, Richard; Zink, Erika M.; Kim, Young-Mo; Kyle, Jennifer E.; Webb-Robertson, Bobbie-Jo M.; Waters, Katrina M.; Metz, Thomas O.; Farin, Federico; Oberlies, Nicholas H.; Polyak, Steve

    2015-08-28

    Silymarin (SM), a natural product, is touted as a liver protectant and preventer of both chronic inflammation and diseases. To define how SM elicits these effects at a systems level, we performed transcriptional profiling, metabolomics, and signaling studies in human liver and T cell lines. Multiple pathways associated with cellular stress and metabolism were modulated by SM treatment within 0.5 to four hours: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed suppression of glycolytic, TCA cycle, and amino acid metabolism by SM treatment. Antiinflammatory effects arose with prolonged (i.e. 24 hours) SM exposure, with suppression of multiple proinflammatory mRNAs and nuclear factor kappa B (NF-κB) and forkhead box O (FOXO) signaling. Studies with murine knock out cells revealed that SM inhibition of both mTOR and NF-κB was partially AMPK dependent, while SM inhibition of the mTOR pathway in part required DDIT4. Thus, SM activates stress and repair responses that culminate in an anti-inflammatory phenotype. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Therefore, natural products like SM may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

  8. Dietary Modulation of Inflammation-Induced Colorectal Cancer through PPARγ

    Directory of Open Access Journals (Sweden)

    Ashlee B. Carter

    2009-01-01

    Full Text Available Mounting evidence suggests that the risk of developing colorectal cancer (CRC is dramatically increased for patients with chronic inflammatory diseases. For instance, patients with Crohn's Disease (CD or Ulcerative Colitis (UC have a 12–20% increased risk for developing CRC. Preventive strategies utilizing nontoxic natural compounds that modulate immune responses could be successful in the suppression of inflammation-driven colorectal cancer in high-risk groups. The increase of peroxisome proliferator-activated receptor-γ (PPAR-γ expression and its transcriptional activity has been identified as a target for anti-inflammatory efforts, and the suppression of inflammation-driven colon cancer. PPARγ down-modulates inflammation and elicits antiproliferative and proapoptotic actions in epithelial cells. All of which may decrease the risk for inflammation-induced CRC. This review will focus on the use of orally active, naturally occurring chemopreventive approaches against inflammation-induced CRC that target PPARγ and therefore down-modulate inflammation.

  9. Ozone-Induced Pulmonary Injury and Inflammation are Modulated by Adrenal-Derived Stress Hormones

    Science.gov (United States)

    Ozone exposure promotes pulmonary injury and inflammation. Previously we have characterized systemic changes that occur immediately after acute ozone exposure and are mediated by neuro-hormonal stress response pathway. Both HPA axis and sympathetic tone alterations induce the rel...

  10. Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system

    DEFF Research Database (Denmark)

    Toft-Hansen, Henrik; Buist, Richard; Sun, Xue-Jun

    2006-01-01

    in the perivascular space in brains of transgenic (Tg) mice that overexpress CCL2 under control of a CNS-specific promoter. The Tg mice show no clinical symptoms, even though leukocytes have crossed the endothelial basement membrane. Pertussis toxin (PTx) given i.p. induced encephalopathy and weight loss in Tg mice...... symptoms. Metalloproteinase (MPs) enzymes are implicated in leukocyte infiltration in neuroinflammation. Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-10, and -12 mRNA in the brain. PTx further induced expression of tissue inhibitor...... of metalloproteinase-1, metalloproteinase disintegrins-12, MMP-8, and -10 in brains of Tg mice. Levels of the microglial-associated MP MMP-15 were not affected in control or PTx-treated Tg mice. PTx also up-regulated expression of proinflammatory cytokines IL-1beta and TNF-alpha mRNA in Tg CNS. Weight loss...

  11. TNF suppresses acute intestinal inflammation by inducing local glucocorticoid synthesis

    Science.gov (United States)

    Noti, Mario; Corazza, Nadia; Mueller, Christoph; Berger, Barbara

    2010-01-01

    Although tumor necrosis factor (α) (TNF) exerts proinflammatory activities in a variety of diseases, including inflammatory bowel disease, there is increasing evidence for antiinflammatory actions of TNF. In contrast, glucocorticoids (GCs) are steroid hormones that suppress inflammation, at least in part by regulating the expression and action of TNF. We report that TNF induces extraadrenal production of immunoregulatory GCs in the intestinal mucosa during acute intestinal inflammation. The absence of TNF results in a lack of colonic GC synthesis and exacerbation of dextran sodium sulfate–induced colitis. TNF seems to promote local steroidogenesis by directly inducing steroidogenic enzymes in intestinal epithelial cells. Therapeutic administration of TNF induces GC synthesis in oxazolone-induced colitis and ameliorates intestinal inflammation, whereas inhibition of intestinal GC synthesis abrogates the therapeutic effect of TNF. These data show that TNF suppresses the pathogenesis of acute intestinal inflammation by promoting local steroidogenesis. PMID:20439544

  12. Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system

    DEFF Research Database (Denmark)

    Toft-Hansen, Henrik; Buist, Richard; Sun, Xue-Jun

    2006-01-01

    . We used flow cytometry, ultra-small superparamagnetic iron oxide-enhanced magnetic resonance imaging, and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma, identifying this as the critical step in inducing clinical...... of metalloproteinase-1, metalloproteinase disintegrins-12, MMP-8, and -10 in brains of Tg mice. Levels of the microglial-associated MP MMP-15 were not affected in control or PTx-treated Tg mice. PTx also up-regulated expression of proinflammatory cytokines IL-1beta and TNF-alpha mRNA in Tg CNS. Weight loss...

  13. Wogonin Induces Eosinophil Apoptosis and Attenuates Allergic Airway Inflammation

    Science.gov (United States)

    Dorward, David A.; Sharma, Sidharth; Rennie, Jillian; Felton, Jennifer M.; Alessandri, Ana L.; Duffin, Rodger; Schwarze, Jurgen; Haslett, Christopher; Rossi, Adriano G.

    2015-01-01

    Rationale: Eosinophils are key effector cells in allergic diseases, including allergic rhinitis, eczema, and asthma. Their tissue presence is regulated by both recruitment and increased longevity at inflamed sites. Objectives: To investigate the ability of the flavone wogonin to induce eosinophil apoptosis in vitro and attenuate eosinophil-dominant allergic inflammation in vivo in mice. Methods: Human and mouse eosinophil apoptosis in response to wogonin was investigated by cellular morphology, flow cytometry, mitochondrial membrane permeability, and pharmacological caspase inhibition. Allergic lung inflammation was modeled in mice sensitized and challenged with ovalbumin. Bronchoalveolar lavage (BAL) and lung tissue were examined for inflammation, mucus production, and inflammatory mediator production. Airway hyperresponsiveness to aerosolized methacholine was measured. Measurements and Main Results: Wogonin induced time- and concentration-dependent human and mouse eosinophil apoptosis in vitro. Wogonin-induced eosinophil apoptosis occurred with activation of caspase-3 and was inhibited by pharmacological caspase inhibition. Wogonin administration attenuated allergic airway inflammation in vivo with reductions in BAL and interstitial eosinophil numbers, increased eosinophil apoptosis, reduced airway mucus production, and attenuated airway hyperresponsiveness. This wogonin-induced reduction in allergic airway inflammation was prevented by concurrent caspase inhibition in vivo. Conclusions: Wogonin induces eosinophil apoptosis and attenuates allergic airway inflammation, suggesting that it has therapeutic potential for the treatment of allergic inflammation in humans. PMID:25629436

  14. Inflammation-induced preterm lung maturation: lessons from animal experimentation.

    Science.gov (United States)

    Moss, Timothy J M; Westover, Alana J

    2017-06-01

    Intrauterine inflammation, or chorioamnionitis, is a major contributor to preterm birth. Prematurity per se is associated with considerable morbidity and mortality resulting from lung immaturity but exposure to chorioamnionitis reduces the risk of neonatal respiratory distress syndrome (RDS) in preterm infants. Animal experiments have identified that an increase in pulmonary surfactant production by the preterm lungs likely underlies this decreased risk of RDS in infants exposed to chorioamnionitis. Further animal experimentation has shown that infectious or inflammatory agents in amniotic fluid exert their effects on lung development by direct effects within the developing respiratory tract, and probably not by systemic pathways. Differences in the effects of intrauterine inflammation and glucocorticoids demonstrate that canonical glucocorticoid-mediated lung maturation is not responsible for inflammation-induced changes in lung development. Animal experimentation is identifying alternative lung maturational pathways, and transgenic animals and cell culture techniques will allow identification of novel mechanisms of lung maturation that may lead to new treatments for the prevention of RDS. Copyright © 2016. Published by Elsevier Ltd.

  15. Oxidative stress induced inflammation initiates functional decline of tear production.

    Directory of Open Access Journals (Sweden)

    Yuichi Uchino

    Full Text Available Oxidative damage and inflammation are proposed to be involved in an age-related functional decline of exocrine glands. However, the molecular mechanism of how oxidative stress affects the secretory function of exocrine glands is unclear. We developed a novel mev-1 conditional transgenic mouse model (Tet-mev-1 using a modified tetracycline system (Tet-On/Off system. This mouse model demonstrated decreased tear production with morphological changes including leukocytic infiltration and fibrosis. We found that the mev-1 gene encodes Cyt-1, which is the cytochrome b(560 large subunit of succinate-ubiquinone oxidoreductase in complex II of mitochondria (homologous to succinate dehydrogenase C subunit (SDHC in humans. The mev-1 gene induced excessive oxidative stress associated with ocular surface epithelial damage and a decrease in protein and aqueous secretory function. This new model provides evidence that mitochondrial oxidative damage in the lacrimal gland induces lacrimal dysfunction resulting in dry eye disease. Tear volume in Tet-mev-1 mice was lower than in wild type mice and histopathological analyses showed the hallmarks of lacrimal gland inflammation by intense mononuclear leukocytic infiltration and fibrosis in the lacrimal gland of Tet-mev-1 mice. These findings strongly suggest that oxidative stress can be a causative factor for the development of dry eye disease.

  16. Plasmodium-induced inflammation by uric acid.

    Directory of Open Access Journals (Sweden)

    Jamie M Orengo

    2008-03-01

    Full Text Available Infection of erythrocytes with the Plasmodium parasite causes the pathologies associated with malaria, which result in at least one million deaths annually. The rupture of infected erythrocytes triggers an inflammatory response, which is induced by parasite-derived factors that still are not fully characterized. Induced secretion of inflammatory cytokines by these factors is considered a major cause of malaria pathogenesis. In particular, the inflammatory cytokine tumor necrosis factor (TNF is thought to mediate most of the life-threatening pathologies of the disease. Here we describe the molecular characterization of a novel pathway that results in the secretion of TNF by host cells. We found that erythrocytes infected by Plasmodium accumulate high concentrations of hypoxanthine and xanthine. Degradation of Plasmodium-derived hypoxanthine/xanthine results in the formation of uric acid, which triggers the secretion of TNF. Since uric acid is considered a "danger signal" released by dying cells to alert the immune system, Plasmodium appears to have co-evolved to exploit this warning system. Identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.

  17. A co-culture system with an organotypic lung slice and an immortal alveolar macrophage cell line to quantify silica-induced inflammation.

    Directory of Open Access Journals (Sweden)

    Falk Hofmann

    Full Text Available There is growing evidence that amorphous silica nanoparticles cause toxic effects on lung cells in vivo as well as in vitro and induce inflammatory processes. The phagocytosis of silica by alveolar macrophages potentiates these effects. To understand the underlying molecular mechanisms of silica toxicity, we applied a co-culture system including the immortal alveolar epithelial mouse cell line E10 and the macrophage cell line AMJ2-C11. In parallel we exposed precision-cut lung slices (lacking any blood cells as well as residual alveolar macrophages of wild type and P2rx7-/- mice with or without AMJ2-C11 cells to silica nanoparticles. Exposure of E10 cells as well as slices of wild type mice resulted in an increase of typical alveolar epithelial type 1 cell proteins like T1α, caveolin-1 and -2 and PKC-β1, whereas the co-culture with AMJ2-C11 showed mostly a slightly lesser increase of these proteins. In P2rx7-/- mice most of these proteins were slightly decreased. ELISA analysis of the supernatant of wild type and P2rx7-/- mice precision-cut lung slices showed decreased amounts of IL-6 and TNF-α when incubated with nano-silica. Our findings indicate that alveolar macrophages influence the early inflammation of the lung and also that cell damaging reagents e.g. silica have a smaller impact on P2rx7-/- mice than on wild type mice. The co-culture system with an organotypic lung slice is a useful tool to study the role of alveolar macrophages during lung injury at the organoid level.

  18. Local inflammation induces complement crosstalk which amplifies the antimicrobial response.

    Directory of Open Access Journals (Sweden)

    Jing Zhang

    2009-01-01

    Full Text Available By eliciting inflammatory responses, the human immunosurveillance system notably combats invading pathogens, during which acute phase proteins (CRP and cytokines are elevated markedly. However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance factors poses grave challenges to patient healthcare management. Using blood samples from infected patients, we demonstrate that P. aeruginosa is effectively killed in the plasma under defined local infection-inflammation condition, where slight acidosis and reduced calcium levels (pH 6.5, 2 mM calcium typically prevail. We showed that this powerful antimicrobial activity is provoked by crosstalk between two plasma proteins; CRPratioL-ficolin interaction led to communication between the complement classical and lectin pathways from which two amplification events emerged. Assays for C4 deposition, phagocytosis, and protein competition consistently proved the functional significance of the amplification pathways in boosting complement-mediated antimicrobial activity. The infection-inflammation condition induced a 100-fold increase in CRPratioL-ficolin interaction in a pH- and calcium-sensitive manner. We conclude that the infection-induced local inflammatory conditions trigger a strong interaction between CRPratioL-ficolin, eliciting complement-amplification pathways which are autonomous and which co-exist with and reinforce the classical and lectin pathways. Our findings provide new insights into the host immune response to P. aeruginosa infection under pathological conditions and the potential development of new therapeutic strategies against bacterial infection.

  19. Chronic psychological stress induces vascular inflammation in rabbits.

    Science.gov (United States)

    Lu, Xiao Ting; Liu, Yun Fang; Zhao, Li; Li, Wen Jing; Yang, Rui Xue; Yan, Fang Fang; Zhao, Yu Xia; Jiang, Fan

    2013-01-01

    Psychological stress is associated with a systemic inflammatory response. It is unclear, however, whether psychological stress contributes to vascular inflammation. Here, we examined the effects of unpredictable chronic mild stress (UCMS) on vascular inflammation in rabbits. One hundred rabbits were randomly divided into control and stress groups. UCMS was induced by a set of defined adverse conditions applied in a shuffled order for 4, 8, 12, or 16 weeks, and rabbits were killed 24 h after the end of the UCMS protocol. Expression of different inflammatory molecules was analyzed by real-time polymerase chain reaction, immunohistochemistry, or enzyme-linked immunosorbent assay. UCMS resulted in depression-like behaviors, decreased body weight gain, and hypertension with no significant effects on serum lipids. Aortic mRNA and protein expression for tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), macrophage migration inhibitory factor, and expression of intercellular adhesion molecule-1 (ICAM-1) protein were increased. UCMS increased circulating concentrations of corticosterone, TNF-α, and CRP throughout. Moreover, stress downregulated the expression of endothelial nitric oxide synthase. At 16 weeks of UCMS, macrophage infiltration and lipid accumulation in the subendothelial space were detected in the aorta. In cultured murine vascular smooth muscle cells, treatment with serum from stressed rabbits significantly increased phosphorylation of p38 and c-Jun N-terminal kinase (JNK), and upregulated expression of MCP-1 and ICAM-1 mRNAs, in which the effect was blunted by a TNF-α neutralizing antibody or p38 and JNK inhibitors. Our results indicate that chronic psychological stress induces vascular inflammation via TNF-α and p38/JNK pathways, which may contribute to the development of atherosclerosis.

  20. lipid profile, hyperglycaemia, systemic inflammation and ...

    African Journals Online (AJOL)

    user

    Lipid profile, hyperglycaemia, systemic inflammation and anthropometry as cardiovascular risk factors and their association with dietary .... Training included sessions on ethical and general research philosophies applicable to ... the training sessions whereby the fieldworkers had to interview and complete multiple 24-hour.

  1. Exercise alleviates depression related systemic inflammation in ...

    African Journals Online (AJOL)

    sion, however our understanding of how to use exercise effectively in COPD patients to alleviate depression related systemic inflammation is incomplete ... bidities (i.e. cardiovascular disease risk factors and glyce- mic control). A prospective ..... T, Ross R. An exercise intervention without weight loss. African Health Sciences ...

  2. Exercise alleviates depression related systemic inflammation in ...

    African Journals Online (AJOL)

    Objective: The aim of this study was to measure the changes in depression related systemic inflammation of aerobic exercise training in COPD patients in Jeddah area. Material and methods: Eighty patients with moderate severity of COPD participated in this study and were divided into two groups; the first group received ...

  3. Ferulic acid ameliorates radiation induced duodenal inflammation

    International Nuclear Information System (INIS)

    Das, Ujjal; Manna, Krishnendu; Sengupta, Aaveri; Biswas, Sushobhan; Chakrabarty, Arpita; Dey, Sanjit

    2016-01-01

    Ionizing radiation creates oxidative stress followed by inflammation through reactive oxygen species (ROS) and altering the status of redox sensitive enzymes. In the current study we aimed to evaluate the effect of ferulic acid (FA) on increasing doses of ionizing radiation mediated oxidative stress and inflammation using in vivo murine duodenum. To delineate the hypothesis we exposed mice with 2.5, 5 and 10 Gy gamma radiation doses in presence and absence of the (FA). FA was administered orally at a fixed dose of 50mg/ kg bw for 5 days before radiation exposure. Different techniques such as biochemical assays, immune blot, and microscopic analysis for histopathology, flow cytometry and scanning electron microscopy were employed to achieve the goal

  4. Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

    Science.gov (United States)

    Kiraly, Orsolya; Gong, Guanyu; Olipitz, Werner; Muthupalani, Sureshkumar; Engelward, Bevin P.

    2015-01-01

    Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence. PMID:25647331

  5. Eleutheroside E inhibits doxorubicin-induced inflammation and ...

    African Journals Online (AJOL)

    Purpose: To identify the effects of eleutheroside E (EE) on apoptosis and inflammation induced by doxorubicin (DOX) in H9c2 cells and to investigate the underlying mechanisms. Methods: The effect of EE on H9c2 cell viability was determined using Cell Counting Kit-8 (CCK8). EE effect on DOX-induced apoptosis and ...

  6. Gum Acacia Improves Renal Function and Ameliorates Systemic Inflammation, Oxidative and Nitrosative Stress in Streptozotocin-Induced Diabetes in Rats with Adenine-Induced Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Mohammed Al Za’abi

    2018-03-01

    Full Text Available Background/Aims: The effect of treatment with gum acacia (GA, a prebiotic shown previously to ameliorate chronic kidney disease (CKD, in diabetic and non – diabetic rats with adenine – induced CKD has been investigated using several conventional and novel physiological, biochemical, and histopathological parameters. Methods: Diabetes mellitus was induced in rats by a single injection of streptozotocin (STZ. Diabetic and non – diabetic rats were randomly divided into several groups, and given either normal food or food mixed with adenine (0.25% w/w, for five weeks to induce CKD. Some of these groups were also concomitantly treated orally with GA in the drinking water (15% w/w. Results: Rats fed adenine alone exhibited physiological (decreased body weight, increased food and water intake and urine output, biochemical (increase in urinary albumin/creatinine ratio, plasma urea and, creatinine, indoxyl sulfate and phosphorus, inflammatory biomarkers (increased in neutrophil gelatinase-associated lipocalin, transforming growth factor beta -1, tumor necrosis factor alpha, adiponectin, cystatin C and interleukin-1β, oxidative biomarkers (8-isoprostane, 8 -hydroxy -2-deoxy guanosine, nitrosative stress biomarkers (nitrite and nitrate and histopathological (increase in tubular necrosis and fibrosis signs of CKD. STZ - induced diabetes alone worsened most of the renal function tests measured. Administration of adenine in STZ – diabetic rats further worsened the renal damage induced by adenine alone. GA significantly ameliorated the renal actions of adenine and STZ, given either singly or in combination, especially with regards to the histopathological damage. Conclusion: GA is a useful dietary agent in attenuating the progression of CKD in rats with streptozotocin-induced diabetes.

  7. Inflammation induced by Bothrops asper venom.

    Science.gov (United States)

    Teixeira, Catarina; Cury, Yara; Moreira, Vanessa; Picolo, Gisele; Chaves, Fernando

    2009-07-01

    Inflammation is a major characteristic of envenomation by snakes from viperine and crotaline species. Bothrops asper snake venom elicits, among other alterations, a pronounced inflammatory response at the site of injection both in humans and experimental animals. This review describes the current status of our understanding of the inflammatory reaction, including pain, triggered by Bothrops asper venom. The experimental studies on the action of this venom as well as the complex network of chemical mediators involved are summarized. Moreover, aspects of the molecular mechanisms orchestrating this important response to envenomation by Bothrops asper are presented. Considering that isolated toxins are relevant tools for understanding the actions of the whole venom, studies dealing with the mechanisms of inflammatory and nociceptive properties of phospholipases A(2), a metalloproteinase and serine-proteases isolated from Bothrops asper venom are also described.

  8. Brain inflammation induced by severe asphyxia in newborn pigs and the impact of alternative resuscitation strategies on the newborn central nervous system.

    Science.gov (United States)

    Dannevig, Ingrid; Solevåg, Anne Lee; Sonerud, Tonje; Saugstad, Ola Didrik; Nakstad, Britt

    2013-02-01

    We compared the current guidelines for neonatal resuscitation with alternative measures and aimed to find out whether this modulated brain inflammation. Progressive asphyxia was induced in 94 newborn pigs until asystole. With the reference being resuscitation guidelines, 30 s of initial positive-pressure ventilation before compression (C) and ventilation (V) (C:V; 3:1) in 21% oxygen, pigs were randomized to (i) ventilation for 30, 60, or 90 s before chest compressions; (ii) C:V ratios of 3:1, 9:3, or 15:2; or (iii) 21% or 100% oxygen. Concentrations of inflammatory markers in the cerebrospinal fluid (CSF) and gene expression in the hippocampus and frontal cortex were measured for different interventions. In CSF, S100 was higher with 90 s than with 30 or 60 s of initial positive-pressure ventilation, whereas concentrations of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were higher with 30 than with 60 s. Matrix metalloproteinase-2 (MMP-2) and intracellular adhesion molecule 1 (ICAM-1) were higher with 30 than with 60 s. No other comparison between ratios and oxygen concentrations used yielded significant results. With respect to signs of brain inflammation, newly born pigs at asystole should be ventilated for longer than 30 s before chest compressions start. C:V ratios of 9:3 and 15:2 as compared with 3:1, or air instead of pure oxygen, did not modulate inflammatory markers.

  9. Minocycline-Suppression of Early Peripheral Inflammation Reduces Hypoxia-Induced Neonatal Brain Injury

    Directory of Open Access Journals (Sweden)

    Yingjun Min

    2017-09-01

    Full Text Available While extensive studies report that neonatal hypoxia-ischemia (HI induces long-term cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral inflammation response in HI injury. Here we used a neonatal hypoxia rodent model by subjecting postnatal day 0 (P0d rat pups to systemic hypoxia (3.5 h, a condition that is commonly seen in clinic neonates, Then, an initial dose of minocycline (45 mg/kg was injected intraperitoneally (i.p. 2 h after the hypoxia exposure ended, followed by half dosage (22.5 mg/kg minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral inflammation responded to hypoxia and whether this peripheral inflammation response was associated to cognitive deficits. We found that neonatal hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS, indicated by presence of C-C chemokine receptor type 2 (CCR2+/CD11b+CD45+ positive cells and CCR2 protein expression level. The early onset of peripheral inflammation response was followed by a late onset of brain inflammation that was demonstrated by level of cytokine IL-1β and ionized calcium binding adapter molecule 1(Iba-1; activated microglial cell marker. Interrupted blood-brain barrier (BBB, hypomyelination and learning and memory deficits were seen after hypoxia. Interestingly, the cognitive function was highly correlated with hypoxia-induced leukocyte response. Notably, administration of minocycline even after the onset of hypoxia significantly suppressed leukocyte-mediated inflammation as well as brain inflammation, demonstrating neuroprotection in systemic hypoxia-induced brain damage. Our data provided new insights that systemic hypoxia induces cognitive dysfunction, which involves the leukocyte-mediated peripheral inflammation response.

  10. Minocycline-Suppression of Early Peripheral Inflammation Reduces Hypoxia-Induced Neonatal Brain Injury

    Science.gov (United States)

    Min, Yingjun; Li, Hongchun; Xu, Kaiyu; Huang, Yilong; Xiao, Jie; Wang, Weizhou; Li, Longjun; Yang, Ting; Huang, Lixuan; Yang, Ling; Jiang, Hong; Wang, Qian; Zhao, Min; Hua, HaiRong; Mei, Rong; Li, Fan

    2017-01-01

    While extensive studies report that neonatal hypoxia-ischemia (HI) induces long-term cognitive impairment via inflammatory responses in the brain, little is known about the role of early peripheral inflammation response in HI injury. Here we used a neonatal hypoxia rodent model by subjecting postnatal day 0 (P0d) rat pups to systemic hypoxia (3.5 h), a condition that is commonly seen in clinic neonates, Then, an initial dose of minocycline (45 mg/kg) was injected intraperitoneally (i.p.) 2 h after the hypoxia exposure ended, followed by half dosage (22.5 mg/kg) minocycline treatment for next 6 consecutive days daily. Saline was injected as vehicle control. To examine how early peripheral inflammation responded to hypoxia and whether this peripheral inflammation response was associated to cognitive deficits. We found that neonatal hypoxia significantly increased leukocytes not only in blood, but also increased the monocytes in central nervous system (CNS), indicated by presence of C-C chemokine receptor type 2 (CCR2+)/CD11b+CD45+ positive cells and CCR2 protein expression level. The early onset of peripheral inflammation response was followed by a late onset of brain inflammation that was demonstrated by level of cytokine IL-1β and ionized calcium binding adapter molecule 1(Iba-1; activated microglial cell marker). Interrupted blood-brain barrier (BBB), hypomyelination and learning and memory deficits were seen after hypoxia. Interestingly, the cognitive function was highly correlated with hypoxia-induced leukocyte response. Notably, administration of minocycline even after the onset of hypoxia significantly suppressed leukocyte-mediated inflammation as well as brain inflammation, demonstrating neuroprotection in systemic hypoxia-induced brain damage. Our data provided new insights that systemic hypoxia induces cognitive dysfunction, which involves the leukocyte-mediated peripheral inflammation response. PMID:28955196

  11. Moderate glucose supply reduces hemolysis during systemic inflammation

    Directory of Open Access Journals (Sweden)

    Jägers J

    2018-03-01

    Full Text Available Johannes Jägers,1 Stephan Brauckmann,2 Michael Kirsch,1 Katharina Effenberger-Neidnicht1,3 1Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany; 2Clinic for Anesthesiology and Intensive Care, University Hospital Essen, Essen, Germany; 3Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany Background: Systemic inflammation alters energy metabolism. A sufficient glucose level, however, is most important for erythrocytes, since erythrocytes rely on glucose as sole source of energy. Damage to erythrocytes leads to hemolysis. Both disorders of glucose metabolism and hemolysis are associated with an increased risk of death. The objective of the study was to investigate the impact of intravenous glucose on hemolysis during systemic inflammation.Materials and methods: Systemic inflammation was accomplished in male Wistar rats by continuous lipopolysaccharide (LPS infusion (1 mg LPS/kg and h, 300 min. Sham control group rats received Ringer’s solution. Glucose was supplied moderately (70 mg glucose/kg and h or excessively (210 mg glucose/kg and h during systemic inflammation. Vital parameters (eg, systemic blood pressure as well as blood and plasma parameters (eg, concentrations of glucose, lactate and cell-free hemoglobin, and activity of lactate dehydrogenase were measured hourly. Clot formation was analyzed by thromboelastometry.Results: Continuous infusion of LPS led to a so-called post-aggression syndrome with disturbed electrolyte homeostasis (hypocalcemia, hyperkalemia, and hypernatremia, changes in hemodynamics (tachycardia and hypertension, and a catabolic metabolism (early hyperglycemia, late hypoglycemia, and lactate formation. It induced severe tissue injury (significant increases in plasma concentrations of transaminases and lactate dehydrogenase, alterations in blood coagulation (disturbed clot formation, and massive hemolysis. Both moderate and excessive glucose supply reduced LPS-induced

  12. Melatonin reduces changes to small intestinal microvasculature during systemic inflammation.

    Science.gov (United States)

    Lansink, Maren Oude; Patyk, Vivien; de Groot, Herbert; Effenberger-Neidnicht, Katharina

    2017-05-01

    Systemic inflammation is known to impair the microcirculation in intestine and other organs as a result of multifactorial events. Here, we show that melatonin selectively reduces changes to the small intestinal microvasculature during systemic inflammation. Lipopolysaccharide (LPS) was infused at a rate of 0.5 mg/kg × h to induce systemic inflammation in male Wistar rats. Melatonin (single dose: 3 mg/kg × 15 min) was intravenously administered before as well as 120 and 240 min after the beginning of the LPS infusion. Systemic parameters were determined in regular intervals. Small intestine, liver, and kidney were histologically (structure of the microvessels, intravascular blood accumulation, and hemorrhages) and immunohistochemically (mast cells, granulocytes, and macrophages) analyzed. Continuous infusion of LPS resulted in dilated microvessels with intravascular blood accumulation (congestion) in liver and small intestine, the latter being particularly pronounced. Blood vessel walls remained intact, there were no hemorrhages. Melatonin significantly reduced these changes to the microvasculature in small intestine, but not in liver. It further reduced mast cell and granulocytes count in small intestine enhanced by LPS. However, except for the systemic blood pressure, melatonin neither improved LPS-dependent changes to systemic parameters nor mortality. Changes to the microvasculature during systemic inflammation are most pronounced in small intestine. Melatonin selectively diminishes these changes to small intestinal microvasculature, probably by reducing the local immune cells recruitment. However, changes to the small intestine are not decisive for the survival. We assume that the therapeutic benefit of melatonin is more likely in local intestinal inflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Sarcopenia correlates with systemic inflammation in COPD.

    Science.gov (United States)

    Byun, Min Kwang; Cho, Eun Na; Chang, Joon; Ahn, Chul Min; Kim, Hyung Jung

    2017-01-01

    Muscle wasting and chronic inflammation are predominant features of patients with COPD. Systemic inflammation is associated with an accelerated decline in lung function. In this study, the prevalence of sarcopenia and the relationships between sarcopenia and systemic inflammations in patients with stable COPD were investigated. In a cross-sectional design, muscle strength and muscle mass were measured by handgrip strength (HGS) and bioelectrical impedance analysis in 80 patients with stable COPD. Patients (≥40 years old) diagnosed with COPD were recruited from outpatient clinics, and then COPD stages were classified. Sarcopenia was defined as the presence of both low muscle strength (by HGS) and low muscle mass (skeletal muscle mass index [SMMI]). Levels of circulating inflammatory biomarkers (IL-6 and high-sensitivity TNFα [hsTNFα]) were measured. Sarcopenia was prevalent in 20 (25%) patients. Patients with sarcopenia were older, had lower body mass index, and a higher percentage of cardiovascular diseases. In addition, they had significantly higher modified Medical Research Council scores and lower 6-minute walk distance than those without sarcopenia. HGS was significantly correlated with age, modified Medical Research Council score, and COPD Assessment Test scores. Both HGS and SMMI had associations with IL-6 and hsTNFα (HGS, r =-0.35, P =0.002; SMMI, r =-0.246, P =0.044) level. In multivariate analysis, old age, lower body mass index, presence of cardiovascular comorbidities, and higher hsTNFα levels were significant determinants for sarcopenia in patients with stable COPD. Sarcopenia is very common in patients with stable COPD, and is associated with more severe dyspnea-scale scores and lower exercise tolerance. Systemic inflammation could be an important contributor to sarcopenia in the stable COPD population.

  14. Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection.

    Science.gov (United States)

    Humanes, Blanca; Camaño, Sonia; Lara, Jose Manuel; Sabbisetti, Venkatta; González-Nicolás, María Ángeles; Bonventre, Joseph V; Tejedor, Alberto; Lázaro, Alberto

    2017-10-01

    Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats. Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators. Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-κB and CD68-positive cell concentrations. Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  15. Perinatal programming of metabolic dysfunction and obesity-induced inflammation

    DEFF Research Database (Denmark)

    Ingvorsen, Camilla; Hellgren, Lars; Pedersen, Susanne Brix

    associated with chronic low grade inflammation. Nobody have yet investigated the role of this inflammatory phenotype, but here we demonst rate that obesity induced inflammation is reversed during pregnancy in mice, and is therefore less likely to affect the fetal programming of metabolic dysfunction. Instead....... However HFHS exposure during fetal life protected against hyperleptinemia in the adult off spring during the challenge. Additionally, offspring expose to high fat/high sucrose diet during lactation displayed a decrease level of inflammatory genes in the blood, which could indicated that perinatal HFHS...

  16. alpha-MSH in systemic inflammation. Central and peripheral actions.

    Science.gov (United States)

    Catania, A; Delgado, R; Airaghi, L; Cutuli, M; Garofalo, L; Carlin, A; Demitri, M T; Lipton, J M

    1999-10-20

    Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.

  17. Lung injury during LPS-induced inflammation occurs independently of the receptor P2Y1.

    Science.gov (United States)

    Liverani, Elisabetta

    2017-03-01

    Disruption of the lung endothelial and epithelial barriers during acute inflammation leads to excessive neutrophil migration. It is likely that activated platelets promote pulmonary recruitment of neutrophils during inflammation, and previous studies have found that anti-platelet therapy and depletion of circulating platelets have lung-protective effects in different models of inflammation. Because ADP signaling is important for platelet activation, I investigated the role of the ADP-receptor P2Y 1 , a G protein-coupled receptor expressed on the surface of circulating platelets, during lipopolysaccharide (LPS)-induced inflammation and lung injury in P2Y 1 -null and wild-type mice. Systemic inflammation was induced by a single intraperitoneal dose of LPS (3 mg/kg), and the mice were analyzed 24 h posttreatment. The data show that the LPS-induced inflammation levels were comparable in the P2Y 1 -null and wild-type mice. Specifically, splenomegaly, counts of circulating platelets and white blood cells (lymphocytes and neutrophils), and assessments of lung injury (tissue architecture and cell infiltration) were similar in the P2Y 1 -null and wild-type mice. Based on my results, I conclude that lung injury during LPS-induced inflammation in mice is independent of P2Y 1 signaling. I propose that if a blockade of purinergic signaling in platelets is a potential lung-protective strategy in the treatment of acute inflammation, then it is more likely to be a result of the disruption of the signaling pathway mediated by P2Y 12 , another G protein-coupled receptor that mediates platelet responses to ADP.

  18. Increased hypothalamic serotonin turnover in inflammation-induced anorexia.

    Science.gov (United States)

    Dwarkasing, J T; Witkamp, R F; Boekschoten, M V; Ter Laak, M C; Heins, M S; van Norren, K

    2016-05-20

    Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections between peripheral inflammation, anorexia and hypothalamic serotonin metabolism and signaling pathways. First, we investigated the response of two hypothalamic neuronal cell lines to TNFα, IL-6 and LPS. Next, we studied transcriptomic changes and serotonergic activity in the hypothalamus of mice after intraperitoneal injection with TNFα, IL-6 or a combination of TNFα and IL-6. In vitro, we showed that hypothalamic neurons responded to inflammatory mediators by releasing cytokines. This inflammatory response was associated with an increased serotonin release. Mice injected with TNFα and IL-6 showed decreased food intake, associated with altered expression of inflammation-related genes in the hypothalamus. In addition, hypothalamic serotonin turnover showed to be elevated in treated mice. Overall, our results underline that peripheral inflammation reaches the hypothalamus where it affects hypothalamic serotoninergic metabolism. These hypothalamic changes in serotonin pathways are associated with decreased food intake, providing evidence for a role of serotonin in inflammation-induced anorexia.

  19. Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation

    Directory of Open Access Journals (Sweden)

    Leo Pruimboom

    2015-01-01

    Full Text Available In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health.

  20. Exposure to nickel oxide nanoparticles induces pulmonary inflammation through NLRP3 inflammasome activation in rats.

    Science.gov (United States)

    Cao, Zhengwang; Fang, Yiliang; Lu, Yonghui; Qian, Fenghua; Ma, Qinglong; He, Mingdi; Pi, Huifeng; Yu, Zhengping; Zhou, Zhou

    2016-01-01

    With recent advances in the manufacture and application of nickel oxide nanoparticles (NiONPs), concerns about their adverse effects on the respiratory system are increasing. However, the underlying cellular and molecular mechanisms of NiONP-induced pulmonary toxicity remain unclear. In this study, we focused on the impacts of NiONPs on pulmonary inflammation and investigated whether the NLRP3 inflammasome is involved in NiONP-induced pulmonary inflammation and injury. NiONP suspensions were administered by single intratracheal instillation to rats, and inflammatory responses were evaluated at 3 days, 7 days, or 28 days after treatment. NiONP exposure resulted in sustained pulmonary inflammation accompanied by inflammatory cell infiltration, alveolar proteinosis, and cytokine secretion. Expression of Nlrp3 was markedly upregulated by the NiONPs, which was accompanied by overexpression of the active form of caspase-1 (p20) and interleukin (IL)-1β secretion in vivo. NiONP-induced IL-1β secretion was partially prevented by co-treatment with a caspase-1 inhibitor in macrophages. Moreover, siRNA-mediated Nlrp3 knockdown completely attenuated NiONP-induced cytokine release and caspase-1 activity in macrophages in vitro. In addition, NiONP-induced NLRP3 inflammasome activation requires particle uptake and reactive oxygen species production. Collectively, our findings suggest that the NLRP3 inflammasome participates in NiONP-induced pulmonary inflammation and offer new strategies to combat the pulmonary toxicity induced by NiONPs.

  1. Titanium Dioxide Exposure Induces Acute Eosinophilic Lung Inflammation in Rabbits

    Science.gov (United States)

    CHOI, Gil Soon; OAK, Chulho; CHUN, Bong-Kwon; WILSON, Donald; JANG, Tae Won; KIM, Hee-Kyoo; JUNG, Mannhong; TUTKUN, Engin; PARK, Eun-Kee

    2014-01-01

    Titanium dioxide (TiO2) is increasingly widely used in industrial, commercial and home products. TiO2 aggravates respiratory symptoms by induction of pulmonary inflammation although the mechanisms have not been well investigated. We aimed to investigate lung inflammation in rabbits after intratracheal instillation of P25 TiO2. One ml of 10, 50 and 250 µg of P25 TiO2 was instilled into one of the lungs of rabbits, chest computed-tomography was performed, and bronchoalveolar lavage (BAL) fluid was collected before, at 1 and 24 h after P25 TiO2 exposure. Changes in inflammatory cells in the BAL fluids were measured. Lung pathological assay was also carried out at 24 h after P25 TiO2 exposure. Ground glass opacities were noted in both lungs 1 h after P25 TiO2 and saline (control) instillation. Although the control lung showed complete resolution at 24 h, the lung exposed to P25 TiO2 showed persistent ground glass opacities at 24 h. The eosinophil counts in BAL fluid were significantly increased after P25 TiO2 exposure. P25 TiO2 induced a dose dependent increase of eosinophils in BAL fluid but no significant differences in neutrophil and lymphocyte cell counts were detected. The present findings suggest that P25 TiO2 induces lung inflammation in rabbits which is associated with eosinophilic inflammation. PMID:24705802

  2. Pulmonary Extracellular Vesicles as Mediators of Local and Systemic Inflammation.

    Science.gov (United States)

    Wahlund, Casper J E; Eklund, Anders; Grunewald, Johan; Gabrielsson, Susanne

    2017-01-01

    Cells of the airways are constantly exposed to environmental hazards including cigarette smoke, irritants, pathogens, and mechanical insults. Maintaining barrier integrity is vital, and mounting responses to threats depends on intercellular communication. Extracellular vesicles (EVs), including exosomes and microvesicles, are major signal mediators between cells, shuttling cargo in health and disease. Depending on the state of the originating cells, EVs are capable of inducing proinflammatory effects including antigen presentation, cellular migration, apoptosis induction, and inflammatory cytokine release. Cells of the airways release EVs, which can be found in bronchoalveolar lavage fluid. EVs of the airways can support inflammation in the lung, but may also exit into the circulation and carry a cocktail of pro-inflammatory molecules to recipient cells in distant organs. In this review, we discuss the possibility that EVs originating from the airways contribute to dissemination of inflammation in both lung disorders and systemic inflammatory conditions.

  3. Pulmonary Extracellular Vesicles as Mediators of Local and Systemic Inflammation

    Directory of Open Access Journals (Sweden)

    Susanne Gabrielsson

    2017-04-01

    Full Text Available Cells of the airways are constantly exposed to environmental hazards including cigarette smoke, irritants, pathogens, and mechanical insults. Maintaining barrier integrity is vital, and mounting responses to threats depends on intercellular communication. Extracellular vesicles (EVs, including exosomes and microvesicles, are major signal mediators between cells, shuttling cargo in health and disease. Depending on the state of the originating cells, EVs are capable of inducing proinflammatory effects including antigen presentation, cellular migration, apoptosis induction, and inflammatory cytokine release. Cells of the airways release EVs, which can be found in bronchoalveolar lavage fluid. EVs of the airways can support inflammation in the lung, but may also exit into the circulation and carry a cocktail of pro-inflammatory molecules to recipient cells in distant organs. In this review, we discuss the possibility that EVs originating from the airways contribute to dissemination of inflammation in both lung disorders and systemic inflammatory conditions.

  4. Obesity-induced vascular inflammation involves elevated arginase activity.

    Science.gov (United States)

    Yao, Lin; Bhatta, Anil; Xu, Zhimin; Chen, Jijun; Toque, Haroldo A; Chen, Yongjun; Xu, Yimin; Bagi, Zsolt; Lucas, Rudolf; Huo, Yuqing; Caldwell, Ruth B; Caldwell, R William

    2017-11-01

    Obesity-induced vascular dysfunction involves pathological remodeling of the visceral adipose tissue (VAT) and increased inflammation. Our previous studies showed that arginase 1 (A1) in endothelial cells (ECs) is critically involved in obesity-induced vascular dysfunction. We tested the hypothesis that EC-A1 activity also drives obesity-related VAT remodeling and inflammation. Our studies utilized wild-type and EC-A1 knockout (KO) mice made obese by high-fat/high-sucrose (HFHS) diet. HFHS diet induced increases in body weight, fasting blood glucose, and VAT expansion. This was accompanied by increased arginase activity and A1 expression in vascular ECs and increased expression of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), interleukin-10 (IL-10), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) mRNA and protein in both VAT and ECs. HFHS also markedly increased circulating inflammatory monocytes and VAT infiltration by inflammatory macrophages, while reducing reparative macrophages. Additionally, adipocyte size and fibrosis increased and capillary density decreased in VAT. These effects of HFHS, except for weight gain and hyperglycemia, were prevented or reduced in mice lacking EC-A1 or treated with the arginase inhibitor 2-( S )-amino-6-boronohexanoic acid (ABH). In mouse aortic ECs, exposure to high glucose (25 mM) and Na palmitate (200 μM) reduced nitric oxide production and increased A1, TNF-α, VCAM-1, ICAM-1, and MCP-1 mRNA, and monocyte adhesion. Knockout of EC-A1 or ABH prevented these effects. HFHS diet-induced VAT inflammation is mediated by EC-A1 expression/activity. Limiting arginase activity is a possible therapeutic means of controlling obesity-induced vascular and VAT inflammation.

  5. Study on MCP-1 related to inflammation induced by biomaterials

    Energy Technology Data Exchange (ETDEWEB)

    Ding Tingting [Ninth People' s Hospital, School of Medicine, Shanghai Jiao Tong University/Shanghai Biomaterials Research and Testing Center, Shanghai 200023 (China); Sun Jiao [Shanghai Key Laboratory of Stomatology, Shanghai 200023 (China); Zhang Ping, E-mail: jiaosun59@yahoo.co [School of Life Science, East China Normal University, Shanghai 200062 (China)

    2009-06-15

    The study of inflammation is important for understanding the reaction between biomaterials and the human body, in particular, the interaction between biomaterials and immune system. In the current study, rat macrophages were induced by multiple biomaterials with different biocompatibilities, including polyvinyl chloride (PVC) containing 8% of organic tin, a positive control material with cellular toxicity. Human umbilical vein endothelial cells (ECV-304), cultured with PRMI-1640, were detached from cells cultured with the supernatant of macrophages containing TNF-alpha and IL-1beta because of stimulation by biomaterials. The cells were then treated with different biomaterials. Then both TNF-alpha and IL-1beta in macrophages were detected by ELISA. Levels of monocyte chemoattractant protein-1 (MCP-1) were measured by RT-PCR. The results suggested that the expression of TNF-alpha and IL-1beta was elevated by polytetrafluoroethylene (PTFE), polylactic-co-glycolic acid (PLGA) and American NPG alloy (p < 0.001). The level of MCP-1 cultured in supernatant of macrophages was higher than in PRMI-1640 with the same biomaterials. And the exposure to PTFE, PLGA and NPG resulted in the high expression of MCP-1 (p < 0.001) following cytokine stimulation. MCP-1 was also significantly expressed in beta-tricalcium phosphate (beta-TCP) and calcium phosphate cement samples (CPC) (p < 0.01). Thus, TNF-alpha, IL-1beta and MCP-1 had played an important role in the immune reaction induced by biomaterials and there was a close relationship between the expression of cytokines and biomcompatibility of biomaterials. Furthermore, these data suggested that MCP-1 was regulated by TNF-alpha and IL-1beta, and activated by both cytokines and biomaterials. The data further suggested that the expression of MCP-1 could be used as a marker to indicate the degree of immune reaction induced by biomaterials.

  6. Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.

    Directory of Open Access Journals (Sweden)

    Connie Slocum

    2014-07-01

    Full Text Available Several successful pathogens have evolved mechanisms to evade host defense, resulting in the establishment of persistent and chronic infections. One such pathogen, Porphyromonas gingivalis, induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. P. gingivalis expresses an atypical lipopolysaccharide (LPS structure containing heterogeneous lipid A species, that exhibit Toll-like receptor-4 (TLR4 agonist or antagonist activity, or are non-activating at TLR4. In this study, we utilized a series of P. gingivalis lipid A mutants to demonstrate that antagonistic lipid A structures enable the pathogen to evade TLR4-mediated bactericidal activity in macrophages resulting in systemic inflammation. Production of antagonistic lipid A was associated with the induction of low levels of TLR4-dependent proinflammatory mediators, failed activation of the inflammasome and increased bacterial survival in macrophages. Oral infection of ApoE(-/- mice with the P. gingivalis strain expressing antagonistic lipid A resulted in vascular inflammation, macrophage accumulation and atherosclerosis progression. In contrast, a P. gingivalis strain producing exclusively agonistic lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner, resulting in host cell lysis and decreased bacterial survival. ApoE(-/- mice infected with this strain exhibited diminished vascular inflammation, macrophage accumulation, and atherosclerosis progression. Notably, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A expression, indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. Collectively, our results point to a pivotal role for activation of the non-canonical inflammasome in P. gingivalis infection and demonstrate that P. gingivalis evades immune

  7. PROGRESSION VARIANTS OF CHRONIC SYSTEMIC INFLAMMATION

    Directory of Open Access Journals (Sweden)

    E. Y. Gusev

    2009-01-01

    Full Text Available Abstract. Fourteen groups of patients have been investigated and divided into 2 classes. The first class included the following cohorts of patients: relatively healthy persons, age 18 to 55 yrs (n = 50; elderly persons 60 yrs old, as well as senior persons (n = 22; persons with chronic adnexitis, women in their 1st trimester of pregnancy (n = 16; climacteric syndrome (n = 16; autoimmune thyroiditis (n = 29. The second class of patients included following cohorts: elderly persons with chronic cardiac insufficiency (CCI II-III stage (n=49; valvular cardiac disease (rheumatism, n = 15; psoriatic arthritis (n = 12; reactive arthritis (n = 17; antiphospholipid syndrome, a sub-group in the 1st trimester of pregnancy (n = 5; systemic lupus erythematosus (n=49; decompensated atherosclerosis of femoral artery (n = 38; end-stage renal disease (n = 42. Plasma cytokines (TNFαα, IL-6, IL-8, IL-10, acute-phase C-reactive protein (CRP, cortisol, troponin I, myoglobin, D-dimers, interleukin-2 soluble receptor (IL-2sR, and eosinophil cationic protein (ECP were determined in all the patients, by means of immune chemiluminescent technique (Immulite; Siemens Medical Solutions Diagnostics, USA. The integral indices of systemic inflammatory reaction (SIR have been calculated, i.e., a Reactivity Coefficient (RC and a Reactivity Level (RL. In the patients belonging to Class 1 cohorts, an absence of chronic systemic inflammation features was revealed, despite of some signs of systemic inflammatory response. Meanwhile, a majority of Class 2 patients have shown the signs of chronic systemic inflammation stage I to III.

  8. Pleurotus eryngii Ameliorates Lipopolysaccharide-Induced Lung Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Junya Kawai

    2014-01-01

    Full Text Available Pleurotus eryngii (P. eryngii is consumed as a fresh cultivated mushroom worldwide and demonstrated to have multiple beneficial effects. We investigated the anti-inflammatory effect of P. eryngii in mice with acute lung injury (ALI. Intranasal instillation of lipopolysaccharide (LPS (10 μg/site/mouse induced marked lung inflammation (increase in the number of inflammatory cells, protein leakage, and production of nitric oxide in bronchoalveolar lavage fluid as well as histopathological damage in the lung, 6 h after treatment. Mice administered heat-treated P. eryngii (0.3–1 g/kg, p.o. (HTPE 1 h before LPS challenge showed decreased pulmonary inflammation and ameliorated histopathological damage. These results suggest that HTPE has anti-inflammatory effects against ALI. Thus, P. eryngii itself may also have anti-inflammatory effects and could be a beneficial food for the prevention of ALI induced by bacterial infection.

  9. "TRP inflammation" relationship in cardiovascular system.

    Science.gov (United States)

    Numata, Tomohiro; Takahashi, Kiriko; Inoue, Ryuji

    2016-05-01

    Despite considerable advances in the research and treatment, the precise relationship between inflammation and cardiovascular (CV) disease remains incompletely understood. Therefore, understanding the immunoinflammatory processes underlying the initiation, progression, and exacerbation of many cardiovascular diseases is of prime importance. The innate immune system has an ancient origin and is well conserved across species. Its activation occurs in response to pathogens or tissue injury. Recent studies suggest that altered ionic balance, and production of noxious gaseous mediators link to immune and inflammatory responses with altered ion channel expression and function. Among plausible candidates for this are transient receptor potential (TRP) channels that function as polymodal sensors and scaffolding proteins involved in many physiological and pathological processes. In this review, we will first focus on the relevance of TRP channel to both exogenous and endogenous factors related to innate immune response and transcription factors related to sustained inflammatory status. The emerging role of inflammasome to regulate innate immunity and its possible connection to TRP channels will also be discussed. Secondly, we will discuss about the linkage of TRP channels to inflammatory CV diseases, from a viewpoint of inflammation in a general sense which is not restricted to the innate immunity. These knowledge may serve to provide new insights into the pathogenesis of various inflammatory CV diseases and their novel therapeutic strategies.

  10. Mesenchymal Stem Cell Treatment of Inflammation-Induced Cancer.

    Science.gov (United States)

    Prakash, Monica D; Miller, Sarah; Randall-Demllo, Sarron; Nurgali, Kulmira

    2016-11-01

    Cancer development is often associated with chronic inflammation. To date, research into inflammation-induced cancer has largely focused on chemokines, cytokines, and their downstream targets. These inflammatory mediators may promote tumor growth, invasion, metastasis, and facilitate angiogenesis. However, the exact mechanisms by which inflammation promotes neoplasia remain unclear. Inflammatory bowel disease (IBD) is characterized by recurrent, idiopathic intestinal inflammation, the complications of which are potentially fatal. IBD incidence in Australia is 24.2 per 100,000 and its peak onset is in people aged 15 to 24 years. Symptoms include abdominal pain, cramps, bloody stool, and persistent diarrhoea or constipation and so seriously compromise quality of life. However, due to its unknown etiology, current treatment strategies combat the symptoms rather than the disease and are limited by inefficacy, toxicity, and adverse side-effects. IBD is also associated with an increased risk of colorectal cancer, for which treatment options are similarly limited. In recent years, there has been much interest in the therapeutic potential of mesenchymal stem cells (MSCs). However, whether MSCs suppress or promote tumor development is still contentious within the literature. Many studies indicate that MSCs exert anti-tumor effects and suppress tumor growth, whereas other studies report pro-tumor effects. Studies using MSCs as treatment for IBD have shown promising results in both animal models and human trials. However, as MSC treatment is still novel, the long-term risks remain unknown. This review aims to summarize the current literature on MSC treatment of inflammation-induced cancer, with a focus on colorectal cancer resulting from IBD.

  11. RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Lingjun, E-mail: menglingjun@nibs.ac.cn [College of Biological Sciences, China Agricultural University, Beijing 100094 (China); National Institute of Biological Sciences, Beijing 102206 (China); Jin, Wei [Institute for Immunology, Tsinghua University, Beijing 100084 (China); Wang, Yuhui [Institute of Cardiovascular Sciences, Health Science Center, Peking University, Beijing 100191 (China); Huang, Huanwei; Li, Jia; Zhang, Cai [National Institute of Biological Sciences, Beijing 102206 (China)

    2016-04-29

    Atherothrombotic vascular disease is already the leading cause of mortality worldwide. Atherosclerosis shares features with diseases caused by chronic inflammation. More attention should concentrates on the innate immunity effect atherosclerosis progress. RIP3 (receptor-interacting protein kinase 3) act through the transcription factor named Nr4a3 (Nuclear orphan receptors) to regulate cytokine production. Deletion RIP3 decreases IL-1α production. Injection of anti-IL-1α antibody protects against the progress of atherosclerosis in ApoE −/− mice. RIP3 as a molecular switch in necrosis, controls macrophage necrotic death caused inflammation. Inhibiting necrosis will certainly reduce atherosclerosis through limit inflammation. Necrotic cell death caused systemic inflammation exacerbated cardiovascular disease. Inhibition of necrosis may yield novel therapeutic targets for treatment in years to come. - Highlights: • RIP3 regulate the Nr4a3 to control cytokine production. • Deletion RIP3 decreases IL-1a production. • Injection anti-IL-1a antibody protects against the progress of atherosclerosis. • RIP3 controls macrophage necrotic dead caused inflammation.

  12. Th17 cells and IL-17 promote the skin and lung inflammation and fibrosis process in a bleomycin-induced murine model of systemic sclerosis.

    Science.gov (United States)

    Lei, Ling; Zhao, Cheng; Qin, Fang; He, Zhi-Yi; Wang, Xu; Zhong, Xiao-Ning

    2016-01-01

    Systemic sclerosis (SSc) is characterised by fibrosis of the skin and internal organs, such as the lungs. Enhanced Th17 responses are associated with skin fibrosis in patients with SSc, however, whether they are associated with lung fibrosis has not been clarified. This study aimed to investigate the potential association of Th17 responses with the skin and pulmonary fibrosis as well as the potential mechanisms in a mouse bleomycin (BLM) model of SSc. BALB/c mice were injected subcutaneously with phosphate buffered saline (PBS) (control) or BLM for 28 days and the skin and pulmonary inflammation and fibrosis were characterized by histology. The percentages of circulating, skin and pulmonary infiltrating Th17 cells and the contents of collagen in mice were analysed. The levels of RORγt, IL-17A, IL-6 and TGF-β1 mRNA transcripts in the skin and lungs were determined by quantitative RTPCR and the levels of serum IL-17A, IL-6 and TGF-β1 were determined by ELISA. Furthermore, the effect of rIL-17A on the proliferation of pulmonary fibroblasts and their cytokine expression was analysed. The potential association of Th17 responses with the severity of skin and lung fibrosis was analysed. In comparison with the control mice, significantly increased skin and pulmonary inflammation and fibrosis and higher levels of hydroxyproline were detected in the BLM mice. Significantly higher frequency of circulating, skin and lung infiltrating Th17 cells and higher levels of serum, skin and lung IL-17A, TGF-β1, IL-6 and RORγt were detected in the BLM mice. The concentrations of serum IL-17A were correlated positively with the percentages of Th17 cells and the contents of skin hydroxyproline in the BLM mice. The levels of IL-17A expression were positively correlated with the skin and lung inflammatory scores as well as the skin fibrosis in the BLM mice. In addition, IL-17A significantly enhanced pulmonary fibroblast proliferation and their type I collagen, TGF-β and IL-6 expression

  13. Sleep apnea is associated with bronchial inflammation and continuous positive airway pressure-induced airway hyperresponsiveness.

    Science.gov (United States)

    Devouassoux, Gilles; Lévy, Patrick; Rossini, Eliane; Pin, Isabelle; Fior-Gozlan, Michèle; Henry, Mireille; Seigneurin, Daniel; Pépin, Jean-Louis

    2007-03-01

    Obstructive sleep apnea syndrome (OSA) is associated with systemic and upper airway inflammation. Pharyngeal inflammation has a potential role in upper airway collapse, whereas systemic inflammation relates to cardiovascular morbidity. However, the presence of an inflammatory involvement of lower airway has been poorly investigated. The aim of the study was to demonstrate an inflammatory process at the bronchial level in patients with OSA and to analyze effects of continuous positive airway pressure (CPAP) application and humidification on bronchial mucosa. The study was conducted by using sequential induced sputum for cell analysis and IL-8 production, nitric oxide exhalation measurement, and methacholine challenge before and after CPAP. Bronchial neutrophilia and a high IL-8 concentration were observed in untreated OSA compared with controls (75% +/- 20% vs 43% +/- 12%, P Obstructive sleep apnea syndrome is associated with bronchial inflammation. Our data demonstrate CPAP effect on the development of AHR, possibly facilitated by the pre-existing inflammation. Both issues should be evaluated during long-term CPAP use. Results showing a spontaneous bronchial inflammation in OSA and the development of a CPAP-related AHR require a long-term follow-up to evaluate consequences on chronic bronchial obstruction.

  14. Inhibition of lipopolysaccharide induced acute inflammation in lung by chlorination

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China); Qiao, Juan, E-mail: qjuan@tsinghua.edu.cn [Department of Chemistry, Tsinghua University, Beijing 100084 (China); Lu, Yun, E-mail: luyun@tsinghua.edu.cn [Environmental Simulation and Pollution Control State Key Joint Laboratory, School of Environment, Tsinghua University, Beijing 100084 (China)

    2016-02-13

    Highlights: • Chlorination is effective to reduce the inflammation inducing capacity of LPS in lung. • LAL-detected endotoxin activity is not correlated to the potency of inflammation induction. • Alkyl chain of LPS was chlorinated in chlorination process. • LPS aggregate size decreases after chlorination. - Abstract: Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies.

  15. N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation.

    Science.gov (United States)

    Gao, Xiao; Lampraki, Eirini-Maria; Al-Khalidi, Sarwah; Qureshi, Muhammad Asif; Desai, Rhea; Wilson, Joanna Beatrice

    2017-01-01

    Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFα S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue-destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure

  16. Low Level Laser Therapy Reduces the Development of Lung Inflammation Induced by Formaldehyde Exposure.

    Directory of Open Access Journals (Sweden)

    Cristiane Miranda da Silva

    Full Text Available Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA, an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1% or vehicle (distillated water during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure. Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant.

  17. The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is "Inflammation" Always Inflammation?

    Science.gov (United States)

    Kulkarni, Onkar P; Lichtnekert, Julia; Anders, Hans-Joachim; Mulay, Shrikant R

    2016-01-01

    Inflammation is a response to infections or tissue injuries. Inflammation was once defined by clinical signs, later by the presence of leukocytes, and nowadays by expression of "proinflammatory" cytokines and chemokines. But leukocytes and cytokines often have rather anti-inflammatory, proregenerative, and homeostatic effects. Is there a need to redefine "inflammation"? In this review, we discuss the functions of "inflammatory" mediators/regulators of the innate immune system that determine tissue environments to fulfill the need of the tissue while regaining homeostasis after injury.

  18. Evaluation of classification systems for nonspecific idiopathic orbital inflammation

    NARCIS (Netherlands)

    Bijlsma, Ward R.; van 't Hullenaar, Fleur C.; Mourits, Maarten P.; Kalmann, Rachel

    2012-01-01

    To systematically analyze existing classification systems for idiopathic orbital inflammation (IOI) and propose and test a new best practice classification system. A systematic literature search was conducted to find all studies that described and applied a classification system for IOI.

  19. Carotid Catheterization and Automated Blood Sampling Induce Systemic IL-6 Secretion and Local Tissue Damage and Inflammation in the Heart, Kidneys, Liver and Salivary Glands in NMRI Mice

    DEFF Research Database (Denmark)

    Teilmann, Anne Charlotte; Rozell, Björn; Kalliokoski, Otto

    2016-01-01

    ) changes at surgical sites of all catheterized mice, with mild inflammatory changes extending into the salivary glands. Several catheterized mice had multifocal degenerative to necrotic changes with inflammation in the heart, kidneys and livers, suggesting that thrombi had detached from the catheter tip...

  20. Comorbidity, systemic inflammation and outcomes in the ECLIPSE cohort

    DEFF Research Database (Denmark)

    Miller, Joy; Edwards, Lisa D; Agustí, Alvar

    2013-01-01

    Comorbidities, are common in COPD, have been associated with poor outcomes and are thought to relate to systemic inflammation. To investigate comorbidities in relation to systemic inflammation and outcomes we recorded comorbidities in a well characterized cohort (ECLIPSE study) for 2164 clinically...

  1. Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat

    Directory of Open Access Journals (Sweden)

    Jian-Dong Li

    2016-01-01

    Full Text Available Heart failure (HF is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS activity and elevated levels of proinflammatory cytokines (PICs. Renal denervation (RD has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO- induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD.

  2. DNA damage-induced inflammation and nuclear architecture.

    Science.gov (United States)

    Stratigi, Kalliopi; Chatzidoukaki, Ourania; Garinis, George A

    2017-07-01

    Nuclear architecture and the chromatin state affect most-if not all- DNA-dependent transactions, including the ability of cells to sense DNA lesions and restore damaged DNA back to its native form. Recent evidence points to functional links between DNA damage sensors, DNA repair mechanisms and the innate immune responses. The latter raises the question of how such seemingly disparate processes operate within the intrinsically complex nuclear landscape and the chromatin environment. Here, we discuss how DNA damage-induced immune responses operate within chromatin and the distinct sub-nuclear compartments highlighting their relevance to chronic inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1β-induced chronic inflammation.

    Science.gov (United States)

    Liang, Wen; Lindeman, Jan H; Menke, Aswin L; Koonen, Debby P; Morrison, Martine; Havekes, Louis M; van den Hoek, Anita M; Kleemann, Robert

    2014-05-01

    The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β (IL-1β), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.huCETP (APOE3L.CETP) mice fed a high-fat diet (HFD) developed BS after 10 weeks. Then, inflammatory triggers were superimposed or not (control) for six more weeks. Mouse livers were analyzed with particular emphasis on hallmarks of inflammation which were defined in human liver biopsies with and without NASH. Livers of HFD-treated control mice remained steatotic and did not progress to NASH. All four inflammatory triggers activated hepatic nuclear factor-κB (NF-κB) significantly and comparably (≥5-fold). However, HFD+LPS or HFD+IL-1β did not induce a NASH-like phenotype and caused intrahepatic accumulation of almost exclusively mononuclear cells. By contrast, mice treated with metabolic triggers developed NASH, characterized by enhanced steatosis, hepatocellular hypertrophy, and formation of mixed-type inflammatory foci containing myeloperoxidase-positive granulocytes (neutrophils) as well as mononuclear cells, essentially as observed in human NASH. Specific for the metabolic inducers was an activation of the proinflammatory transcription factor activator protein-1 (AP-1), neutrophil infiltration, and induction of risk factors associated with human NASH, that is, dyslipidemia (by cholesterol) and insulin resistance (by carbohydrate). In conclusion, HFD feeding followed by NF-κB activation per se (LPS, IL-1β) does not promote the transition from BS to NASH. HFD feeding followed by metabolically evoked inflammation induces additional inflammatory components

  4. Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung.

    Science.gov (United States)

    Hwang, Ji Young; Randall, Troy D; Silva-Sanchez, Aaron

    2016-01-01

    Following pulmonary inflammation, leukocytes that infiltrate the lung often assemble into structures known as inducible Bronchus-Associated Lymphoid Tissue (iBALT). Like conventional lymphoid organs, areas of iBALT have segregated B and T cell areas, specialized stromal cells, high endothelial venules, and lymphatic vessels. After inflammation is resolved, iBALT is maintained for months, independently of inflammation. Once iBALT is formed, it participates in immune responses to pulmonary antigens, including those that are unrelated to the iBALT-initiating antigen, and often alters the clinical course of disease. However, the mechanisms that govern immune responses in iBALT and determine how iBALT impacts local and systemic immunity are poorly understood. Here, we review our current understanding of iBALT formation and discuss how iBALT participates in pulmonary immunity.

  5. Ficolins do not alter host immune responses to lipopolysaccharide-induced inflammation in vivo

    DEFF Research Database (Denmark)

    Genster, Ninette; Østrup, Olga; Schjalm, Camilla

    2017-01-01

    Ficolins are a family of pattern recognition molecules that are capable of activating the lectin pathway of complement. A limited number of reports have demonstrated a protective role of ficolins in animal models of infection. In addition, an immune modulatory role of ficolins has been suggested....... Yet, the contribution of ficolins to inflammatory disease processes remains elusive. To address this, we investigated ficolin deficient mice during a lipopolysaccharide (LPS)-induced model of systemic inflammation. Although murine serum ficolin was shown to bind LPS in vitro, there was no difference...... an unaltered spleen transcriptome profile in ficolin deficient mice compared to wildtype mice. Collectively, results from this study demonstrate that ficolins are not involved in host response to LPS-induced systemic inflammation....

  6. Hypoxia augments LPS-induced inflammation and triggers high altitude cerebral edema in mice.

    Science.gov (United States)

    Zhou, Yanzhao; Huang, Xin; Zhao, Tong; Qiao, Meng; Zhao, Xingnan; Zhao, Ming; Xu, Lun; Zhao, Yongqi; Wu, Liying; Wu, Kuiwu; Chen, Ruoli; Fan, Ming; Zhu, Lingling

    2017-08-01

    High altitude cerebral edema (HACE) is a life-threatening illness that develops during the rapid ascent to high altitudes, but its underlying mechanisms remain unclear. Growing evidence has implicated inflammation in the susceptibility to and development of brain edema. In the present study, we investigated the inflammatory response and its roles in HACE in mice following high altitude hypoxic injury. We report that acute hypobaric hypoxia induced a slight inflammatory response or brain edema within 24h in mice. However, the lipopolysaccharide (LPS)-induced systemic inflammatory response rapidly aggravated brain edema upon acute hypobaric hypoxia exposure by disrupting blood-brain barrier integrity and activating microglia, increasing water permeability via the accumulation of aquaporin-4 (AQP4), and eventually leading to impaired cognitive and motor function. These findings demonstrate that hypoxia augments LPS-induced inflammation and induces the occurrence and development of cerebral edema in mice at high altitude. Here, we provide new information on the impact of systemic inflammation on the susceptibility to and outcomes of HACE. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Pentoxifylline besides naltrexone recovers morphine-induced inflammation in male reproductive system of rats by regulating Toll-like receptor pathway.

    Science.gov (United States)

    Chehrei, S; Moradi, M; Ghiabi, H R; Falahi, M; Kaviani, S; Ghanbari, A

    2017-11-01

    This study aimed to investigate the effect of pentoxifylline on complications of prolonged usage of morphine upon the testis and sperm parameters of rats. In this study, forty male Wistar rats were divided into five groups (n = 8) and treated for 56 days to only saline, only morphine, only pentoxifylline, pentoxifylline + morphine and naltrexone + morphine. The diameters of seminiferous tubules, the maturity of germ line epithelium and sperm parameters were evaluated. The expression of inflammatory-related factors in testis tissues were also investigated at gene and protein levels. The data were calculated by one-way ANOVA test followed by Tukey's post hoc test using SPSS software for windows (version 20). Seminiferous tubule diameter, the maturity of spermatogonia and sperm parameters were significantly decreased in morphine group in comparison with control, pentoxifylline and pentoxifylline + morphine groups (p < .001). The expression of anti-inflammatory markers, at both gene and protein levels, was significantly increased in testis of morphine-treated rats in comparison with other groups (p < .001). Chronic morphine administration induces destructive effects on male reproductive system by regulating inflammatory responses. Pentoxifylline recovers the destructive effects of morphine on male reproductive system by inhibiting TLR (Toll-like receptor) activity, as an anti-inflammatory response. © 2016 Blackwell Verlag GmbH.

  8. A systems biology approach to study systemic inflammation.

    Science.gov (United States)

    Chen, Bor-Sen; Wu, Chia-Chou

    2014-01-01

    Systemic inflammation needs a precise control on the sequence and magnitude of occurring events. The high throughput data on the host-pathogen interactions gives us an opportunity to have a glimpse on the systemic inflammation. In this article, a dynamic Candida albicans-zebrafish interactive infectious network is built as an example to demonstrate how systems biology approach can be used to study systematic inflammation. In particular, based on microarray data of C. albicans and zebrafish during infection, the hyphal growth, zebrafish, and host-pathogen intercellular PPI networks were combined to form an integrated infectious PPI network that helps us understand the systematic mechanisms underlying the pathogenicity of C. albicans and the immune response of the host. The signaling pathways for morphogenesis and hyphal growth of C. albicans were 2 significant interactions found in the intercellular PPI network. Two cellular networks were also developed corresponding to the different infection stages (adhesion and invasion), and then compared with each other to identify proteins to gain more insight into the pathogenic role of hyphal development in the C. albicans infection process. Important defense-related proteins in zebrafish were predicted using the same approach. This integrated network consisting of intercellular invasion and cellular defense processes during infection can improve medical therapies and facilitate development of new antifungal drugs.

  9. Effect of 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis-like skin lesions on systemic inflammation and atherosclerosis in hypercholesterolaemic apolipoprotein E deficient mice

    DEFF Research Database (Denmark)

    Madsen, Marie; Hansen, Peter Riis; Nielsen, Lars Bo

    2016-01-01

    BACKGROUND: Risk of cardiovascular disease is increased in patients with psoriasis, but molecular mechanisms linking the two conditions have not been clearly established. Lack of appropriate animal models has hampered generation of new knowledge in this area of research and we therefore sought...... to develop an animal model with combined atherosclerosis and psoriasis-like skin inflammation. METHODS: Topical 12-O-tetradecanoylphorbol-13-acetate (TPA) was applied to the ears twice per week for 8 weeks in atherosclerosis-prone apolipoprotein E deficient (ApoE(-/-)) mice. RESULTS: TPA led to localized...

  10. Systems Approaches to Modeling Chronic Mucosal Inflammation

    Science.gov (United States)

    Gao, Boning; Choudhary, Sanjeev; Wood, Thomas G.; Carmical, Joseph R.; Boldogh, Istvan; Mitra, Sankar; Minna, John D.; Brasier, Allan R.

    2013-01-01

    The respiratory mucosa is a major coordinator of the inflammatory response in chronic airway diseases, including asthma and chronic obstructive pulmonary disease (COPD). Signals produced by the chronic inflammatory process induce epithelial mesenchymal transition (EMT) that dramatically alters the epithelial cell phenotype. The effects of EMT on epigenetic reprogramming and the activation of transcriptional networks are known, its effects on the innate inflammatory response are underexplored. We used a multiplex gene expression profiling platform to investigate the perturbations of the innate pathways induced by TGFβ in a primary airway epithelial cell model of EMT. EMT had dramatic effects on the induction of the innate pathway and the coupling interval of the canonical and noncanonical NF-κB pathways. Simulation experiments demonstrate that rapid, coordinated cap-independent translation of TRAF-1 and NF-κB2 is required to reduce the noncanonical pathway coupling interval. Experiments using amantadine confirmed the prediction that TRAF-1 and NF-κB2/p100 production is mediated by an IRES-dependent mechanism. These data indicate that the epigenetic changes produced by EMT induce dynamic state changes of the innate signaling pathway. Further applications of systems approaches will provide understanding of this complex phenotype through deterministic modeling and multidimensional (genomic and proteomic) profiling. PMID:24228254

  11. Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD.

    Science.gov (United States)

    Pouwels, Simon D; Hesse, Laura; Faiz, Alen; Lubbers, Jaap; Bodha, Priya K; Ten Hacken, Nick H T; van Oosterhout, Antoon J M; Nawijn, Martijn C; Heijink, Irene H

    2016-11-01

    Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD). We investigated whether CS-induced damage-associated molecular pattern (DAMP) release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings, were collected from young and old individuals, susceptible and nonsusceptible for the development of COPD, before and after smoking, and used for gene profiling and airway epithelial cell (AEC) culture. AECs were exposed to CS extract (CSE) or specific DAMPs. BALB/cByJ and DBA/2J mice were intranasally exposed to LL-37 and mitochondrial (mt)DAMPs. Functional gene-set enrichment analysis showed that CS significantly increases the airway epithelial gene expression of DAMPs and DAMP receptors in COPD patients. In cultured AECs, we observed that CSE induces necrosis and DAMP release, with specifically higher galectin-3 release from COPD-derived compared with control-derived cells. Galectin-3, LL-37, and mtDAMPs increased CXCL8 secretion in AECs. LL-37 and mtDAMPs induced neutrophilic airway inflammation, exclusively in mice susceptible for CS-induced airway inflammation. Collectively, we show that in airway epithelium from COPD patients, the CS-induced expression of DAMPs and DAMP receptors in vivo and the release of galectin-3 in vitro is exaggerated. Furthermore, our studies indicate that a predisposition to release DAMPs and subsequent induction of inflammation may contribute to the development of COPD. Copyright © 2016 the American Physiological Society.

  12. Lipopolysaccharide induced inflammation in the perivascular space in lungs

    Directory of Open Access Journals (Sweden)

    Pabst Reinhard

    2008-07-01

    Full Text Available Abstract Background Lipopolysaccharide (LPS contained in tobacco smoke and a variety of environmental and occupational dusts is a toxic agent causing lung inflammation characterized by migration of neutrophils and monocytes into alveoli. Although migration of inflammatory cells into alveoli of LPS-treated rats is well characterized, the dynamics of their accumulation in the perivascular space (PVS leading to a perivascular inflammation (PVI of pulmonary arteries is not well described. Methods Therefore, we investigated migration of neutrophils and monocytes into PVS in lungs of male Sprague-Dawley rats treated intratracheally with E. coli LPS and euthanized after 1, 6, 12, 24 and 36 hours. Control rats were treated with endotoxin-free saline. H&E stained slides were made and immunohistochemistry was performed using a monocyte marker and the chemokine Monocyte-Chemoattractant-Protein-1 (MCP-1. Computer-assisted microscopy was performed to count infiltrating cells. Results Surprisingly, the periarterial infiltration was not a constant finding in each animal although LPS-induced alveolitis was present. A clear tendency was observed that neutrophils were appearing in the PVS first within 6 hours after LPS application and were decreasing at later time points. In contrast, mononuclear cell infiltration was observed after 24 hours. In addition, MCP-1 expression was present in perivascular capillaries, arteries and the epithelium. Conclusion PVI might be a certain lung reaction pattern in the defense to infectious attacks.

  13. Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring

    Science.gov (United States)

    Deng, Youcai; Deng, Yafei; He, Xiaoyan; Chu, Jianhong; Zhou, Jianzhi; Zhang, Qi; Guo, Wei; Huang, Pei; Guan, Xiao; Tang, Yuan; Wei, Yanling; Zhao, Shanyu; Zhang, Xingxing; Wei, Chiming; Namaka, Michael; Yi, Ping; Yu, Jianhua; Li, Xiaohui

    2016-01-01

    Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention. PMID:26877256

  14. Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring.

    Science.gov (United States)

    Deng, Youcai; Deng, Yafei; He, Xiaoyan; Chu, Jianhong; Zhou, Jianzhi; Zhang, Qi; Guo, Wei; Huang, Pei; Guan, Xiao; Tang, Yuan; Wei, Yanling; Zhao, Shanyu; Zhang, Xingxing; Wei, Chiming; Namaka, Michael; Yi, Ping; Yu, Jianhua; Li, Xiaohui

    2016-02-15

    Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring's aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention.

  15. Stress induces endotoxemia and low-grade inflammation by increasing barrier permeability

    Directory of Open Access Journals (Sweden)

    Karin ede Punder

    2015-05-01

    Full Text Available Chronic non-communicable diseases (NCDs are the leading causes of work absence, disability and mortality worldwide. Most of these diseases are associated with low-grade inflammation. Here we hypothesize that stresses (defined as homeostatic disturbances can induce low-grade inflammation by increasing the availability of water, sodium and energy-rich substances to meet the increased metabolic demand induced by the stressor. One way of triggering low-grade inflammation is by increasing intestinal barrier permeability through activation of various components of the stress system. Although beneficial to meet the demands necessary during stress, increased intestinal barrier permeability also raises the possibility of the translocation of bacteria and their toxins across the intestinal lumen into the blood circulation. In combination with modern life-style factors, the increase in bacteria/bacterial toxin translocation arising from a more permeable intestinal wall causes a low-grade inflammatory state. We support this hypothesis with numerous studies finding associations with NCDs and markers of endotoxemia, suggesting that this process plays a pivotal and perhaps even a causal role in the development of low-grade inflammation and its related diseases.

  16. Neurological and cellular regulation of visceral hypersensitivity induced by chronic stress and colonic inflammation in rats

    Science.gov (United States)

    Chen, Jinghong; Winston, John H.; Sarna, Sushil K.

    2013-01-01

    The role of inflammation in inducing visceral hypersensitivity (VHS) in ulcerative colitis patients remains unknown. We tested the hypothesis that acute ulcerative colitis-like inflammation does not induce VHS. However, it sets up molecular conditions such that chronic stress following inflammation exaggerates single unit afferent discharges to colorectal distension. We used dextran sodium sulfate (DSS) to induce ulcerative colitis-like inflammation and a 9-day heterotypic chronic stress protocol in rats. DSS upregulated Nav1.8 mRNA in colon-responsive DRG neurons, TRPV1 in colonic muscularis externae (ME) and BDNF in spinal cord without affecting the spike frequency in spinal afferents or VMR to CRD. By contrast, chronic stress did not induce inflammation but it downregulated Kv1.1 and Kv1.4 mRNA in DRG neurons, and upregulated TRPA1 and NGF in ME, which mediated the increase of spike frequency and VMR to CRD. Chronic stress following inflammation exacerbated spike frequency in spinal afferent neurons. TRPA1 antagonist suppressed the sensitization of afferent neurons. DSS-inflammation did not affect the composition or excitation thresholds of low-threshold and high-threshold fibers. Chronic stress following inflammation increased the percent composition of high-threshold fibers and lowered the excitation threshold of both types of fibers. We conclude that not all types of inflammation induce VHS, whereas chronic stress induces VHS in the absence of inflammation. PMID:23806714

  17. Inhibition of systemic inflammation by central action of the neuropeptide alpha-melanocyte- stimulating hormone.

    Science.gov (United States)

    Delgado Hernàndez, R; Demitri, M T; Carlin, A; Meazza, C; Villa, P; Ghezzi, P; Lipton, J M; Catania, A

    1999-01-01

    The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) reduces fever and acute inflammation in the skin when administered centrally. The aim of the present research was to determine whether central alpha-MSH can also reduce signs of systemic inflammation in mice with endotoxemia. Increases in serum tumor necrosis factor-alpha and nitric oxide, induced by intraperitoneal administration of endotoxin, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Lung myeloperoxidase activity, a marker of neutrophil infiltration, was increased in endotoxemic mice; the increase was significantly less in lungs of mice treated with central alpha-MSH. Intraperitoneal administration of the small dose of alpha-MSH that was effective centrally did not alter any of the markers of inflammation. In experiments using immunoneutralization of central alpha-MSH, we tested the idea that endogenous peptide induced within the brain during systemic inflammation modulates host responses to endotoxic challenge in peripheral tissues. The data showed that proinflammatory agents induced by endotoxin in the circulation, lungs, and liver were significantly greater after blockade of central alpha-MSH. The results suggest that anti-inflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation.

  18. MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

    Directory of Open Access Journals (Sweden)

    Inge Van Hove

    2016-11-01

    Full Text Available Matrix metalloproteinase-3 (MMP-3 is known to mediate neuroinflammatory processes by activating microglia, disrupting blood–central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE and the blood–retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1, interleukin 6 (Il6, cytokine-inducible nitrogen oxide synthase (Nos2 and tumor necrosis factor α (Tnfα, which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP-1 and (C-X-C motif ligand 1 (CXCL1. These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation.

  19. Acrolein exposure suppresses antigen-induced pulmonary inflammation

    Science.gov (United States)

    2013-01-01

    Background Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. The impact of smoking on allergic asthma remains unclear, with various reports demonstrating that cigarette smoke enhances asthma development but can also suppress allergic airway inflammation. Based on our previous findings that immunosuppressive effects of smoking may be largely attributed to one of its main reactive electrophiles, acrolein, we explored the impact of acrolein exposure in a mouse model of ovalbumin (OVA)-induced allergic asthma. Methods C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection with the adjuvant aluminum hydroxide on days 0 and 7, and challenged with aerosolized OVA on days 14–16. In some cases, mice were also exposed to 5 ppm acrolein vapor for 6 hrs/day on days 14–17. Lung tissues or brochoalveolar lavage fluids (BALF) were collected either 6 hrs after a single initial OVA challenge and/or acrolein exposure on day 14 or 48 hrs after the last OVA challenge, on day 18. Inflammatory cells and Th1/Th2 cytokine levels were measured in BALF, and lung tissue samples were collected for analysis of mucus and Th1/Th2 cytokine expression, determination of protein alkylation, cellular thiol status and transcription factor activity. Results Exposure to acrolein following OVA challenge of OVA-sensitized mice resulted in markedly attenuated allergic airway inflammation, demonstrated by decreased inflammatory cell infiltrates, mucus hyperplasia and Th2 cytokines. Acrolein exposure rapidly depleted lung tissue glutathione (GSH) levels, and induced activation of the Nrf2 pathway, indicated by accumulation of Nrf2, increased alkylation of Keap1, and induction of Nrf2-target genes such as HO-1. Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein

  20. Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD

    NARCIS (Netherlands)

    Pouwels, Simon D.; Hesse, Laura; Faiz, Alen; Lubbers, Jaap; Bodha, Priya K.; ten Hacken, Nick H. T.; van Oosterhout, Antoon J. M.; Nawijn, Martijn C.; Heijink, Irene H.

    2016-01-01

    Cigarette smoke (CS) exposure is a major risk factor for chronic obstructive pulmonary disease (COPD). We investigated whether CS-induced damage-associated molecular pattern (DAMP) release or DAMP-mediated inflammation contributes to susceptibility for COPD. Samples, including bronchial brushings,

  1. Anti-inflammatory effects of dexamethasone and meloxicam on Borrelia burgdorferi-induced inflammation in neuronal cultures of dorsal root ganglia and myelinating cells of the peripheral nervous system.

    Science.gov (United States)

    Ramesh, Geeta; Meisner, Olivia C; Philipp, Mario T

    2015-12-23

    Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi (Bb), could result in cognitive impairment, motor dysfunction, and radiculoneuritis. We hypothesized that inflammation is a key factor in LNB pathogenesis and recently evaluated the effects of dexamethasone, a steroidal anti-inflammatory drug, and meloxicam a non-steroidal anti-inflammatory drug (NSAID), in a rhesus monkey model of acute LNB. Dexamethasone treatment significantly reduced the levels of immune mediators, and prevented inflammatory and/or neurodegenerative lesions in the central and peripheral nervous systems, and apoptosis in the dorsal root ganglia (DRG). However, infected animals treated with meloxicam showed levels of inflammatory mediators, inflammatory lesions, and DRG cell apoptosis that were similar to that of the infected animals that were left untreated. To address the differential anti-inflammatory effects of dexamethasone and meloxicam on neuronal and myelinating cells of the peripheral nervous system (PNS), we evaluated the potential of these drugs to alter the levels of Bb-induced inflammatory mediators in rhesus DRG cell cultures and primary human Schwann cells (HSC), using multiplex enzyme-linked immunosorbent assays (ELISA). We also ascertained the ability of these drugs to modulate cell death as induced by live Bb in HSC using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay and the potential of dexamethasone to modulate Bb-induced apoptosis in HSC by the TUNEL assay. Earlier, we reported that dexamethasone significantly reduced Bb-induced immune mediators and apoptosis in rhesus DRG cell cultures. Here, we report that dexamethasone but not meloxicam significantly reduces the levels of several cytokines and chemokines as induced by live Bb, in HSC and DRG cell cultures. Further, meloxicam does not significantly alter Bb-induced cell death in HSC, while dexamethasone protects HSC against Bb-induced cell death. These data

  2. Activation-Induced Cytidine Deaminase Links Ovulation-Induced Inflammation and Serous Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Stav Sapoznik

    2016-02-01

    Full Text Available In recent years, the notion that ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs has gained evidence. However, the mechanistic pathway for this process has not been revealed yet. In the current study, we propose the mutator protein activation-induced cytidine deaminase (AID as a link between ovulation-induced inflammation in FTECs and genotoxic damage leading to ovarian carcinogenesis. We show that AID, previously shown to be functional only in B lymphocytes, is expressed in FTECs under physiological conditions, and is induced in vitro upon ovulatory-like stimulation and in vivo in carcinoma-associated FTECs. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs. Overall, our data provides new insights into the etiology of ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early detection.

  3. Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism

    OpenAIRE

    Yang, Rui; Chen, Wei; Lu, Ye; Li, Yingke; Du, Hongli; Gao, Songyan; Dong, Xin; Yuan, Hongbin

    2017-01-01

    Sepsis, in addition to causing fatality, is an independent risk factor for cognitive impairment among sepsis survivors. The pathologic mechanism of endotoxemia induced acute neuro-inflammation still has not been fully understood. For the first time, we found the disruption of neurotransmitters 5-HT, impaired neurogenesis and activation of astrocytes coupled with concomitant neuro-inflammation were the potential pathogenesis of endotoxemia induced acute neuro-inflammation in sepsis survivors. ...

  4. Omega-3 Fatty Acid Intervention Suppresses Lipopolysaccharide-Induced Inflammation and Weight Loss in Mice

    Directory of Open Access Journals (Sweden)

    Ying-Hua Liu

    2015-02-01

    Full Text Available Bacterial endotoxin lipopolysaccharide (LPS-induced sepsis is a critical medical condition, characterized by a severe systemic inflammation and rapid loss of muscle mass. Preventive and therapeutic strategies for this complex disease are still lacking. Here, we evaluated the effect of omega-3 (n-3 polyunsaturated fatty acid (PUFA intervention on LPS-challenged mice with respect to inflammation, body weight and the expression of Toll-like receptor 4 (TLR4 pathway components. LPS administration induced a dramatic loss of body weight within two days. Treatment with n-3 PUFA not only stopped loss of body weight but also gradually reversed it back to baseline levels within one week. Accordingly, the animals treated with n-3 PUFA exhibited markedly lower levels of inflammatory cytokines or markers in plasma and tissues, as well as down-regulation of TLR4 pathway components compared to animals without n-3 PUFA treatment or those treated with omega-6 PUFA. Our data demonstrate that n-3 PUFA intervention can suppress LPS-induced inflammation and weight loss via, at least in part, down-regulation of pro-inflammatory targets of the TLR4 signaling pathway, and highlight the therapeutic potential of n-3 PUFA in the management of sepsis.

  5. TIM-3 is not essential for development of airway inflammation induced by house dust mite antigens

    Directory of Open Access Journals (Sweden)

    Yoshihisa Hiraishi

    2016-10-01

    Conclusions: Our findings indicate that, in mice, TIM-3 is not essential for development of HDM-induced acute or chronic allergic airway inflammation, although it appears to be involved in reduced lymphocyte recruitment during HDM-induced chronic allergic airway inflammation.

  6. Bacillus licheniformis in geogenic dust induces inflammation in respiratory epithelium.

    Science.gov (United States)

    Pickering, Janessa; Teo, Teck Hui; Thornton, Ruth B; Kirkham, Lea-Ann; Zosky, Graeme R; Clifford, Holly D

    2018-07-01

    Exposure to environmental geogenic (or earth-derived) dust can lead to more frequent and severe infections in the human airway. Particulate matter Bacillus licheniformis, a spore-forming, environmentally abundant bacterium. We next investigated the interaction of B. licheniformis with respiratory epithelium in vitro to determine whether this exacerbated infection with a bacterial respiratory pathogen (non-typeable Haemophilus influenzae, NTHi). Heat treatment (100 °C) of all PM 10 samples eliminated B. licheniformis contamination and reduced epithelial inflammatory responses, suggesting that heat-labile and/or microbial factors were involved in the host response to geogenic dust PM 10 . We then exposed NuLi-1 epithelium to increasing doses of the isolated Bacillus licheniformis (multiplicity of infection of 10:1, 1:1 or 0.1:1 bacteria: cells) for 1, 3, and 24 h. B. licheniformis and NTHi infection (association and invasion) was assessed using a standard gentamicin survival assay, and epithelial release of IL-6 and IL-8 was measured using a bead based immunoassay. B. licheniformis was cytotoxic to NuLi-1 cells at 24 h. At 3 h post-challenge, B. licheniformis elicited high IL-6 and IL-8 inflammatory responses from NuLi-1 cells compared with cells treated with heat-treated geogenic dust PM 10 (p licheniformis increased inflammation, this did not make the cells more susceptible to NTHi infection. This study highlights that geogenic dust PM 10 can harbour viable bacterial spores that induce inflammation in respiratory epithelium. The impact on respiratory health from inhalation of bacterial spores in PM 10 in arid environments may be underestimated. Further investigation into the contribution of B. licheniformis and the wider dust microbiome to respiratory infection is warranted. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Didecyldimethylammonium chloride induces pulmonary inflammation and fibrosis in mice.

    Science.gov (United States)

    Ohnuma, Aya; Yoshida, Toshinori; Tajima, Haruka; Fukuyama, Tomoki; Hayashi, Koichi; Yamaguchi, Satoru; Ohtsuka, Ryoichi; Sasaki, Junya; Fukumori, Junko; Tomita, Mariko; Kojima, Sayuri; Takahashi, Naofumi; Takeuchi, Yukiko; Kuwahara, Maki; Takeda, Makio; Kosaka, Tadashi; Nakashima, Nobuaki; Harada, Takanori

    2010-11-01

    Didecyldimethylammonium chloride (DDAC) is used worldwide as a germicide, in antiseptics, and as a wood preservative, and can cause adverse pulmonary disease in humans. However, the pulmonary toxicity of DDAC has not yet been thoroughly investigated. Mice were intratracheally instilled with DDAC to the lung and the bronchoalveolar lavage (BAL) fluid and lung tissues were collected to assess dose- and time-related pulmonary injury. Exposure to 1500 μg/kg of DDAC caused severe morbidity with pulmonary congestive oedema. When the BAL fluid from survivors was examined on day 3 after treatment, exposure to 150 μg/kg of DDAC caused weakly induced inflammation, and exposure to 15μg/kg did not cause any visible effects. Next, we observed pulmonary changes that occurred up to day 20 after 150 μg/kg of DDAC exposure. Pulmonary inflammation peaked on day 7 and was confirmed by expression of interleukin-6, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, and regulated upon activation, normal T-cell expressed and secreted in the BAL fluid; these changes were accompanied by altered gene expression of their chemokine (C-C motif) receptor (Ccr) 1, Ccr2, Ccr3, and Ccr5. Cytotoxicity evoked by DDAC was related to the inflammatory changes and was confirmed by an in vitro study using isolated mouse lung fibroblasts. The inflammatory phase was accompanied or followed by pulmonary remodeling, i.e., fibrosis, which was evident in the mRNA expression of type I procollagen. These results suggest that administering DDAC by intratracheal instillation causes pulmonary injury in mice, and occupational exposure to DDAC might be a potential hazard to human health. Copyright © 2009 Elsevier GmbH. All rights reserved.

  8. Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial

    DEFF Research Database (Denmark)

    Roager, Henrik Munch; Vogt, Josef Korbinian; Kristensen, Mette

    2017-01-01

    .0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did...

  9. Impact of lipopolysaccharide-induced acute inflammation on baroreflex-controlled sympathetic arterial pressure regulation.

    Science.gov (United States)

    Tohyama, Takeshi; Saku, Keita; Kawada, Toru; Kishi, Takuya; Yoshida, Keimei; Nishikawa, Takuya; Mannoji, Hiroshi; Kamada, Kazuhiro; Sunagawa, Kenji; Tsutsui, Hiroyuki

    2018-01-01

    Lipopolysaccharide (LPS) induces acute inflammation, activates sympathetic nerve activity (SNA) and alters hemodynamics. Since the arterial baroreflex is a negative feedback system to stabilize arterial pressure (AP), examining the arterial baroreflex function is a prerequisite to understanding complex hemodynamics under LPS challenge. We investigated the impact of LPS-induced acute inflammation on SNA and AP regulation by performing baroreflex open-loop analysis. Ten anesthetized Sprague-Dawley rats were used. Acute inflammation was induced by an intravenous injection of LPS (60 μg/kg). We isolated the carotid sinuses from the systemic circulation and controlled carotid sinus pressure (CSP) by a servo-controlled piston pump. We matched CSP to AP to establish the baroreflex closed-loop condition, whereas we decoupled CSP from AP to establish the baroreflex open-loop condition and changed CSP stepwise to evaluate the baroreflex open-loop function. We recorded splanchnic SNA and hemodynamic parameters under baroreflex open- and closed-loop conditions at baseline and at 60 and 120 min after LPS injection. In the baroreflex closed-loop condition, SNA continued to increase after LPS injection, reaching three-fold the baseline value at 120 min (baseline: 94.7 ± 3.6 vs. 120 min: 283.9 ± 31.9 a.u.). In contrast, AP increased initially (until 75 min), then declined to the baseline level. In the baroreflex open-loop condition, LPS reset the neural arc (CSP-SNA relationship) upward to higher SNA, while shifted the peripheral arc (SNA-AP relationship) downward at 120 min after the injection. As a result, the operating point determined by the intersection between function curves of neural arc and peripheral arc showed marked sympatho-excitation without substantial changes in AP. LPS-induced acute inflammation markedly increased SNA via resetting of the baroreflex neural arc, and suppressed the peripheral arc. The balance between the augmented neural arc and suppressed

  10. Why sickness hurts: A central mechanism for pain induced by peripheral inflammation.

    Science.gov (United States)

    Karshikoff, B; Jensen, K B; Kosek, E; Kalpouzos, G; Soop, A; Ingvar, M; Olgart Höglund, C; Lekander, M; Axelsson, J

    2016-10-01

    Low-grade systemic inflammation has been implicated in chronic pain, as well as in comorbid diseases like depression and fatigue. We have previously shown that women's pain perception and regulation is more affected by systemic inflammation than that of men. Here we investigated the neural substrates underlying these effects using an fMRI paradigm previously employed in a clinical population. Fifty-one participants (29 women) were injected with 0.6ng/kg lipopolysaccharide (LPS) or saline to induce a peripheral inflammatory response. The subjects were then tested with a pressure pain fMRI paradigm designed to capture descending pain inhibitory activity 2h after injection, and blood was sampled for cytokine analysis. The subjects injected with LPS became more pain sensitive compared to the placebo group, and the heightened pain sensitivity was paralleled by decreased activity in the ventrolateral prefrontal cortex and the rostral anterior cingulate cortex (rACC) compared to placebo; areas involved in descending pain regulation. The LPS group also had higher activity in the anterior insular cortex, an area underpinning affective and interoceptive pain processing. Women displayed overall less pain-evoked rACC activity compared to men, which may have rendered women less resilient to immune provocation, possibly explaining sex differences in LPS-induced pain sensitivity. Our findings elucidate the pain-related brain circuits affected by experimental peripheral inflammation, strengthening the theoretical link between systemic inflammation and weakened pain regulation in chronic pain disorders. The results further suggest a possible mechanism underlying the female predominance in many chronic pain disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Models of Inflammation: Carrageenan- or Complete Freund's Adjuvant (CFA)-Induced Edema and Hypersensitivity in the Rat.

    Science.gov (United States)

    McCarson, Kenneth E

    2015-09-01

    Animal models of inflammation are used to assess the production of inflammatory mediators at sites of inflammation, the processing of pain sensation at CNS sites, the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), and the efficacy of putative analgesic compounds in reversing cutaneous hypersensitivity. Detailed in this unit are methods to elicit and measure carrageenan- and complete Freund's adjuvant (CFA)-induced cutaneous inflammation. Due to possible differences between the dorsal root sensory system and the trigeminal sensory system, injections into either the footpad or vibrissal pad are described. In this manner, cutaneous inflammation can be assessed in tissue innervated by the lumbar dorsal root ganglion neurons (footpad) or by the trigeminal ganglion neurons (vibrissal pad). Copyright © 2015 John Wiley & Sons, Inc.

  12. Intermittent Hypoxia-Induced Spinal Inflammation Impairs Respiratory Motor Plasticity by a Spinal p38 MAP Kinase-Dependent Mechanism.

    Science.gov (United States)

    Huxtable, Adrianne G; Smith, Stephanie M C; Peterson, Timothy J; Watters, Jyoti J; Mitchell, Gordon S

    2015-04-29

    Inflammation is characteristic of most clinical disorders that challenge the neural control of breathing. Since inflammation modulates neuroplasticity, we studied the impact of inflammation caused by prolonged intermittent hypoxia on an important form of respiratory plasticity, acute intermittent hypoxia (three, 5 min hypoxic episodes, 5 min normoxic intervals) induced phrenic long-term facilitation (pLTF). Because chronic intermittent hypoxia elicits neuroinflammation and pLTF is undermined by lipopolysaccharide-induced systemic inflammation, we hypothesized that one night of intermittent hypoxia (IH-1) elicits spinal inflammation, thereby impairing pLTF by a p38 MAP kinase-dependent mechanism. pLTF and spinal inflammation were assessed in anesthetized rats pretreated with IH-1 (2 min hypoxia, 2 min normoxia; 8 h) or sham normoxia and allowed 16 h for recovery. IH-1 (1) transiently increased IL-6 (1.5 ± 0.2-fold; p = 0.02) and inducible nitric oxide synthase (iNOS) (2.4 ± 0.4-fold; p = 0.01) mRNA in cervical spinal homogenates, (2) elicited a sustained increase in IL-1β mRNA (2.4 ± 0.2-fold; p e.g., sleep apnea, apnea of prematurity, spinal injury, or motor neuron disease). Copyright © 2015 the authors 0270-6474/15/356871-10$15.00/0.

  13. Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation

    OpenAIRE

    Eunsun Jung; Jung-A Lee; Seoungwoo Shin; Kyung-Baeg Roh; Jang-Hyun Kim; Deokhoon Park

    2013-01-01

    Madecassoside (MA), a pentacyclic triterpene isolated from Centella asitica (L.), is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV)-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and mel...

  14. Systemic inflammation alters satellite glial cell function and structure. A possible contribution to pain.

    Science.gov (United States)

    Blum, E; Procacci, P; Conte, V; Hanani, M

    2014-08-22

    Local peripheral injury activates satellite glial cells (SGCs) in sensory ganglia, which may contribute to chronic pain. We hypothesized that systemic inflammation affects sensory ganglia like local injury. We induced systemic inflammation in mice by injecting lipopolysaccharide (LPS) intraperitoneally, and characterized SGCs and neurons in dorsal root ganglia (DRG), using dye injection, calcium imaging, electron microscopy (EM), immunohistochemistry, and electrical recordings. Several days post-LPS, SGCs were activated, and dye coupling among SGCs increased 3-4.5-fold. EM showed abnormal growth of SGC processes and the formation of new gap junctions. Sensitivity of SGCs to ATP increased twofold, and neuronal excitability was augmented. Blocking gap junctions reduced pain behavior in LPS-treated mice. Thus, changes in DRG due to systemic inflammation are similar to those due to local injury, which may explain the pain in sickness behavior and in other systemic diseases. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Therapeutic effects of systemic vitamin k2 and vitamin d3 on gingival inflammation and alveolar bone in rats with experimentally induced periodontitis.

    Science.gov (United States)

    Aral, Kübra; Alkan, Banu Arzu; Saraymen, Recep; Yay, Arzu; Şen, Ahmet; Önder, Gözde Özge

    2015-05-01

    The synergistic effects of vitamin D3 and vitamin K2 on bone loss prevention have been reported. This study evaluates the effects of vitamin D3 and vitamin K2 supplementation in conjunction with conventional periodontal therapy (scaling and root planing [SRP]) on gingival interleukin (IL)-1β and IL-10, serum bone alkaline phosphatase (B-ALP) and tartrate-resistant acid phosphatase 5b (TRAP-5b), and calcium and alveolar bone levels in rats with experimentally induced periodontitis. Seventy-two rats were divided into the following groups: 1) healthy; 2) periodontitis; 3) SRP; 4) SRP + vitamin D3; 5) SRP + vitamin K2; and 6) SRP + vitamins K2 and D3. Periodontitis was induced by ligature placement for 7 days, and vitamin K2 (30 mg/kg) and/or vitamin D3 (2 μg/kg) were administered for 10 days in the SRP + vitamin D3, SRP + vitamin K2, and SRP + vitamins K2 and D3 groups by oral gavage. On day 18, the animals were sacrificed, serum B-ALP, TRAP-5b, and calcium levels were measured, gingiva specimens were extracted for IL-1β and IL-10 analysis, and distances between the cemento-enamel junction and alveolar bone crest were evaluated. Alveolar bone levels in the periodontitis group were significantly greater than those in the other five groups. No significant differences were found in gingival IL-1β and IL-10, serum B-ALP and TRAP-5b, and calcium and alveolar bone levels between the groups receiving SRP and vitamins and the group receiving SRP alone. Within the limitations of this study, vitamin D3 and K2 alone or in combination did not affect gingival IL-1β and IL-10, serum B-ALP and TRAP-5b levels, or alveolar bone compared with conventional periodontal therapy alone.

  16. Human endotoxemia as a model of systemic inflammation

    DEFF Research Database (Denmark)

    Krabbe, K.S.; Krogh-Madsen, R.; Taudorf, S.

    2008-01-01

    Systemic inflammation is a pathogenetic component in a vast number of acute and chronic diseases such as sepsis, trauma, type 2 diabetes, atherosclerosis, and Alzheimer's disease, all of which are associated with a substantial morbidity and mortality. However, the molecular mechanisms...... and physiological significance of the systemic inflammatory response are still not fully understood. The human endotoxin model, an in vivo model of systemic inflammation in which lipopolysaccharide is injected or infused intravenously in healthy volunteers, may be helpful in unravelling these issues. The present...

  17. Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation

    NARCIS (Netherlands)

    Daemen, M. A.; van 't Veer, C.; Denecker, G.; Heemskerk, V. H.; Wolfs, T. G.; Clauss, M.; Vandenabeele, P.; Buurman, W. A.

    1999-01-01

    Ischemia followed by reperfusion leads to severe organ injury and dysfunction. Inflammation is considered to be the most important cause of tissue injury in organs subjected to ischemia. The mechanism that triggers inflammation and organ injury after ischemia remains to be elucidated, although

  18. Intestinal parasites : associations with intestinal and systemic inflammation

    NARCIS (Netherlands)

    Zavala, Gerardo A; García, Olga P; Camacho, Mariela; Ronquillo, Dolores; Campos-Ponce, Maiza; Doak, Colleen; Polman, Katja; Rosado, Jorge L

    2018-01-01

    AIMS: Evaluate associations between intestinal parasitic infection with intestinal and systemic inflammatory markers in school-aged children with high rates of obesity. METHODS AND RESULTS: Plasma concentrations of CRP, leptin, TNF-α, IL-6 and IL-10 were measured as systemic inflammation markers and

  19. Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation.

    Science.gov (United States)

    Desai, Harsh R; Sivasubramaniyam, Tharini; Revelo, Xavier S; Schroer, Stephanie A; Luk, Cynthia T; Rikkala, Prashanth R; Metherel, Adam H; Dodington, David W; Park, Yoo Jin; Kim, Min Jeong; Rapps, Joshua A; Besla, Rickvinder; Robbins, Clinton S; Wagner, Kay-Uwe; Bazinet, Richard P; Winer, Daniel A; Woo, Minna

    2017-08-09

    During obesity, macrophages can infiltrate metabolic tissues, and contribute to chronic low-grade inflammation, and mediate insulin resistance and diabetes. Recent studies have elucidated the metabolic role of JAK2, a key mediator downstream of various cytokines and growth factors. Our study addresses the essential role of macrophage JAK2 in the pathogenesis to obesity-associated inflammation and insulin resistance. During high-fat diet (HFD) feeding, macrophage-specific JAK2 knockout (M-JAK2 -/- ) mice gained less body weight compared to wildtype littermate control (M-JAK2 +/+ ) mice and were protected from HFD-induced systemic insulin resistance. Histological analysis revealed smaller adipocytes and qPCR analysis showed upregulated expression of some adipogenesis markers in visceral adipose tissue (VAT) of HFD-fed M-JAK2 -/- mice. There were decreased crown-like structures in VAT along with reduced mRNA expression of some macrophage markers and chemokines in liver and VAT of HFD-fed M-JAK2 -/- mice. Peritoneal macrophages from M-JAK2 -/- mice and Jak2 knockdown in macrophage cell line RAW 264.7 also showed lower levels of chemokine expression and reduced phosphorylated STAT3. However, leptin-dependent effects on augmenting chemokine expression in RAW 264.7 cells did not require JAK2. Collectively, our findings show that macrophage JAK2 deficiency improves systemic insulin sensitivity and reduces inflammation in VAT and liver in response to metabolic stress.

  20. Inflammatory bowel disease: a model of chronic inflammation-induced cancer.

    Science.gov (United States)

    Yang, Guang-Yu; Taboada, Sofia; Liao, Jie

    2009-01-01

    Chronic inflammation is a well-recognized risk factor for the development of human cancer. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a typical longstanding inflammatory disease of the colon with increased risk for the development of colorectal carcinoma. Several molecular events involved in chronic inflammatory process may contribute to multistage progression of human cancer development, including the overproduction of reactive oxygen and nitrogen species, overproduction/activation of key arachidonic acid metabolites and cytokines/growth factors, and immunity system dysfunction. Multiple animal models of IBD have been established, and in general, these models can be mainly categorized into chemically induced, genetically engineered (transgenic or gene knock-out), spontaneous, and adoptive transferring animal models. This chapter mainly focuses on (1) epidemiologic and molecular evidence on IBD and risk of colorectal cancer, (2) molecular pathogenesis of IBD-induced carcinogenesis, and (3) modeling of IBD-induced carcinogenesis in rodents and its application.

  1. Exosomes from Human Dental Pulp Stem Cells Suppress Carrageenan-Induced Acute Inflammation in Mice.

    Science.gov (United States)

    Pivoraitė, Ugnė; Jarmalavičiūtė, Akvilė; Tunaitis, Virginijus; Ramanauskaitė, Giedrė; Vaitkuvienė, Aida; Kašėta, Vytautas; Biziulevičienė, Genė; Venalis, Algirdas; Pivoriūnas, Augustas

    2015-10-01

    The primary goal of this study was to examine the effects of human dental pulp stem cell-derived exosomes on the carrageenan-induced acute inflammation in mice. Exosomes were purified by differential ultracentrifugation from the supernatants of stem cells derived from the dental pulp of human exfoliated deciduous teeth (SHEDs) cultivated in serum-free medium. At 1 h post-carrageenan injection, exosomes derived from supernatants of 2 × 10(6) SHEDs were administered by intraplantar injection to BALB/c mice; 30 mg/kg of prednisolone and phosphate-buffered saline (PBS) were used as positive and negative controls, respectively. Edema was measured at 6, 24, and 48 h after carrageenan injection. For the in vivo imaging experiments, AngioSPARK750, Cat B 750 FAST, and MMPSense 750 FAST were administered into the mouse tail vein 2 h post-carrageenan injection. Fluorescence images were acquired at 6, 24, and 48 h after edema induction by IVIS Spectrum in vivo imaging system. Exosomes significantly reduced the carrageenan-induced edema at all the time points studied (by 39.5, 41.6, and 25.6% at 6, 24, and 48 h after injection, respectively), to similar levels seen with the positive control (prednisolone). In vivo imaging experiments revealed that, both exosomes and prednisolone suppress activities of cathepsin B and matrix metalloproteinases (MMPs) at the site of carrageenan-induced acute inflammation, showing more prominent effects of prednisolone at the early stages, while exosomes exerted their suppressive effects gradually and at later time points. Our study demonstrates for the first time that exosomes derived from human dental pulp stem cells suppress carrageenan-induced acute inflammation in mice.

  2. Intraluminal Flagellin Differentially Contributes to Gut Dysbiosis and Systemic Inflammation following Burn Injury.

    Directory of Open Access Journals (Sweden)

    Logan Grimes

    Full Text Available Burn injury is associated with a loss of gut barrier function, resulting in systemic dissemination of gut-derived bacteria and their products. The bacterial protein and TLR5 agonist, flagellin, induces non-specific innate immune responses. Because we detected flagellin in the serum of burn patients, we investigated whether gut-derived flagellin was a primary or secondary contributor to intestinal dysfunction and systemic inflammation following burn injury. The apical surface of polarized human intestinal epithelial cells (IECs, Caco-2BBe, were exposed to 50 or 500 ng of purified flagellin and 1 x 105 of an intestinal E. coli (EC isolate as follows: 1 flagellin added 30 min prior to EC, 2 flagellin and EC added simultaneously, or 3 EC added 30 min prior to flagellin. Our results showed that luminal flagellin and EC modulated each other's biological actions, which influenced their ability to induce basolateral secretion of inflammatory cytokines and subsequent translocation of bacteria and their products. A low dose of flagellin accompanied by an enteric EC in the lumen, tempered inflammation in a dose- and time-dependent manner. However, higher doses of flagellin acted synergistically with EC to induce both intestinal and systemic inflammation that compromised barrier integrity, increasing systemic inflammation following burn injury, a process we have termed flagellemia. In a murine model of burn injury we found that oral gavage of flagellin (1 μg/mouse significantly affected the gut microbiome after burn injury. In these mice, flagellin disseminated out of the intestine into the serum and to distal organs (mesenteric lymph nodes and lungs where it induced secretion of monocyte chemoattractant protein (MCP-1 and CXCL1/KC (mouse equivalent of human IL-8 at 24 and 48h post-burn. Our results illustrated that gut-derived flagellin alone or accompanied by a non-pathogenic enteric EC strain can function as an initiator of luminal and systemic

  3. Critical role of aldehydes in cigarette smoke-induced acute airway inflammation

    NARCIS (Netherlands)

    van der Toorn, Marco; Slebos, Dirk-Jan; de Bruin, Harold G.; Gras, Renee; Rezayat, Delaram; Jorge, Lucie; Sandra, Koen; van Oosterhout, Antoon J. M.

    2013-01-01

    Background: Cigarette smoking (CS) is the most important risk factor for COPD, which is associated with neutrophilic airway inflammation. We hypothesize, that highly reactive aldehydes are critical for CS-induced neutrophilic airway inflammation. Methods: BALB/c mice were exposed to CS, water

  4. Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus

    NARCIS (Netherlands)

    The, F. O.; Bennink, R. J.; Ankum, W. M.; Buist, M. R.; Busch, O. R. C.; Gouma, D. J.; van der Heide, S.; van den Wijngaard, R. M.; de Jonge, W. J.; Boeckxstaens, G. E.

    2008-01-01

    Background: Murine postoperative ileus results from intestinal inflammation triggered by manipulation-induced mast cell activation. As its extent depends on the degree of handling and subsequent inflammation, it is hypothesised that the faster recovery after minimal invasive surgery results from

  5. Intestinal handling-induced mast cell activation and inflammation in human postoperative ileus

    NARCIS (Netherlands)

    The, F. O.; Bennink, R. J.; Ankum, W. M.; Buist, M. R.; Busch, O. R. C.; Gouma, D. J.; Van der Heide, S.; van den Wijngaard, R. M.; Boeckxstaens, G. E.; de Jonge, Wouter J.

    Background: Murine postoperative ileus results from intestinal inflammation triggered by manipulation-induced mast cell activation. As its extent depends on the degree of handling and subsequent inflammation, it is hypothesised that the faster recovery after minimal invasive surgery results from

  6. Green tea polyphenols avert chronic inflammation-induced myocardial fibrosis of female rats

    Science.gov (United States)

    Objective: Green tea proposes anti-inflammatory properties which may attenuate chronic inflammation-induced fibrosis of vessels. This study evaluated whether green tea polyphenols (GTP) can avert fibrosis or vascular disruption along with mechanisms in rats with chronic inflammation. Treatments: Fo...

  7. Chemokines and chemokine receptors in inflammation of the nervous system

    DEFF Research Database (Denmark)

    Huang, D; Han, Yong-Chang; Rani, M R

    2000-01-01

    This article focuses on the production of chemokines by resident glial cells of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as seen in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis...... (MS) and post-traumatic inflammation. We provide evidence that chemokines play a role in amplifying the inflammatory reaction in EAE (and, probably, MS). In the context of neural trauma, chemokines appear to be primary stimuli for leukocyte recruitment. Strikingly, expression of monocyte...... that produce aggregates of simultaneous stimuli. These characteristics, in turn, mirror the expression patterns of the endogenous genes: MCP-1 is expressed under a variety of circumstances, while IP-10 appears primarily during immune-mediated processes that feature exposure of resident neuroglia to high levels...

  8. Endothelial Semaphorin 7A Promotes Inflammation in Seawater Aspiration-Induced Acute Lung Injury

    Directory of Open Access Journals (Sweden)

    Minlong Zhang

    2014-10-01

    Full Text Available Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI. Although several studies have shown that Semaphorin 7A (SEMA7A promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague–Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease.

  9. Endothelial Semaphorin 7A promotes inflammation in seawater aspiration-induced acute lung injury.

    Science.gov (United States)

    Zhang, Minlong; Wang, Li; Dong, Mingqing; Li, Zhichao; Jin, Faguang

    2014-10-28

    Inflammation is involved in the pathogenesis of seawater aspiration-induced acute lung injury (ALI). Although several studies have shown that Semaphorin 7A (SEMA7A) promotes inflammation, there are limited reports regarding immunological function of SEMA7A in seawater aspiration-induced ALI. Therefore, we investigated the role of SEMA7A during seawater aspiration-induced ALI. Male Sprague-Dawley rats were underwent seawater instillation. Then, lung samples were collected at an indicated time for analysis. In addition, rat pulmonary microvascular endothelial cells (RPMVECs) were cultured and then stimulated with 25% seawater for indicated time point. After these treatments, cells samples were collected for analysis. In vivo, seawater instillation induced lung histopathologic changes, pro-inflammation cytokines release and increased expression of SEMA7A. In vitro, seawater stimulation led to pro-inflammation cytokine release, cytoskeleton remodeling and increased monolayer permeability in pulmonary microvascular endothelial cells. In addition, knockdown of hypoxia-inducible factor (HIF)-1α inhibited the seawater induced increase expression of SEMA7A. Meanwhile, knockdown of SEMA7A by specific siRNA inhibited the seawater induced aberrant inflammation, endothelial cytoskeleton remodeling and endothelial permeability. These results suggest that SEMA7A is critical in the development of lung inflammation and pulmonary edema in seawater aspiration-induced ALI, and may be a therapeutic target for this disease.

  10. Immunosuppression after Sepsis: Systemic Inflammation and Sepsis Induce a Loss of Naïve T-Cells but No Enduring Cell-Autonomous Defects in T-Cell Function

    Science.gov (United States)

    Markwart, Robby; Condotta, Stephanie A.; Requardt, Robert P.; Borken, Farina; Schubert, Katja; Weigel, Cynthia; Bauer, Michael; Griffith, Thomas S.; Förster, Martin; Brunkhorst, Frank M.; Badovinac, Vladimir P.; Rubio, Ignacio

    2014-01-01

    Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4+/CD8+ T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells. PMID:25541945

  11. Innervation changes induced by inflammation of the rat thoracolumbar fascia.

    Science.gov (United States)

    Hoheisel, U; Rosner, J; Mense, S

    2015-08-06

    Recently, the fascia innervation has become an important issue, particularly the existence of nociceptive fibers. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, nothing is known about possible changes of the fascia innervation under pathological circumstances. This question is important, because theoretically pain from the fascia cannot only be due to increased nociceptor discharges, but also to a denser innervation of the fascia by nociceptive endings. In this histological study, an inflammation was induced in the thoracolumbar fascia (TLF) of rats and the innervation by various fiber types compared between the inflamed and intact TLF. Although the TLF is generally considered to have proprioceptive functions, no corpuscular proprioceptors (Pacini and Ruffini corpuscles) were found. To obtain quantitative data, the length of fibers and free nerve endings were determined in the three layers of the rat TLF: inner layer (IL, adjacent to the multifidus muscle), middle layer (ML) and outer layer (OL). The main results were that the overall innervation density showed little change; however, there were significant changes in some of the layers. The innervation density was significantly decreased in the OL, but this change was partly compensated for by an increase in the IL. The density of substance P (SP)-positive - presumably nociceptive - fibers was significantly increased. In contrast, the postganglionic sympathetic fibers were significantly decreased. In conclusion, the inflamed TLF showed an increase of presumably nociceptive fibers, which may explain the pain from a pathologically altered fascia. The meaning of the decreased innervation by sympathetic fibers is obscure at present. The lack of proprioceptive corpuscular receptors within the TLF does not preclude its role as a proprioceptive structure, because some of the free nerve endings may function as proprioceptors. Copyright © 2015 IBRO. Published

  12. Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance

    OpenAIRE

    Brenachot, Xavier; Ramadori, Giorgio; Ioris, Rafael M.; Veyrat-Durebex, Christelle; Altirriba, Jordi; Aras, Ebru; Ljubicic, Sanda; Kohno, Daisuke; Fabbiano, Salvatore; Clement, Sophie; Goossens, Nicolas; Trajkovski, Mirko; Harroch, Sheila; Negro, Francesco; Coppari, Roberto

    2017-01-01

    Obesity-induced inflammation engenders insulin resistance and type 2 diabetes mellitus (T2DM) but the inflammatory effectors linking obesity to insulin resistance are incompletely understood. Here, we show that hepatic expression of Protein Tyrosine Phosphatase Receptor Gamma (PTPR-γ) is stimulated by inflammation in obese/T2DM mice and positively correlates with indices of inflammation and insulin resistance in humans. NF-κB binds to the promoter of Ptprg and is required for inflammation-ind...

  13. STAT3 in the systemic inflammation of cancer cachexia.

    Science.gov (United States)

    Zimmers, Teresa A; Fishel, Melissa L; Bonetto, Andrea

    2016-06-01

    Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both pathological and protective functions for STAT3 in other organs during cachexia. STAT3 also contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia and the potential and perils for targeting STAT3 to reduce cachexia and prolong survival in cancer patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Madecassoside inhibits melanin synthesis by blocking ultraviolet-induced inflammation.

    Science.gov (United States)

    Jung, Eunsun; Lee, Jung-A; Shin, Seoungwoo; Roh, Kyung-Baeg; Kim, Jang-Hyun; Park, Deokhoon

    2013-12-16

    Madecassoside (MA), a pentacyclic triterpene isolated from Centella asitica (L.), is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV)-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and melanosome transfer in the co-culture system. These effects were further demonstrated by the MA-induced inhibition of protease-activated receptor-2 expression and its signaling pathway, cyclooxygenase-2, prostaglandin E2 and prostaglandin F2 alpha in keratinocytes. The clinical efficacy of MA was confirmed on artificially tanned human skin. MA significantly reduced UV-induced melanin index at 8 weeks after topical application. Overall, the study demonstrated significant benefits of MA use in the inhibition of hyperpigmentation caused by UV irradiation.

  15. Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Eunsun Jung

    2013-12-01

    Full Text Available Madecassoside (MA, a pentacyclic triterpene isolated from Centella asitica (L., is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and melanosome transfer in the co-culture system. These effects were further demonstrated by the MA-induced inhibition of protease-activated receptor-2 expression and its signaling pathway, cyclooxygenase-2, prostaglandin E2 and prostaglandin F2 alpha in keratinocytes. The clinical efficacy of MA was confirmed on artificially tanned human skin. MA significantly reduced UV-induced melanin index at 8 weeks after topical application. Overall, the study demonstrated significant benefits of MA use in the inhibition of hyperpigmentation caused by UV irradiation.

  16. Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia?

    Science.gov (United States)

    Wegner, Alexander; Elsenbruch, Sigrid; Rebernik, Laura; Roderigo, Till; Engelbrecht, Elisa; Jäger, Marcus; Engler, Harald; Schedlowski, Manfred; Benson, Sven

    2015-10-01

    A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation-induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-α and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P pain thresholds were significantly decreased in the LPS condition (all P inflammation-induced pain sensitization in both sexes.

  17. Protective role of interleukin-10 in Ozone-induced pulmonary inflammation**

    Science.gov (United States)

    Background: The mechanisms underlying ozone (03)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: We investigated the molecular mechanisms underlying interleuken-10...

  18. Meconium aspiration syndrome: a role for fetal systemic inflammation.

    Science.gov (United States)

    Lee, JoonHo; Romero, Roberto; Lee, Kyung A; Kim, Eun Na; Korzeniewski, Steven J; Chaemsaithong, Piya; Yoon, Bo Hyun

    2016-03-01

    Meconium aspiration syndrome (MAS) is a leading cause of morbidity and mortality in term infants. Meconium-stained amniotic fluid (MSAF) occurs in approximately 1 of every 7 pregnancies, but only 5% of neonates exposed to MSAF develop MAS. Why some infants exposed to meconium develop MAS while others do not is a fundamental question. Patients with MSAF have a higher frequency of intraamniotic inflammation/infection than those with clear fluid. We propose that fetal systemic inflammation is a risk factor for the development of MAS in patients with MSAF. We sought to investigate whether intraamniotic inflammation and funisitis, the histopathologic landmark of a fetal inflammatory response, predispose to MAS. A prospective cohort study was conducted from 1995 through 2009. Amniotic fluid (AF) samples (n = 1281) were collected at the time of cesarean delivery from women who delivered singleton newborns at term (gestational age ≥38 weeks). Intraamniotic inflammation was diagnosed if the AF concentration of matrix metalloproteinase-8 was >23 ng/mL. Funisitis was diagnosed by histologic examination if inflammation was present in the umbilical cord. The prevalence of MSAF was 9.2% (118/1281), and 10.2% (12/118) of neonates exposed to MSAF developed MAS. There were no significant differences in the median gestational age or umbilical cord arterial pH at birth between neonates who developed MAS and those who did not (each P > .1). Mothers whose newborns developed MAS had a higher median of AF matrix metalloproteinase-8 (456.8 vs 157.2 ng/mL, P < .05). Newborns exposed to intraamniotic inflammation had a higher rate of MAS than those who were not exposed to intraamniotic inflammation [13.0% (10/77) vs 0% (0/32), P = .03], as did those exposed to funisitis [31.3% (5/16) vs 7.3% (6/82); relative risk, 4.3; 95% confidence interval, 1.5-12.3]. Among the 89 newborns for whom both AF and placental histology were available, MAS was more common in patients with both intraamniotic

  19. The endocannabinoid system: an emerging key player in inflammation

    NARCIS (Netherlands)

    Witkamp, R.F.; Meijerink, J.

    2014-01-01

    Purpose of review: The purpose of this review is to illustrate the expanding view of the endocannabinoid system (ECS) in relation to its roles in inflammation. Recent findings: According to the formal classification, the ECS consists of two cannabinoid receptors, their endogenous fatty acid-derived

  20. Systemic inflammation decreases pain threshold in humans in vivo

    NARCIS (Netherlands)

    Goeij, M. de; Eijk, L.T.G.J. van; Vanelderen, P.; Wilder-Smith, O.H.G.; Vissers, K.C.P.; Hoeven, J.G. van der; Kox, M.; Scheffer, G.J.; Pickkers, P.

    2013-01-01

    BACKGROUND: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory

  1. Ethylene, an early marker of systemic inflammation in humans

    NARCIS (Netherlands)

    Paardekooper, L.M.; Bogaart, G. van den; Kox, M.; Dingjan, I.; Neerincx, A.H.; Bendix, M.B.; Beest, M.T.; Harren, F.J.M; Risby, T.; Pickkers, P.; Marczin, N.; Cristescu, S.M.

    2017-01-01

    Ethylene is a major plant hormone mediating developmental processes and stress responses to stimuli such as infection. We show here that ethylene is also produced during systemic inflammation in humans and is released in exhaled breath. Traces of ethylene were detected by laser spectroscopy both in

  2. Antinociception induced by galanin in anterior cingulate cortex in rats with acute inflammation.

    Science.gov (United States)

    Zhang, Meng-Lin; Fu, Feng-Hua; Yu, Long-Chuan

    2017-01-18

    The present study was performed to explore the role of galanin in nociceptive modulation in anterior cingulate cortex (ACC) of rats with acute inflammation, and the changes in galanin and galanin receptor 2 (Gal R2) expressions in rats with acute inflammation. Intra-ACC injection of galanin induced antinociception in rats with acute inflammation, the antinociceptive effects induced by galanin were attenuated significantly by intra-ACC injection of the Gal R2 antagonist M871, indicating an involvement of Gal R2 in nociceptive modulation in ACC in rats with acute inflammation. Furthermore, we found that both the galanin mRNA expression and galanin content increased significantly in ACC in rats with acute inflammation than that in normal rats. Moreover, both the mRNA levels of Gal R2 and the content of Gal R2 in ACC increased significantly in rats with acute inflammation than that in normal rats. These results demonstrated that galanin induced antinociception in ACC in rats with acute inflammation. And there were changes in the expression of galanin and Gal R2 in rats with acute inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. PM2.5-induced airway inflammation and hyperresponsiveness in NC/Nga mice.

    Science.gov (United States)

    Ogino, Keiki; Nagaoka, Kenjiro; Okuda, Tomoaki; Oka, Akira; Kubo, Masayuki; Eguchi, Eri; Fujikura, Yoshihisa

    2017-03-01

    The allergic inflammatory effects of particulate matter (PM) 2.5, collected with the cyclone system in Yokohama city in Japan, were investigated in NC/Nga mice, which are hypersensitive to mite allergens. PM2.5 with alum was injected intraperitoneally for sensitization. Five days later, 200 μg of PM2.5 in 25 μL of saline was administered to mice intranasally five times for further sensitization. On the 11th day, PM2.5 was administered as a challenge. On the 12th day, mice were examined for airway hyperresponsiveness (AHR), the bronchoalveolar lavage fluid (BALF) cell count, mRNA expression of Th 1 , Th 2 cytokines, and metallothioneins in lung tissue, and histopathology. PM2.5 increased AHR, total cell numbers including eosinophils in BALF, and mRNA levels of IL-5, IL-22, eotaxin, eotaxin 2, and metallothionein 3. In PM2.5-induced lungs, inflammation was observed around the bronchus. These results demonstrate that PM2.5 alone, collected with the cyclone system in Yokohama city in Japan, induces asthma-like airway inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1047-1054, 2017. © 2016 Wiley Periodicals, Inc.

  4. Manganese (II) induces chemical hypoxia by inhibiting HIF-prolyl hydroxylase: Implication in manganese-induced pulmonary inflammation

    International Nuclear Information System (INIS)

    Han, Jeongoh; Lee, Jong-Suk; Choi, Daekyu; Lee, Youna; Hong, Sungchae; Choi, Jungyun; Han, Songyi; Ko, Yujin; Kim, Jung-Ae; Mi Kim, Young; Jung, Yunjin

    2009-01-01

    Manganese (II), a transition metal, causes pulmonary inflammation upon environmental or occupational inhalation in excess. We investigated a potential molecular mechanism underlying manganese-induced pulmonary inflammation. Manganese (II) delayed HIF-1α protein disappearance, which occurred by inhibiting HIF-prolyl hydroxylase (HPH), the key enzyme for HIF-1α hydroxylation and subsequent von Hippel-Lindau(VHL)-dependent HIF-1α degradation. HPH inhibition by manganese (II) was neutralized significantly by elevated dose of iron. Consistent with this, the induction of cellular HIF-1α protein by manganese (II) was abolished by pretreatment with iron. Manganese (II) induced the HIF-1 target gene involved in pulmonary inflammation, vascular endothelial growth factor (VEGF), in lung carcinoma cell lines. The induction of VEGF was dependent on HIF-1. Manganese-induced VEGF promoted tube formation of HUVEC. Taken together, these data suggest that HIF-1 may be a potential mediator of manganese-induced pulmonary inflammation

  5. Cell walls of Saccharomyces cerevisiae differentially modulated innate immunity and glucose metabolism during late systemic inflammation.

    Directory of Open Access Journals (Sweden)

    Bushansingh Baurhoo

    Full Text Available BACKGROUND: Salmonella causes acute systemic inflammation by using its virulence factors to invade the intestinal epithelium. But, prolonged inflammation may provoke severe body catabolism and immunological diseases. Salmonella has become more life-threatening due to emergence of multiple-antibiotic resistant strains. Mannose-rich oligosaccharides (MOS from cells walls of Saccharomyces cerevisiae have shown to bind mannose-specific lectin of Gram-negative bacteria including Salmonella, and prevent their adherence to intestinal epithelial cells. However, whether MOS may potentially mitigate systemic inflammation is not investigated yet. Moreover, molecular events underlying innate immune responses and metabolic activities during late inflammation, in presence or absence of MOS, are unknown. METHODS AND PRINCIPAL FINDINGS: Using a Salmonella LPS-induced systemic inflammation chicken model and microarray analysis, we investigated the effects of MOS and virginiamycin (VIRG, a sub-therapeutic antibiotic on innate immunity and glucose metabolism during late inflammation. Here, we demonstrate that MOS and VIRG modulated innate immunity and metabolic genes differently. Innate immune responses were principally mediated by intestinal IL-3, but not TNF-α, IL-1 or IL-6, whereas glucose mobilization occurred through intestinal gluconeogenesis only. MOS inherently induced IL-3 expression in control hosts. Consequent to LPS challenge, IL-3 induction in VIRG hosts but not differentially expressed in MOS hosts revealed that MOS counteracted LPS's detrimental inflammatory effects. Metabolic pathways are built to elucidate the mechanisms by which VIRG host's higher energy requirements were met: including gene up-regulations for intestinal gluconeogenesis (PEPCK and liver glycolysis (ENO2, and intriguingly liver fatty acid synthesis through ATP citrate synthase (CS down-regulation and ATP citrate lyase (ACLY and malic enzyme (ME up-regulations. However, MOS host

  6. Systemic inflammation and lung function: A longitudinal analysis.

    Science.gov (United States)

    Hancox, Robert J; Gray, Andrew R; Sears, Malcolm R; Poulton, Richie

    2016-02-01

    Systemic inflammation is associated with impaired lung function in healthy adults as well as in patients with lung disease. The mechanism for this association is unknown and it is unclear if systemic inflammation leads to impaired lung function or if poor lung function leads to inflammation. We explored the temporal associations between blood C-reactive protein (CRP), fibrinogen, and white blood cells, and lung function in young adults. Spirometry, plethysmography, and diffusion capacity were measured in a population-based cohort at ages 32 and 38 years. High-sensitivity CRP, fibrinogen, and white blood cells were measured at the same ages. Higher levels of CRP and, to a lesser extent, fibrinogen were associated with lower lung volumes in cross-sectional analyses at both ages 32 and 38 years. Higher CRP and fibrinogen at age 32 were associated with higher FEV1 and FEV1/FVC at age 38, but not other measures of lung function. Lower lung volumes (total lung capacity, functional residual capacity, and residual volume) but not airflow obstruction (FEV1/FVC) at age 32 were associated with higher CRP at age 38. Associations between age 32 lung function and fibrinogen at follow-up were weaker, but consistent. There were no longitudinal associations between white blood cells and lung function. We found no evidence that systemic inflammation causes a decline in lung function. However, lower lung volumes were associated with higher CRP and fibrinogen at follow-up indicating that pulmonary restriction may be a risk factor for systemic inflammation. The mechanism for this association remains unclear. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers.

    Science.gov (United States)

    Andersen, H H; Imai, Y; Petersen, K K; Koenig, J; Elberling, J; Arendt-Nielsen, L

    2016-03-01

    This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers.

  8. Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers

    DEFF Research Database (Denmark)

    Andersen, Hjalte Holm; Imai, Yosuke; Petersen, Kristian Kjær

    2016-01-01

    This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar...... forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive...... signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers....

  9. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

    Science.gov (United States)

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong

    2015-01-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

  10. Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity.

    Science.gov (United States)

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-12-01

    Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. © 2015 Authors; published by Portland Press Limited.

  11. Eleutheroside E inhibits doxorubicin-induced inflammation and ...

    African Journals Online (AJOL)

    oxidative stress and cardiac inflammation were involved in the process [7-10]. Therefore 3- hydroxy-3-methylglutaryl coenzyme A (reductase inhibitor, which has anti-inflammatory ... (Sigma, St. Louis, MO, USA) nuclear dye (10. μM) for 5 min, the cells were washed twice with. PBS, then observed and photographed under an.

  12. Resolution of inflammation in obesity-induced liver disease

    Directory of Open Access Journals (Sweden)

    Bibiana eRius

    2012-08-01

    Full Text Available Low-grade inflammation in adipose tissue is recognized as a critical event in the development of obesity-related co-morbidities. This chronic inflammation is powerfully augmented through the infiltration of macrophages, which together with adipocytes, perpetuate a vicious cycle of inflammatory cell recruitment and secretion of free fatty acids and deleterious adipokines that predispose to greater incidence of metabolic complications. In the last decade, many factors have been identified to contribute to mounting unresolved inflammation in obese adipose tissue. Among them, pro-inflammatory lipid mediators (i.e. leukotrienes derived from the omega-6 polyunsaturated arachidonic acid have been shown to play a prominent role. Of note, the same lipid mediators that initially trigger the inflammatory response also signal its termination by stimulating the formation of anti-inflammatory signals. Resolvins and protectins derived from the omega-3 polyunsaturated docosahexaenoic and eicosapentaenoic acids have emerged as a representative family of this novel class of autacoids with dual anti-inflammatory and pro-resolving properties that act as stop signals of the inflammatory response. This review discusses the participation of these endogenous autacoids in the resolution of adipose tissue inflammation, with a special emphasis in the amelioration of obesity-related metabolic dysfunctions, namely insulin resistance and non-alcoholic fatty liver disease.

  13. Grouping nanomaterials to predict their potential to induce pulmonary inflammation

    NARCIS (Netherlands)

    Braakhuis, Hedwig M|info:eu-repo/dai/nl/371685028; Oomen, Agnes G; Cassee, Flemming R|info:eu-repo/dai/nl/143038990

    2016-01-01

    The rapidly expanding manufacturing, production and use of nanomaterials have raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in

  14. Increased hypothalamic serotonin turnover in inflammation-induced anorexia

    NARCIS (Netherlands)

    Dwarkasing, J.T.; Witkamp, R.F.; Boekschoten, M.V.; Laak, ter M.C.; Heins, M.S.; Norren, van K.

    2016-01-01

    Background: Anorexia can occur as a serious complication of disease. Increasing evidence suggests that inflammation plays a major role, along with a hypothalamic dysregulation characterized by locally elevated serotonin levels. The present study was undertaken to further explore the connections

  15. Role of Macrophage-induced Inflammation in Mesothelioma

    Science.gov (United States)

    2012-07-01

    the immune cell population during pregnancyand lactation (Watson 2009). This ple- thora of immune mediators remains a fertile area both for discovery...adipogenesis at least during obesity , through their secretion of adipocyte growth factors and matrix re- modeling molecules (Pollard 2009). However...inflammation that precedes neoplasia provides a fertile microenvironment whereby secreted growth factors, reactive oxygen species and cytokines support epithe

  16. Neuropeptide Y (NPY) promotes inflammation-induced tumorigenesis by enhancing epithelial cell proliferation.

    Science.gov (United States)

    Jeppsson, Sabrina; Srinivasan, Shanthi; Chandrasekharan, Bindu

    2017-02-01

    We have demonstrated that neuropeptide Y (NPY), abundantly produced by enteric neurons, is an important regulator of intestinal inflammation. However, the role of NPY in the progression of chronic inflammation to tumorigenesis is unknown. We investigated whether NPY could modulate epithelial cell proliferation and apoptosis, and thus regulate tumorigenesis. Repeated cycles of dextran sodium sulfate (DSS) were used to model inflammation-induced tumorigenesis in wild-type (WT) and NPY knockout (NPY -/- ) mice. Intestinal epithelial cell lines (T84) were used to assess the effects of NPY (0.1 µM) on epithelial proliferation and apoptosis in vitro. DSS-WT mice exhibited enhanced intestinal inflammation, polyp size, and polyp number (7.5 ± 0.8) compared with DSS-NPY -/- mice (4 ± 0.5, P inflammation-induced tumorigenesis by NPY-epithelial cross talk as mediated by activation of PI3-K signaling and downregulation of miR-375. Our work exemplifies a novel role of neuropeptide Y (NPY) in regulating inflammation-induced tumorigenesis via two modalities: first by enhanced proliferation (PI3-K/pAkt), and second by downregulation of microRNA-375 (miR-375)-dependent apoptosis in intestinal epithelial cells. Our data establish the existence of a microRNA-mediated cross talk between enteric neurons producing NPY and intestinal epithelial cells, and the potential of neuropeptide-regulated miRNAs as potential therapeutic molecules for the management of inflammation-associated tumors in the gut.

  17. Eupafolin nanoparticles protect HaCaT keratinocytes from particulate matter-induced inflammation and oxidative stress

    Science.gov (United States)

    Lin, Zih-Chan; Lee, Chiang-Wen; Tsai, Ming-Horng; Ko, Horng-Huey; Fang, Jia-You; Chiang, Yao-Chang; Liang, Chan-Jung; Hsu, Lee-Fen; Hu, Stephen Chu-Sung; Yen, Feng-Lin

    2016-01-01

    Exposure to particulate matter (PM), a major form of air pollution, can induce oxidative stress and inflammation and may lead to many diseases in various organ systems including the skin. Eupafolin, a flavonoid compound derived from Phyla nodiflora, has been previously shown to exhibit various pharmacological activities, including antioxidant and anti-inflammatory effects. Unfortunately, eupafolin is characterized by poor water solubility and skin penetration, which limits its clinical applications. To address these issues, we successfully synthesized a eupafolin nanoparticle delivery system (ENDS). Our findings showed that ENDS could overcome the physicochemical drawbacks of raw eupafolin with respect to water solubility and skin penetration, through reduction of particle size and formation of an amorphous state with hydrogen bonding. Moreover, ENDS was superior to raw eupafolin in attenuating PM-induced oxidative stress and inflammation in HaCaT keratinocytes, by mediating the antioxidant pathway (decreased reactive oxygen species production and nicotinamide adenine dinucleotide phosphate oxidase activity) and anti-inflammation pathway (decreased cyclooxygenase-2 expression and prostaglandin E2 production through downregulation of mitogen-activated protein kinase and nuclear factor-κB signaling). In summary, ENDS shows better antioxidant and anti-inflammatory activities than raw eupafolin through improvement of water solubility and skin penetration. Therefore, ENDS may potentially be used as a medicinal drug and/or cosmeceutical product to prevent PM-induced skin inflammation. PMID:27570454

  18. Indenes and tetralenes analogues attenuates lipopolysaccharide-induced inflammation: An in-vitro and in-vivo study.

    Science.gov (United States)

    Mohanty, Shilpa; Gautam, Yashveer; Maurya, Anil Kumar; Negi, Arvind S; Prakash, Om; Khan, Feroz; Bawankule, Dnyaneshwar Umrao

    2016-02-05

    In an effort to evaluate novel pharmacological activity of 1-chloro-2-formyl indene and tetralene analogues possessing potential antitubercular and antistaphylococcal agents, we explored its anti-inflammatory potential against lipopolysaccharide(LPS)-induced inflammation using in-vitro and in-vivo bioassay. Synthesized analogues significantly inhibited the production and expression of pro-inflammatory cytokines against LPS-induced inflammation in macrophages isolated from mice. Among all the analogues, TAF-5 (1-Chloro-2-formyl-1-tetralene) exhibited most potent anti-inflammatory activity without any cytotoxic effect. We have further evaluated the therapeutic efficacy and safety of TAF-5 in in-vivo system using LPS-induced sepsis, a systemic inflammation model and acute oral toxicity respectively in mice. Oral administration of TAF-5 inhibited the pro-inflammatory cytokines in serum, attenuated the organs injuries and improved host survival in dose dependent manner. Acute oral toxicity study showed TAF-5 is non-toxic at higher dose in mice. These results suggest the suitability of indene and tetralene analogues as new chemical entities for further investigation towards the management of inflammation related diseases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  19. The prokineticin system: an interface between neural inflammation and pain.

    Science.gov (United States)

    Franchi, Silvia; Sacerdote, Paola; Panerai, Alberto

    2017-05-01

    Prokineticins (PK) 1 and 2 belong to a new family of chemokines capable to interact with two different G coupled receptors: Prokineticin receptor (PKR)1 and 2. Both prokineticins and their receptors are widely distributed in different tissues and regulate several biological functions. In particular, a role of the PK system in inflammation and nociception has been established. PKRs are expressed in regions of the nervous system associated with pain and in primary sensitive neurons they colocalize with transient potential receptor vanilloid-TRPV1 providing an anatomical interaction in nociceptor sensitization. Moreover, PKs are strongly upregulated in immune and glial cells and sustain a proinflammatory loop in inflamed tissues. Recent evidences indicate that the block of the PK system represents a promising strategy to contrast inflammation and pain.

  20. Acute and chronic effects of treatment with mesenchymal stromal cells on LPS-induced pulmonary inflammation, emphysema and atherosclerosis development.

    Directory of Open Access Journals (Sweden)

    P Padmini S J Khedoe

    Full Text Available COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD, and current treatment of this comorbidity is suboptimal. Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD. Mesenchymal stromal cells (MSC possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases. Therefore, we investigated the immunomodulatory properties of MSC in an acute and chronic model of lipopolysaccharide (LPS-induced inflammation, emphysema and atherosclerosis development in APOE*3-Leiden (E3L mice.Hyperlipidemic E3L mice were intranasally instilled with 10 μg LPS or vehicle twice in an acute 4-day study, or twice weekly during 20 weeks Western-type diet feeding in a chronic study. Mice received 0.5x106 MSC or vehicle intravenously twice after the first LPS instillation (acute study or in week 14, 16, 18 and 20 (chronic study. Inflammatory parameters were measured in bronchoalveolar lavage (BAL and lung tissue. Emphysema, pulmonary inflammation and atherosclerosis were assessed in the chronic study.In the acute study, intranasal LPS administration induced a marked systemic IL-6 response on day 3, which was inhibited after MSC treatment. Furthermore, MSC treatment reduced LPS-induced total cell count in BAL due to reduced neutrophil numbers. In the chronic study, LPS increased emphysema but did not aggravate atherosclerosis. Emphysema and atherosclerosis development were unaffected after MSC treatment.These data show that MSC inhibit LPS-induced pulmonary and systemic inflammation in the acute study, whereas MSC treatment had no effect on inflammation, emphysema and atherosclerosis development in the chronic study.

  1. Acute and chronic effects of treatment with mesenchymal stromal cells on LPS-induced pulmonary inflammation, emphysema and atherosclerosis development.

    Science.gov (United States)

    Khedoe, P Padmini S J; de Kleijn, Stan; van Oeveren-Rietdijk, Annemarie M; Plomp, Jaap J; de Boer, Hetty C; van Pel, Melissa; Rensen, Patrick C N; Berbée, Jimmy F P; Hiemstra, Pieter S

    2017-01-01

    COPD is a pulmonary disorder often accompanied by cardiovascular disease (CVD), and current treatment of this comorbidity is suboptimal. Systemic inflammation in COPD triggered by smoke and microbial exposure is suggested to link COPD and CVD. Mesenchymal stromal cells (MSC) possess anti-inflammatory capacities and MSC treatment is considered an attractive treatment option for various chronic inflammatory diseases. Therefore, we investigated the immunomodulatory properties of MSC in an acute and chronic model of lipopolysaccharide (LPS)-induced inflammation, emphysema and atherosclerosis development in APOE*3-Leiden (E3L) mice. Hyperlipidemic E3L mice were intranasally instilled with 10 μg LPS or vehicle twice in an acute 4-day study, or twice weekly during 20 weeks Western-type diet feeding in a chronic study. Mice received 0.5x106 MSC or vehicle intravenously twice after the first LPS instillation (acute study) or in week 14, 16, 18 and 20 (chronic study). Inflammatory parameters were measured in bronchoalveolar lavage (BAL) and lung tissue. Emphysema, pulmonary inflammation and atherosclerosis were assessed in the chronic study. In the acute study, intranasal LPS administration induced a marked systemic IL-6 response on day 3, which was inhibited after MSC treatment. Furthermore, MSC treatment reduced LPS-induced total cell count in BAL due to reduced neutrophil numbers. In the chronic study, LPS increased emphysema but did not aggravate atherosclerosis. Emphysema and atherosclerosis development were unaffected after MSC treatment. These data show that MSC inhibit LPS-induced pulmonary and systemic inflammation in the acute study, whereas MSC treatment had no effect on inflammation, emphysema and atherosclerosis development in the chronic study.

  2. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Takeda-Watanabe, Ai; Kitada, Munehiro; Kanasaki, Keizo [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan); Koya, Daisuke, E-mail: koya0516@kanazawa-med.ac.jp [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer SIRT1 inactivation decreases autophagy in THP-1 cell. Black-Right-Pointing-Pointer Inhibition of autophagy induces inflammation. Black-Right-Pointing-Pointer SIRT1 inactivation induces inflammation through NF-{kappa}B activation. Black-Right-Pointing-Pointer The p62/Sqstm1 accumulation by impairment of autophagy is related to NF-{kappa}B activation. Black-Right-Pointing-Pointer SIRT1 inactivation is involved in the activation of mTOR and decreased AMPK activation. -- Abstract: Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are some of the cells involved in the inflammatory process in atherogenesis. Autophagy exerts a protective effect against cellular stresses like inflammation, and it is regulated by nutrient-sensing pathways. The nutrient-sensing pathway includes SIRT1, a NAD{sup +}-dependent histone deacetylase, which is implicated in the regulation of a variety of cellular processes including inflammation and autophagy. The mechanism through which the dysfunction of SIRT1 contributes to the regulation of inflammation in relation to autophagy in monocytes/macrophages is unclear. In the present study, we demonstrate that treatment with 2-[(2-Hydroxynaphthalen-1-ylmethylene)amino]-N-(1-phenethyl)benzamide (Sirtinol), a chemical inhibitor of SIRT1, induces the overexpression of inflammation-related genes such as tumor necrosis factor (TNF)-{alpha} and interleukin (IL)-6 through nuclear factor (NF)-{kappa}B signaling activation, which is associated with autophagy dysfunction, as shown through p62/Sqstm1 accumulation and decreased expression of light chain (LC) 3 II in THP-1 cells. The autophagy inhibitor, 3-methyladenine, also induces inflammation-related NF-{kappa}B activation. In p62/Sqstm1 knockdown cells, Sirtinol-induced inflammation through NF-{kappa}B activation is blocked. In addition, inhibition of SIRT1 is involved in the activation of the mammalian target of rapamycin (mTOR) pathway and

  3. Interplay between rumen digestive disorders and diet-induced inflammation in dairy cattle.

    Science.gov (United States)

    Zebeli, Q; Metzler-Zebeli, B U

    2012-12-01

    In this review, an overview is provided on the current achievements regarding the interplay between rumen digestive disorders and diet-induced inflammation in dairy cattle. It starts with a review of factors favoring the disturbances in the rumen metabolism, which culminate with development of sub-acute rumen acidosis (SARA). The latter digestive disorder is often linked to greater metabolic stress of gastrointestinal (GI) microbiota and lowered fiber digestion, as well as with disruption of the barrier functions of the GI epithelia, which open the route of deleterious molecules to translocate from the GI lumen into the portal system. A model is suggested to illustrate the mechanisms of the involvement of digestive disorders in the disruption of the host's inner homeostasis leading to activation of acute phase response (APR). The latter is part of multifaceted innate immune and metabolic responses of the host. According to this model, endotoxin, its toxicity, and other metabolic compounds of microbial origin are regarded as important immunogenic components of GI tract, which when favored by disruption of host barriers triggers a systemic APR. Although the activation of an APR is viewed as a protective reaction aiming to reestablish the disturbed homeostasis, the presence of inflammatory state over long periods might be associated with negative consequences for the host. The review concludes that prolonged systemic inflammation can: (1) cause significant changes in the energy and lipid metabolism in different body tissues, (2) lead to the development of refractory states associated with immune suppression and increased susceptibility to various diseases, and (3) artificially increase host's requirements in energy and nutrients, lowering the efficiency of energy and feed use by the animal. The paper emphasizes the critical role that formulation of healthy diets plays for curbing down inflammation and enhancing metabolic health of dairy cows. Copyright © 2012

  4. Systemic inflammation worsens outcomes in emergency surgical patients.

    Science.gov (United States)

    Becher, Robert D; Hoth, J Jason; Miller, Preston R; Meredith, J Wayne; Chang, Michael C

    2012-05-01

    Acute care surgeons are uniquely aware of the importance of systemic inflammatory response and its influence on postoperative outcomes; concepts like damage control have evolved from this experience. For surgeons whose practice is mostly elective, the significance of such systemic inflammation may be underappreciated. This study sought to determine the influence of preoperative systemic inflammation on postoperative outcome in patients requiring emergent colon surgery. Emergent colorectal operations were identified in the American College of Surgeons National Surgical Quality Improvement Program 2008 dataset. Four groups were defined by the presence and magnitude of the inflammatory response before operation: no inflammation, systemic inflammatory response syndrome (SIRS), sepsis, or severe sepsis/septic shock. Thirty-day survival was analyzed by Kaplan-Meier method. A total of 3,305 patients were identified. Thirty-day survival was significantly different (p emergency surgical patients. In SIRS or sepsis patients, operations surgical intervention and suggest a potential role for damage control operations in emergency general surgery. II, prognostic study.

  5. Enhanced sympathetic nerve activity induced by neonatal colon inflammation induces gastric hypersensitivity and anxiety-like behavior in adult rats.

    Science.gov (United States)

    Winston, John H; Sarna, Sushil K

    2016-07-01

    Gastric hypersensitivity (GHS) and anxiety are prevalent in functional dyspepsia patients; their underlying mechanisms remain unknown largely because of lack of availability of live visceral tissues from human subjects. Recently, we demonstrated in a preclinical model that rats subjected to neonatal colon inflammation show increased basal plasma norepinephrine (NE), which contributes to GHS through the upregulation of nerve growth factor (NGF) expression in the gastric fundus. We tested the hypothesis that neonatal colon inflammation increases anxiety-like behavior and sympathetic nervous system activity, which upregulates the expression of NGF to induce GHS in adult life. Chemical sympathectomy, but not adrenalectomy, suppressed the elevated NGF expression in the fundus muscularis externa and GHS. The measurement of heart rate variability showed a significant increase in the low frequency-to-high frequency ratio in GHS vs. the control rats. Stimulus-evoked release of NE from the fundus muscularis externa strips was significantly greater in GHS than in the control rats. Tyrosine hydroxylase expression was increased in the celiac ganglia of the GHS vs. the control rats. We found an increase in trait but not stress-induced anxiety-like behavior in GHS rats in an elevated plus maze. We concluded that neonatal programming triggered by colon inflammation upregulates tyrosine hydroxylase in the celiac ganglia, which upregulates the release of NE in the gastric fundus muscularis externa. The increase of NE release from the sympathetic nerve terminals concentration dependently upregulates NGF, which proportionately increases the visceromotor response to gastric distention. Neonatal programming concurrently increases anxiety-like behavior in GHS rats. Copyright © 2016 the American Physiological Society.

  6. Zinc oxide nanoparticles induce eosinophilic airway inflammation in mice.

    Science.gov (United States)

    Huang, Kuo-Liang; Lee, Yi-Hsin; Chen, Hau-Inh; Liao, Huang-Shen; Chiang, Bor-Luen; Cheng, Tsun-Jen

    2015-10-30

    Zinc oxide nanoparticles (ZnO NPs) have been widely used in industry. The metal composition of PM2.5 might contribute to the higher prevalence of asthma. To investigate the effects of ZnO NPs on allergic airway inflammation, mice were first exposed to different concentrations of ZnO NPs (0.1 mg/kg, 0.5 mg/kg) or to a combination of ZnO NPs and chicken egg ovalbumin (OVA) by oropharyngeal aspiration on day 0 and day 7 and then were sacrificed 5 days later. The subsequent time course of airway inflammation in the mice after ZnO NPs exposure was evaluated on days 1, 7, and 14. To further determine the role of zinc ions, ZnCl2 was also administered. The inflammatory cell count, cytokine levels in the bronchoalveolar lavage fluid (BALF), and lung histopathology were examined. We found significant neutrophilia after exposure to high-dose ZnO NPs on day 1 and significant eosinophilia in the BALF at 7 days. However, the expression levels of the T helper 2 (Th2) cytokines IL-4, IL-5, and IL-13 increased significantly after 24h of exposure to only ZnO NPs and then decreased gradually. These results suggested that ZnO NPs could cause eosinophilic airway inflammation in the absence of allergens. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Moderate glucose supply reduces hemolysis during systemic inflammation

    OpenAIRE

    Jägers J; Brauckmann S; Kirsch M; Effenberger-Neidnicht K

    2018-01-01

    Johannes Jägers,1 Stephan Brauckmann,2 Michael Kirsch,1 Katharina Effenberger-Neidnicht1,3 1Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany; 2Clinic for Anesthesiology and Intensive Care, University Hospital Essen, Essen, Germany; 3Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany Background: Systemic inflammation alters energy metabolism. A sufficient glucose level, however, is most important for erythrocytes, since erythrocy...

  8. Moderate glucose supply reduces hemolysis during systemic inflammation

    OpenAIRE

    Jägers,Johannes; Brauckmann,Stephan; Kirsch,Michael; Effenberger-Neidnicht,Katharina

    2018-01-01

    Johannes Jägers,1 Stephan Brauckmann,2 Michael Kirsch,1 Katharina Effenberger-Neidnicht1,3 1Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany; 2Clinic for Anesthesiology and Intensive Care, University Hospital Essen, Essen, Germany; 3Institute of Physiological Chemistry, University Hospital Essen, Essen, Germany Background: Systemic inflammation alters energy metabolism. A sufficient glucose level, however, is most important for erythrocytes, since eryth...

  9. Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation

    NARCIS (Netherlands)

    Pruimboom, Leo; Raison, Charles L.; Muskiet, Frits A. J.

    2015-01-01

    In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often

  10. Inhalation toxicology models of endotoxin- and bioaerosol-induced inflammation.

    Science.gov (United States)

    Thorne, P S

    2000-11-02

    Inhalation toxicology studies in rodents have proven their usefulness for furthering our understanding of the causal agents, mechanisms, and pathology associated with exposures to environmental endotoxins and bioaerosols. Inhalation animal models are used to determine which components of a mixture are the most important toxicants for inducing the observed adverse outcome. They are used to obtain exposure-response relationships for allergens and pro-inflammatory agents to help elucidate disease mechanisms and contribute quantitative data to the risk assessment process. Inhalation models serve as important adjuncts to epidemiology studies and human exposure studies. They are also useful for establishing phenotype in studies of genetic polymorphisms and disease susceptibility and are widely applied for evaluation of safety and efficacy for potential therapeutic agents. In order to produce reliable data, rigorous exposure chamber design, aerosol generation systems, exposure quantitation and experimental protocols must be utilized.

  11. Characterization and differentiation of equine experimental local and early systemic inflammation by expression responses of inflammation-related genes in peripheral blood leukocytes

    DEFF Research Database (Denmark)

    Vinther, Anne Mette L; Heegaard, Peter M. H.; Skovgaard, Kerstin

    2016-01-01

    , the aim of this study was to investigate the innate peripheral blood leukocyte (PBL) immune response to local inflammation in horses, and to compare this response with the PBL immune response during the early phase of acute systemic inflammation. Expression of 22 selected inflammation-related genes......Local inflammation may progress into systemic inflammation. To increase our understanding of the basic immunological processes during transition of equine local inflammation into a systemic state, investigation into the equine systemic immune response to local inflammation is warranted. Therefore...... in horses initiated an innate transcriptional response in PBLs, which differed from the transcriptional response during the early phase of systemic inflammation. This study may provide new insights into the immunobiology of PBLs during the transition of local inflammation into a systemic state....

  12. Acute lung inflammation in Klebsiella pneumoniae B5055-induced pneumonia and sepsis in BALB/c mice: a comparative study.

    Science.gov (United States)

    Kumar, Vijay; Chhibber, Sanjay

    2011-10-01

    Lungs play an important role in the body's defense against a variety of pathogens, but this network of immune system-mediated defense can be deregulated during acute pulmonary infections. The present study compares acute lung inflammation occurring during Klebsiella pneumoniae B5055-induced pneumonia and sepsis in BALB/c mice. Pneumonia was induced by intranasal instillation of bacteria (10(4) cfu), while sepsis was developed by placing the fibrin-thrombin clot containing known amount of bacteria (10(2) cfu) into the peritoneal cavity of animals. Mice with sepsis showed 100% mortality within five post-infection days, whereas all the animals with pneumonia survived. In animals suffering from K. pneumoniae B5055-induced pneumonia, all the inflammatory parameters (TNF-α, IL-1α, MPO, MDA, and NO) were found to be maximum till third post-infection day, after that, a decline was observed, whereas in septic animals, all the above-mentioned markers of inflammation kept on increasing. Histopathological study showed presence of alternatively activated alveolar macrophages (or foam cells) in lungs of mice with pneumonia after third post-infection day, which might have contributed to the induction of resolution of inflammation, but no such observation was made in lungs of septic mice. Hence, during pneumonia, controlled activation of macrophages may lead to resolution of inflammation.

  13. Soyabean oil supplementation effects on perivascular inflammation in lungs induced by bisphenol a: a histological study

    International Nuclear Information System (INIS)

    Shaukat, S.; Hamid, S.; Umbreen, F.

    2017-01-01

    To determine the effect of soyabean oil supplementation on perivascular inflammation in lungs of adult mice induced by Bisphenol A (BPA). Study Design: An experimental study. Place and Duration of Study: Department of Anatomy, Army Medical College, Rawalpindi, in collaboration with the Animal House, National Institute of Health, Islamabad, from June to November 2016. Methodology:Thirty male and female BALB/c mice were divided into three groups, of 10 animals each. Group A animals served as control. Group B animals were given BPA at a dose of 50 mg/Kg body weight/day. Group C animals were given BPA and soyabean oil at doses of 50 mg/Kg body weight/day and 500 mg/day, respectively. All treatments were given once daily for a period of eight weeks. Animals were dissected 24 hours after receiving the last dose. Lung tissue specimen processing and H and E staining was carried out for routine histological study. Perivascular inflammation was morphometrically graded and statistically analysed using Chi-square test with p<0.05. Results: Grade 2 inflammation was recorded in two (20%) animals and grade 3 perivascular inflammation in 80% specimens in Group B; whereas 20% specimens of Group C had grade 2 inflammation and eight (80%) showed grade 1 inflammation. None of the control animals showed any inflammation. All groups were significantly different at p<0.001. Conclusion: BPA produced perivascular inflammation and con-commitant administration of soyabean oil diet protected against it in rodent. (author)

  14. Effects of acupuncture and electroacupuncture on estradiol-induced inflammation and oxidative stress in health rodents.

    Science.gov (United States)

    Santos, Elba Lucia Wanderley; Dias, Bruno Hállan Meneses; Andrade, Ana Carolina Rodrigues de; Pascoal, Angélica Maria Holanda; Vasconcelos Filho, Francisco Eugênio de; Medeiros, Francisco das Chagas; Guimarães, Sergio Botelho

    2013-08-01

    To investigate the effects of classical acupuncture (Ac) and electroacupuncture (EAc) on estradiol-induced inflammation and oxidative stress in health rodents. Twenty-four eight-week old female rats were treated with estradiol valerate (EV) 4.0 mg i.m. single dose and randomly assigned to four groups (n=6): G1(control), G2 (Ac), G3 (EAc 2 Hz) and G4 (EAc 100 Hz). After 60 days all rats were anesthetized with chloral hydrate 10% (0.1 ml/30 g weight of the animal) and submitted to Ac/EAc for twenty minutes. The procedures were repeated on days three, five, seven and nine of the study. The equivalent of the human right ST-36 (Zusanli) and SP-6 (Sanyinjiao) acupoints were chosen for needling and electrical stimulation. On the 10th day of the experiment, all rats were anesthetized for collection of blood and tissues (ovaries) samples for biochemical analysis and histological examination. Glutathione (GSH) and malonaldehyde (MDA) concentrations increased significantly in all groups (plasma and ovary) while myeloperoxidase (MPO) activity decreased significantly in all groups compared with control group (G1). Both classical acupuncture and electroacupuncture decrease systemic and local oxidative stress and ovary inflammation in healthy rats exposed to estrogenic stimulation. EAc enhances lipid peroxidation at systemic and local levels in female rats exposed to estrogenic stimulation.

  15. Temporal Role for MyD88 in a Model of Brucella-Induced Arthritis and Musculoskeletal Inflammation.

    Science.gov (United States)

    Lacey, Carolyn A; Mitchell, William J; Brown, Charles R; Skyberg, Jerod A

    2017-03-01

    Brucella spp. are facultative intracellular Gram-negative bacteria that cause the zoonotic disease brucellosis, one of the most common global zoonoses. Osteomyelitis, arthritis, and musculoskeletal inflammation are common focal complications of brucellosis in humans; however, wild-type (WT) mice infected systemically with conventional doses of Brucella do not develop these complications. Here we report C57BL/6 WT mice infected via the footpad with 10 3 to 10 6 CFU of Brucella spp. display neutrophil and monocyte infiltration of the joint space and surrounding musculoskeletal tissue. Joint inflammation is detectable as early as 1 day postinfection and peaks 1 to 2 weeks later, after which WT mice are able to slowly resolve inflammation. B and T cells were dispensable for the onset of swelling but required for resolution of joint inflammation and infection. At early time points, MyD88 -/- mice display decreased joint inflammation, swelling, and proinflammatory cytokine levels relative to WT mice. Subsequently, swelling of MyD88 -/- joints surpassed WT joint swelling, and resolution of joint inflammation was prolonged. Joint bacterial loads in MyD88 -/- mice were significantly greater than those in WT mice by day 3 postinfection and at all time points thereafter. In addition, MyD88 -/- joint inflammatory cytokine levels on day 3 and beyond were similar to WT levels. Collectively these data demonstrate MyD88 signaling mediates early inflammatory responses in the joint but also contributes to subsequent clearance of Brucella and resolution of inflammation. This work also establishes a mouse model for studying Brucella -induced arthritis, musculoskeletal complications, and systemic responses, which will lead to a better understanding of focal complications of brucellosis. Copyright © 2017 American Society for Microbiology.

  16. Genetic susceptibility for air pollution-induced airway inflammation in the SALIA study.

    Science.gov (United States)

    Hüls, Anke; Krämer, Ursula; Herder, Christian; Fehsel, Karin; Luckhaus, Christian; Stolz, Sabine; Vierkötter, Andrea; Schikowski, Tamara

    2017-01-01

    Long-term air pollution exposure has been associated with chronic inflammation providing a link to the development of chronic health effects. Furthermore, there is evidence that pathways activated by endoplasmatic reticulum (ER) stress induce airway inflammation and thereby play an important role in the pathogenesis of inflammatory diseases. We investigated the role of genetic variation of the ER stress pathway on air pollution-induced inflammation. We used the follow-up examination of the German SALIA study (N=402, age 68-79 years). Biomarkers of inflammation were determined in induced sputum. We calculated biomarker-specific weighted genetic risk scores (GRS) out of eight ER stress related single nucleotide polymorphisms and tested their interaction with PM 2.5 , PM 2.5 absorbance, PM 10 and NO 2 exposure on inflammation by adjusted linear regression. Genetic variation of the ER stress pathway was associated with higher concentration of inflammation-related biomarkers (levels of leukotriene (LT)B 4 , tumor necrosis factor-α (TNF-α), the total number of cells and nitric oxide (NO) derivatives). Furthermore, we observed a significant interaction between air pollution exposure and the ER stress risk score on the concentration of inflammation-related biomarkers. The strongest gene-environment interaction was found for LTB 4 (PM 2.5 : p-value=0.002, PM 2.5 absorbance: p-value=0.002, PM 10 : p-value=0.001 and NO 2 : p-value=0.004). Women with a high GRS had a 38% (95%-CI: 16-64%) higher LTB 4 level for an increase of 2.06μg/m³(IQR) in PM 2.5 (no associations in women with a low GRS). These results indicate that genetic variation in the ER stress pathway might play a role in air pollution induced inflammation in the lung. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Sesame Oil Attenuates Ovalbumin-Induced Pulmonary Edema and Bronchial Neutrophilic Inflammation in Mice

    OpenAIRE

    Hsu, Dur-Zong; Liu, Chuan-Teng; Chu, Pei-Yi; Li, Ya-Hui; Periasamy, Srinivasan; Liu, Ming-Yie

    2013-01-01

    Background. Allergic asthma is one of the most common chronic inflammatory diseases of airways. Severe asthma may lead to hospitalization and death. Sesame oil is a natural product with anti-inflammatory property. However, the effect of sesame oil on allergic asthma has never been studied. Objective. We investigate the effect of sesame oil on pulmonary inflammation in allergic asthma model. Methods. Allergic airway inflammation was induced by sensitizing with two doses of 10?mg ovalbumin (OVA...

  18. Systemic inflammation predicts all-cause mortality: a glasgow inflammation outcome study.

    Directory of Open Access Journals (Sweden)

    Michael J Proctor

    Full Text Available Markers of the systemic inflammatory response, including C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score, as well as neutrophil, lymphocyte and platelet counts have been shown to be prognostic of survival in patients with cancer. The aim of the present study was to examine the prognostic relationship between these markers of the systemic inflammatory response and all-cause, cancer, cardiovascular and cerebrovascular mortality in a large incidentally sampled cohort.Patients (n = 160 481 who had an incidental blood sample taken between 2000 and 2008 were studied for the prognostic value of C-reactive protein (>10mg/l, albumin (>35mg/l, neutrophil (>7.5×109/l lymphocyte and platelet counts. Also, patients (n = 52 091 sampled following the introduction of high sensitivity C-reactive protein (>3mg/l measurements were studied. A combination of these markers, to make cumulative inflammation-based scores, were investigated.In all patients (n = 160 481 C-reactive protein (>10mg/l (HR 2.71, p35mg/l (HR 3.68, p3mg/l (n = 52 091. A combination of high sensitivity C-reactive protein (>3mg/l, albumin and neutrophil count predicted all-cause (HR 7.37, p<0.001, AUC 0.723, cancer (HR 9.32, p<0.001, AUC 0.731, cardiovascular (HR 4.03, p<0.001, AUC 0.650 and cerebrovascular (HR 3.10, p<0.001, AUC 0.623 mortality.The results of the present study showed that an inflammation-based prognostic score, combining high sensitivity C-reactive protein, albumin and neutrophil count is prognostic of all-cause mortality.

  19. Tetrastarch sustains pulmonary microvascular perfusion and gas exchange during systemic inflammation.

    Science.gov (United States)

    Heckel, Kai; Winkelmann, Bjoern; Strunden, Mike S; Basedow, Annika; Schuster, Anke; Schumacher, Udo; Kiefmann, Rainer; Reuter, Daniel A; Goetz, Alwin E

    2012-02-01

    According to Fick's law of diffusion, gas exchange depends on the size and thickness of the blood perfused alveolocapillary membrane. Impairment of either one is tenuous. No data are available concerning the impact of hydroxyethyl starches and saline on pulmonary microperfusion and gas exchange during systemic inflammation. Prospective, randomized, controlled experimental study. University research laboratory. Thirty-two anesthetized rabbits assigned to four groups (n = 8). Except for the control group, systemic inflammation was induced by lipopolysaccharide. Fluid resuscitation was performed with saline alone or in conjunction with tetrastarch or pentastarch. Pulmonary microcirculation was analyzed at 0 hr and 2 hrs using intravital microscopy. Thickness of the alveolocapillary membrane was measured using electron microscopy. Macrohemodynamics were stable in all groups. In pulmonary arterioles, lipopolysaccharide reduced the erythrocyte velocity and impeded the microvascular decrease of the hematocrit in the saline and pentastarch group. In contrast, infusion of tetrastarch normalized these perfusion parameters. In capillaries, lipopolysaccharide decreased the functional capillary segment density and the capillary perfusion index, which was prevented by both starches. However, compared with saline and pentastarch, treatment with tetrastarch prevented the lipopolysaccharide-induced reduction of the capillary erythrocyte flux and inversely reduced the erythrocyte capillary transit time. Thickening of alveolocapillary septae after lipopolysaccharide application was solely observed in the saline and pentastarch group. In contrast to pentastarch and saline, the application of tetrastarch prevented the lipopolysaccharide-induced increase of the alveoloarterial oxygen difference. Tetrastarch sustains pulmonary gas exchange during experimental systemic inflammation more effectively than saline and pentastarch by protecting the diffusion distance and the size of the

  20. One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice.

    Science.gov (United States)

    Waise, T M Zaved; Toshinai, Koji; Naznin, Farhana; NamKoong, Cherl; Md Moin, Abu Saleh; Sakoda, Hideyuki; Nakazato, Masamitsu

    2015-09-04

    A high-fat diet (HFD) induces inflammation in systemic organs including the hypothalamus, resulting in obesity and diabetes. The vagus nerve connects the visceral organs and central nervous system, and the gastric-derived orexigenic peptide ghrelin transmits its starvation signals to the hypothalamus via the vagal afferent nerve. Here we investigated the inflammatory response in vagal afferent neurons and the hypothalamus in mice following one day of HFD feeding. This treatment increased the number of macrophages/microglia in the nodose ganglion and hypothalamus. Furthermore, one-day HFD induced expression of Toll-like receptor 4 in the goblet cells of the colon and upregulated mRNA expressions of the proinflammatory biomarkers Emr1, Iba1, Il6, and Tnfα in the nodose ganglion and hypothalamus. Both subcutaneous administration of ghrelin and celiac vagotomy reduced HFD-induced inflammation in these tissues. HFD intake triggered inflammatory responses in the gut, nodose ganglion, and subsequently in the hypothalamus within 24 h. These findings suggest that the vagal afferent nerve may transfer gut-derived inflammatory signals to the hypothalamus via the nodose ganglion, and that ghrelin may protect against HFD-induced inflammation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Longitudinal effects of systemic inflammation markers on periodontitis.

    Science.gov (United States)

    Pink, Christiane; Kocher, Thomas; Meisel, Peter; Dörr, Marcus; Markus, Marcello R P; Jablonowski, Lukasz; Grotevendt, Anne; Nauck, Matthias; Holtfreter, Birte

    2015-11-01

    Systemic low-grade inflammation represents a central hallmark of chronic diseases and has been proposed as the underlying mechanism linking factors like obesity or diabetes with periodontitis. However, the impact of inflammatory markers on periodontitis has not yet been investigated. The study population comprised 1784 subjects from the Study of Health in Pomerania with complete 11-year follow-up. Fibrinogen and white blood cell (WBC) counts were measured as markers of inflammation. Periodontitis was assessed by probing depth (PD), clinical attachment loss (CAL) and the CDC/AAP case definition. Multilevel regression analyses revealed significant coefficients for the impact of both inflammation markers on the percentage of sites with PD/CAL ≥ 3 mm. Increases in fibrinogen about 1 g/l were associated with 3.0% and 2.7% more sites with PD/CAL ≥ 3 mm respectively. Consistent associations were found using mean values of PD/CAL but not using missing teeth or caries. Regarding the CDC/AAP case definition, 11-year changes in fibrinogen and WBC counts were significantly associated with ≥1 category progression (OR: 1.36 and 1.11). Fibrinogen levels and WBC counts showed consistent long-term associations with PD, CAL and the CDC/AAP case definition. Results indicate that systemic low-grade inflammation might indeed represent one possible pathway for effects of obesity, diabetes or other chronic inflammatory conditions on periodontitis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Linalool inhibits cigarette smoke-induced lung inflammation by inhibiting NF-κB activation.

    Science.gov (United States)

    Ma, Jianqun; Xu, Hai; Wu, Jun; Qu, Changfa; Sun, Fenglin; Xu, Shidong

    2015-12-01

    Linalool, a natural compound that exists in the essential oils of several aromatic plants species, has been reported to have anti-inflammatory effects. However, the effects of linalool on cigarette smoke (CS)-induced acute lung inflammation have not been reported. In the present study, we investigated the protective effects of linalool on CS-induced acute lung inflammation in mice. Linalool was given i.p. to mice 2h before CS exposure daily for five consecutive days. The numbers of macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) were measured. The production of TNF-α, IL-6, IL-1β, IL-8 and MCP-1 were detected by ELISA. The expression of NF-κB was detected by Western blotting. Our results showed that treatment of linalool significantly attenuated CS-induced lung inflammation, coupled with inhibited the infiltration of inflammatory cells and TNF-α, IL-6, IL-1β, IL-8 and MCP-1 production. Meanwhile, treatment of linalool inhibited CS-induced lung MPO activity and pathological changes. Furthermore, linalool suppressed CS-induced NF-κB activation in a dose-dependent manner. In conclusion, our results demonstrated that linalool protected against CS-induced lung inflammation through inhibiting CS-induced NF-κB activation. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. A rat model of picornavirus-induced airway infection and inflammation

    Directory of Open Access Journals (Sweden)

    Szakaly Renee J

    2009-08-01

    Full Text Available Abstract Background Infection of the lower airways by rhinovirus, a member of the picornavirus family, is an important cause of wheezing illnesses in infants, and plays an important role in the pathogenesis of rhinovirus-induced asthma exacerbations. Given the absence of natural rhinovirus infections in rodents, we investigated whether an attenuated form of mengovirus, a picornavirus whose wild-type form causes systemic rather than respiratory infections in its natural rodent hosts, could induce airway infections in rats with inflammatory responses similar to those in human rhinovirus infections. Results After inoculation with 107 plaque-forming units of attenuated mengovirus through an inhalation route, infectious mengovirus was consistently recovered on days 1 and 3 postinoculation from left lung homogenates (median Log10 plaque-forming units = 6.0 and 4.8, respectively and right lung bronchoalveolar lavage fluid (median Log10 plaque-forming units = 5.8 and 4.0, respectively. Insufflation of attenuated mengovirus, but not vehicle or UV-inactivated virus, into the lungs of BN rats caused significant increases (P P Conclusion Attenuated mengovirus caused a respiratory infection in rats with several days of viral shedding accompanied by a lower airway inflammatory response consisting of neutrophils and lymphocytes. These features suggest that mengovirus-induced airway infection in rodents could be a useful model to define mechanisms of rhinovirus-induced airway inflammation in humans.

  4. Necrosis-Induced Sterile Inflammation Mediated by Interleukin-1α in Retinal Pigment Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Yang Liu

    Full Text Available Endogenous danger signals released from necrotic cells contribute to retinal inflammation. We have now investigated the effects of necrotic cell extracts prepared from ARPE-19 human retinal pigment epithelial cells (ANCE on the release of proinflammatory cytokines and chemokines by healthy ARPE-19 cells. ANCE were prepared by subjection of ARPE-19 cells to freeze-thaw cycles. The release of various cytokines and chemokines from ARPE-19 cells was measured with a multiplex assay system or enzyme-linked immunosorbent assays. The expression of interleukin (IL-1α and the phosphorylation and degradation of the endogenous nuclear factor-κB (NF-κB inhibitor IκB-α were examined by immunoblot analysis. Among the various cytokines and chemokines examined, we found that ANCE markedly stimulated the release of the proinflammatory cytokine IL-6 and the chemokines IL-8 and monocyte chemoattractant protein (MCP-1 by ARPE-19 cells. ANCE-induced IL-6, IL-8, and MCP-1 release was inhibited by IL-1 receptor antagonist and by an IKK2 inhibitor (a blocker of NF-κB signaling in a concentration-dependent manner, but was not affected by a pan-caspase inhibitor (Z-VAD-FMK. Recombinant IL-1α also induced the secretion of IL-6, IL-8, and MCP-1 from ARPE-19 cells, and IL-1α was detected in ANCE. Furthermore, ANCE induced the phosphorylation and degradation of IκB-α in ARPE-19 cells. Our findings thus suggest that IL-1α is an important danger signal that is released from necrotic retinal pigment epithelial cells and triggers proinflammatory cytokine and chemokine secretion from intact cells in a manner dependent on NF-κB signaling. IL-1α is therefore a potential therapeutic target for amelioration of sterile inflammation in the retina.

  5. Exacerbation of cigarette smoke-induced pulmonary inflammation by Staphylococcus aureus Enterotoxin B in mice

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    Brusselle Guy G

    2011-05-01

    Full Text Available Abstract Background Cigarette smoke (CS is a major risk factor for the development of COPD. CS exposure is associated with an increased risk of bacterial colonization and respiratory tract infection, because of suppressed antibacterial activities of the immune system and delayed clearance of microbial agents from the lungs. Colonization with Staphylococcus aureus results in release of virulent enterotoxins, with superantigen activity which causes T cell activation. Objective To study the effect of Staphylococcus aureus enterotoxin B (SEB on CS-induced inflammation, in a mouse model of COPD. Methods C57/Bl6 mice were exposed to CS or air for 4 weeks (5 cigarettes/exposure, 4x/day, 5 days/week. Endonasal SEB (10 μg/ml or saline was concomitantly applied starting from week 3, on alternate days. 24 h after the last CS and SEB exposure, mice were sacrificed and bronchoalveolar lavage (BAL fluid and lung tissue were collected. Results Combined exposure to CS and SEB resulted in a raised number of lymphocytes and neutrophils in BAL, as well as increased numbers of CD8+ T lymphocytes and granulocytes in lung tissue, compared to sole CS or SEB exposure. Moreover, concomitant CS/SEB exposure induced both IL-13 mRNA expression in lungs and goblet cell hyperplasia in the airway wall. In addition, combined CS/SEB exposure stimulated the formation of dense, organized aggregates of B- and T- lymphocytes in lungs, as well as significant higher CXCL-13 (protein, mRNA and CCL19 (mRNA levels in lungs. Conclusions Combined CS and SEB exposure aggravates CS-induced inflammation in mice, suggesting that Staphylococcus aureus could influence the pathogenesis of COPD.

  6. Regulatory effects of zinc on cadmium-induced cytotoxicity in chronic inflammation.

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    Paola Bonaventura

    Full Text Available Zinc (Zn has major effects on immune system activation while Cadmium (Cd has anti-inflammatory and anti-proliferative effects in several chronic inflammatory contexts. The aim of this work was to investigate by which mechanisms Zn could compete with Cd and eventually counteract its deleterious effects. Rheumatoid arthritis (RA synoviocytes exposed to cytokines were used as a model of chronic inflammation; osteoarthritis (OA synoviocytes were used as control.Cell/medium fractionation constants were analyzed for different metals by inductively-coupled-plasma mass-spectrometry by comparison to the 70Zn spike. Interleukin-17 (IL-17 and tumor necrosis factor-alpha (TNF-α were used to mimic inflammation. Gene expression of ZIP-8 importer, metallothioneins-1 (MT-1s and the ratio between metalloprotease-3 and the tissue inhibitor of metalloproteinases (MMP-3/TIMP-1 were evaluated after pre-exposure to cytokines and Cd, with or without the addition of exogenous Zn (0.9 ppm. Cell viability was measured by neutral red assay and IL-6 production by ELISA.Synoviocytes selectively absorbed and retained Cd in comparison to Zn. Metal import increased with IL-17/TNF-α exposure, through the enhanced ZIP-8 expression. Zn did not modify ZIP-8 expression, while Cd reduced it (p<0.05. Zn induced a reduction of Cd-induced MT-1s expression, in particular of MT-1X (3-fold, and subsequently the final intra-cellular content of Cd. By reducing Cd accumulation in cells, Zn reversed Cd anti-proliferative and anti-inflammatory effects but preserved the low MMP-3/TIMP-1 ratio induced by Cd, which was enhanced by inflammatory conditions.Zinc counteracts the deleterious effect of Cd by reducing its import and accumulation in the cell, without the reactivation of destructive pathways such as MMPs.

  7. HMGB1 Inhibition During Zymosan-Induced Inflammation: The Potential Therapeutic Action of Riboflavin.

    Science.gov (United States)

    Mazur-Bialy, Agnieszka Irena; Pocheć, Ewa

    2016-04-01

    Sepsis, also known as systemic inflammatory response syndrome, is a life-threatening condition caused by a pathogenic agent and leading to multiple organ dysfunction syndrome. One of the factors responsible for the excessive intensification of the inflammatory response in the course of inflammation is high-mobility group protein B1 (HMGB1). HMG-1 is a nuclear protein which, after being released to the intercellular space, has a highly pro-inflammatory effect and acts as a late mediator of lethal damage. The purpose of this study was to examine whether the anti-inflammatory action of riboflavin is accompanied by inhibition of HMGB1 release during peritoneal inflammation and zymosan stimulation of macrophages. Peritonitis was induced in male BALB/c and C57BL/6J mice via intraperitoneal injection of zymosan (40 mg/kg). RAW 264.7 macrophages were activated with zymosan (250 µg/ml). Riboflavin (mice, 50 mg/kg; RAW 264.7, 25 µg/ml) was administered 30 min before zymosan, simultaneously with, or 2, 4, 6 h after zymosan. Additionally, mRNA expression of HMGB1 and its intracellular and serum levels were evaluated. The research showed that riboflavin significantly reduces both the expression and the release of HMGB1; however, the effect of riboflavin was time-dependent. The greatest efficacy was found when riboflavin was given 30 min prior to zymosan, and also 2 and 4 h (C57BL/6J; RAW 264.7) or 4 and 6 h (BALB/c) after zymosan. Research showed that riboflavin influences the level of HMGB1 released in the course of inflammation; however, further study is necessary to determine its mechanisms of action.

  8. Elimination of neutrophils in zymosan-induced ankle inflammation by etoposide

    Directory of Open Access Journals (Sweden)

    Viktoriya I. Milanova

    2014-12-01

    Full Text Available Neutrophils play a crucial role in the pathogenesis of joint inflammatory diseases such as rheumatoid arthritis (RA. Therefore their elimination and/or a functional inhibition might have beneficial or even therapeutic effects in these diseases. In the present study we exploited the cytotoxic action of etoposide to deplete neutrophils. We administrated the drug twice (at day -3 and day -1 to SCID mice having intact innate immunity and a fail in T- and B-cell maturation. Ankle inflammation was induced by the injection of zymosan (ZY. Joint damage was evaluated by histology grading system for cell infiltration and proteoglycan loss and degree of cartilage erosion. The frequencies of mature Ly6G+CD11b+ cells in bone marrow (BM were monitored at days -4, -2 and 0 by flow cytometry. At day 7 of ankle inflammation the amounts of pro-inflammatory cytokines tumor necrosis factor (TNF-α and interleukin (IL-17 were measured by enzyme-linked immunosorbent assay (ELISA. Histological analysis of the joint sections showed decreased scores for cell infiltration and cartilage proteoglycan loss and reduced cartilage erosion in drug-treated zymosan injected mice in comparison to untreated group with ankle inflammation. Etoposide diminished cell numbers in BM, inhibits granulopoiesis triggered by zymosan and decreased the frequencies of mature Ly6G+CD11b+ cells in BM and eliminated Ly6G+ cells from blood and synovial fluid. We observed reduced TNF-α and impaired IL-17 production in etoposide-treated ZY group. Our data provide a proof-of principle that the elimination of neutrophils might be exploited in a design of new therapeutic approaches for joint inflammatory diseases.

  9. Important role of platelets in modulating endotoxin-induced lung inflammation in CFTR-deficient mice.

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    Caiqi Zhao

    Full Text Available Mutation of CFTR (cystic fibrosis transmembrane conductance regulator leads to cystic fibrosis (CF. Patients with CF develop abnormalities of blood platelets and recurrent lung inflammation. However, whether CFTR-mutated platelets play a role in the development of lung inflammation is elusive. Therefore, we intratracheally challenged wildtype and F508del (a common type of CFTR mutation mice with LPS to observe changes of F508del platelets in the peripheral blood and indexes of lung inflammation (BAL neutrophils and protein levels. Furthermore, we investigated whether or not and how F508del platelets modulate the LPS-induced acute lung inflammation by targeting anti-platelet aggregation, depletion of neutrophils, reconstitution of bone marrow or neutrophils, blockade of P-selectin glycoprotein ligand-1 (PSGL-1, platelet activating factor (PAF, and correction of mutated CFTR trafficking. We found that LPS-challenged F508del mice developed severe thrombocytopenia and had higher levels of plasma TXB2 coincided with neutrophilic lung inflammation relative to wildtype control. Inhibition of F508del platelet aggregation or depletion of F508del neutrophils diminished the LPS-induced lung inflammation in the F508del mice. Moreover, wildtype mice reconstituted with either F508del bone marrow or neutrophils developed worse thrombocytopenia. Blocking PSGL-1, platelet activating factor (PAF, or rectifying trafficking of mutated CFTR in F508del mice diminished and alveolar neutrophil transmigration in the LPS-challenged F508del mice. These findings suggest that F508del platelets and their interaction with neutrophils are requisite for the development of LPS-induced lung inflammation and injury. As such, targeting platelets might be an emerging strategy for dampening recurrent lung inflammation in cystic fibrosis patients.

  10. Allergic Conjunctivitis-induced Retinal Inflammation Promotes Myopia Progression

    Directory of Open Access Journals (Sweden)

    Chang-Ching Wei

    2018-02-01

    Full Text Available Myopia is a highly prevalent eye disease. There is limited information suggesting a relationship between myopia and inflammation. We found children with allergic conjunctivitis (AC had the highest adjusted odds ratio (1.75, 95% confidence interval [CI], 1.72–1.77 for myopia among the four allergic diseases. A cohort study was conducted and confirmed that children with AC had a higher incidence and subsequent risk of myopia (hazard ratio 2.35, 95%CI 2.29–2.40 compared to those without AC. Lower refractive error and longer axial length were observed in an AC animal model. Myopia progression was enhanced by tumor necrosis factor (TNF-α or interleukin (IL-6 administration, two cytokines secreted by mast cell degranulation. The TNF-α or IL-6 weakened the tight junction formed by corneal epithelial (CEP cells and inflammatory cytokines across the layer of CEP cells, which increased the levels of TNF-α, IL-6, and IL-8 secreted by retinal pigment epithelial cells. The expression levels of TNF-α, IL-6, IL-8, monocyte chemoattractant protein-1, and nuclear factor kappa B were up-regulated in eyes with AC, whereas IL-10 and the inhibitor of kappa B were down-regulated. In conclusion, the experimental findings in mice corroborate the epidemiological data showing that allergic inflammation influences the development of myopia.

  11. Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation

    International Nuclear Information System (INIS)

    Gremy, O.

    2006-12-01

    The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

  12. Therapeutic Down-Modulators of Staphylococcal Superantigen-Induced Inflammation and Toxic Shock

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    Teresa Krakauer

    2010-07-01

    Full Text Available Staphylococcal enterotoxin B (SEB and related superantigenic toxins are potent stimulators of the immune system and cause a variety of diseases in humans, ranging from food poisoning to toxic shock. These toxins bind directly to major histocompatibility complex (MHC class II molecules on antigen-presenting cells and specific Vb regions of T-cell receptors (TCR, resulting in hyperactivation of both monocytes/macrophages and T lymphocytes. Activated host cells produce massive amounts of proinflammatory cytokines and chemokines, activating inflammation and coagulation, causing clinical symptoms that include fever, hypotension, and shock. This review summarizes the in vitro and in vivo effects of staphylococcal superantigens, the role of pivotal mediators induced by these toxins in the pathogenic mechanisms of tissue injury, and the therapeutic agents to mitigate the toxic effects of superantigens.

  13. Gastrointestinal microbiota and local inflammation during oxazolone-induced dermatitis in BALB/cA mice

    DEFF Research Database (Denmark)

    Lundberg, Randi; Clausen, Susanne; Pang, Wanyong

    2012-01-01

    -induced skin inflammation model of atopic dermatitis. BALB/cA mice were sensitized with oxazolone over a 28-d period and variation in gastrointestinal microbiota in fecal and cecal samples was assessed by PCR-denaturing gradient gel electrophoresis. Clinical parameters included transepidermal water loss, ear...... thickness, inflammatory factors in ear tissue and plasma, and histopathologic evaluation. The fecal microbiota before induction of skin inflammation strongly correlated with the levels of some proinflammatory cytokines (IFNγ, IL1β, IL12, and TNFα), the antiinflammatory cytokines IL4 and IL10...... period in the oxazolone-treated mice, whereas this was not the case for the control mice. The current study shows that the GM of mice influences the development of oxazolone-induced skin inflammation and that the model itself likely induces a pathophysiologic response that alters the composition...

  14. PA401, a novel CXCL8-based biologic therapeutic with increased glycosaminoglycan binding, reduces bronchoalveolar lavage neutrophils and systemic inflammatory markers in a murine model of LPS-induced lung inflammation.

    Science.gov (United States)

    Adage, Tiziana; Del Bene, Francesca; Fiorentini, Francesco; Doornbos, Robert P; Zankl, Christina; Bartley, Michael R; Kungl, Andreas J

    2015-12-01

    Neutrophils play a fundamental role in a number of chronic lung diseases. Among the mediators of their recruitment to the lung, CXCL8 (IL-8) is considered to be one of the major players. CXCL8 exerts its chemotactic activity by binding to its GPCR receptors (CXCR1/R2) located on neutrophils, as well as through interactions with glycosaminoglycans (GAGs) on cell surfaces including those of the microvascular endothelium. Binding to GAG co-receptors is required to generate a solid-phase haptotactic gradient and to present IL-8/CXCL8 in a proper conformation to its receptors on circulating neutrophils. We have engineered increased GAG-binding affinity into human CXCL8, thereby obtaining a competitive inhibitor that displaces wild-type IL-8/CXCL8 from GAGs. By additionally knocking-out the GPCR binding domain of the chemokine, we generated a dominant negative protein (dnCXCL8; PA401) with potent anti-inflammatory characteristics proven in vivo in a murine model of LPS-induced lung inflammation (Adage et al., 2015). Here we have further investigated PA401 activity in this pulmonary model by evaluating plasma changes induced by LPS on white blood cells (WBC) and a broad range of inflammatory markers, especially chemokines, by addressing immediate effects of PA401 on these parameters in healthy and LPS exposed mice. Aerosolized LPS induced a significant increase in bronchoalveolar lavage (BAL) neutrophils after 3 and 7h, as well as an increase in total WBC and changes in 21 of the 59 measured plasma markers, mostly belonging to the chemokine family. PA401 treatment in saline exposed mice didn't induce major changes in any of the measured parameters. When administered to LPS aerosolized mice, PA401 caused a significant normalization of KC/mCXCL1 and other inflammatory markers, as well as of blood WBC count. In addition, BAL neutrophils were significantly reduced, confirming the previously observed lung anti-inflammatory activity of PA401 in this experiment. PA401 is a new

  15. Thrombospondin1 deficiency reduces obesity-associated inflammation and improves insulin sensitivity in a diet-induced obese mouse model.

    Directory of Open Access Journals (Sweden)

    Yanzhang Li

    Full Text Available Obesity is prevalent worldwide and is associated with insulin resistance. Advanced studies suggest that obesity-associated low-grade chronic inflammation contributes to the development of insulin resistance and other metabolic complications. Thrombospondin 1 (TSP1 is a multifunctional extracellular matrix protein that is up-regulated in inflamed adipose tissue. A recent study suggests a positive correlation of TSP1 with obesity, adipose inflammation, and insulin resistance. However, the direct effect of TSP1 on obesity and insulin resistance is not known. Therefore, we investigated the role of TSP1 in mediating obesity-associated inflammation and insulin resistance by using TSP1 knockout mice.Male TSP1-/- mice and wild type littermate controls were fed a low-fat (LF or a high-fat (HF diet for 16 weeks. Throughout the study, body weight and fat mass increased similarly between the TSP1-/- mice and WT mice under HF feeding conditions, suggesting that TSP1 deficiency does not affect the development of obesity. However, obese TSP1-/- mice had improved glucose tolerance and increased insulin sensitivity compared to the obese wild type mice. Macrophage accumulation and inflammatory cytokine expression in adipose tissue were reduced in obese TSP1-/- mice. Consistent with the local decrease in pro-inflammatory cytokine levels, systemic inflammation was also decreased in the obese TSP1-/- mice. Furthermore, in vitro data demonstrated that TSP1 deficient macrophages had decreased mobility and a reduced inflammatory phenotype.TSP1 deficiency did not affect the development of high-fat diet induced obesity. However, TSP1 deficiency reduced macrophage accumulation in adipose tissue and protected against obesity related inflammation and insulin resistance. Our data demonstrate that TSP1 may play an important role in regulating macrophage function and mediating obesity-induced inflammation and insulin resistance. These data suggest that TSP1 may serve as a

  16. An increase in exhaled CO concentration in systemic inflammation/sepsis.

    Science.gov (United States)

    Morimatsu, Hiroshi; Takahashi, Toru; Matsusaki, Takashi; Hayashi, Masao; Matsumi, Jyunya; Shimizu, Hiroko; Matsumi, Masaki; Morita, Kiyoshi

    2010-12-01

    Despite recent progress in Critical Care Medicine, sepsis is still a major medical problem with a high rate of mortality and morbidity especially in intensive care units. Oxidative stress induced by inflammation associated with sepsis causes degradation of heme protein, increases microsomal free heme content, promotes further oxidative stress and results in cellular and organ damage. Heme-oxygenase-1 (HO-1) is a rate-limiting enzyme for heme breakdown. HO-1 breaks down heme to yield CO, iron and biliverdin. Measurement of CO in exhaled air may potentially be useful in monitoring changes in HO enzyme activity in vivo, which might reflect the degree of inflammation or oxidative stress in patients with systemic inflammation. The increased exhaled CO concentrations were observed after anesthesia/surgery, in critically ill patients and also in systemic inflammation/sepsis. Some reports also showed that exhaled CO concentration is related to mortality. Further studies are needed to elucidate whether increased endogenous CO production may predict a patient's morbidity and mortality. Techniques for monitoring CO are continuously being refined and this technique may find its way into the office of clinicians.

  17. Elevated leukocyte count as a harbinger of systemic inflammation, disease progression, and poor prognosis: a review.

    Science.gov (United States)

    Chmielewski, Piotr Paweł; Strzelec, Bartłomiej

    2017-10-24

    Total leukocyte count increases significantly in response to infection, trauma, inflammation, and certain diseases. Factors affecting leukocyte count in healthy adults include sex, hormonal milieu, genetic inheritance, stress level, diet, nutrition, and lifestyle (e.g. tobacco-induced inflammatory changes, chronic psychological stress, etc.). To date, numerous studies have reported that high but normal leukocyte counts at baseline predict increased cardiovascular and noncardiovascular mortality in older adults. Recent findings suggest that elevated leukocyte count within the normal range, but especially neutrophil and monocyte counts, may be a harbinger of increased systemic inflammation and subclinical disease. Moreover, elderly people who tend to have high but normal leukocyte counts are at greater risk of cancer, cardiovascular disease, type 2 diabetes, some other age-related conditions, and they also have increased all-cause mortality. These results indicate that strong and reliable inflammatory markers, such as leukocyte count, may reflect the rate of ageing and therefore can predict long-term survival in the elderly. Remarkably, leukocyte count correlates positively with genuine markers of systemic inflammation like C-reactive protein and interleukin 6. Interestingly, some authors conclude that leukocyte counts have a stronger prognostic ability with regard to total and cardiovascular mortality than total cholesterol or low-density lipoproteins. The fact that these inflammatory markers are clinically useful predictors of long-term survival in the elderly is quite remarkable as these blood parameters are included in routine medical check-ups. Therefore, they can be used as simple and reliable morphological indicators of chronic systemic inflammation, disease progression, and poor prognosis, especially among individuals who are likely to develop age-related conditions. Nevertheless, the pathomechanism that links elevated but normal leukocyte counts to increased

  18. Endotoxin-induced inflammation disturbs melatonin secretion in ewe.

    Science.gov (United States)

    Herman, Andrzej Przemysław; Wojtulewicz, Karolina; Bochenek, Joanna; Krawczyńska, Agata; Antushevich, Hanna; Pawlina, Bartosz; Zielińska-Górska, Marlena; Herman, Anna; Romanowicz, Katarzyna; Tomaszewska-Zaremba, Dorota

    2017-12-01

    The study examined the effect of intravenous administration of bacterial endotoxin-lipopolysaccharide (LPS) -on the nocturnal secretion of melatonin and on the expression of enzymes of the melatonin biosynthetic pathway in the pineal gland of ewes, taking into account two different photoperiodic conditions: short-night (SN; n = 12) and long-night (LN; n = 12). In both experiments, animals (n = 12) were randomly divided into two groups: control (n = 6) and LPS-treated (n = 6) one. Two hours after sunset, animals received an injection of LPS or saline. Blood samples were collected starting one hour after sunset and continuing for 3 hours after the treatment. The ewes were euthanized 3 hours after LPS/saline treatment. The concentration of hormones in plasma was assayed by radioimmunoassay. In the pineal gland, the content of serotonin and its metabolite was determined by HPLC; whereas the expression of examined genes and protein was assayed using real-time polymerase chain reaction and Western Blot, respectively. Endotoxin administration lowered (pewes from SN photoperiod only in the third hour after the injection. Inflammation more substantially suppressed biosynthesis of melatonin in ewes from SN photoperiod, which were also characterised by lower (pewes subjected to SN photoperiod, LPS reduced (p<0.05) serotonin content and the expression of melatonin biosynthetic pathway enzymes, such as tryptophan hydroxylase and arylalkylamine-N-acetyltransferase. Pineal activity may be disturbed by circulating LPS and proinflammatory cytokines because the expression of mRNAs encoding their corresponding receptors was determined in this gland. The present study showed that peripheral inflammation reduces the secretion of melatonin, but this effect may be influenced by the photoperiod.

  19. Endotoxin-induced inflammation disturbs melatonin secretion in ewe

    Directory of Open Access Journals (Sweden)

    Andrzej Przemysław Herman

    2017-12-01

    Full Text Available Objective The study examined the effect of intravenous administration of bacterial endotoxin—lipopolysaccharide (LPS —on the nocturnal secretion of melatonin and on the expression of enzymes of the melatonin biosynthetic pathway in the pineal gland of ewes, taking into account two different photoperiodic conditions: short-night (SN; n = 12 and long-night (LN; n = 12. Methods In both experiments, animals (n = 12 were randomly divided into two groups: control (n = 6 and LPS-treated (n = 6 one. Two hours after sunset, animals received an injection of LPS or saline. Blood samples were collected starting one hour after sunset and continuing for 3 hours after the treatment. The ewes were euthanized 3 hours after LPS/saline treatment. The concentration of hormones in plasma was assayed by radioimmunoassay. In the pineal gland, the content of serotonin and its metabolite was determined by HPLC; whereas the expression of examined genes and protein was assayed using real-time polymerase chain reaction and Western Blot, respectively. Results Endotoxin administration lowered (p<0.05 levels of circulating melatonin in animals from LN photoperiod only during the first hour after treatment, while in ewes from SN photoperiod only in the third hour after the injection. Inflammation more substantially suppressed biosynthesis of melatonin in ewes from SN photoperiod, which were also characterised by lower (p<0.05 cortisol concentrations after LPS treatment compared with animals from LN photoperiod. In the pineal gland of ewes subjected to SN photoperiod, LPS reduced (p<0.05 serotonin content and the expression of melatonin biosynthetic pathway enzymes, such as tryptophan hydroxylase and arylalkylamine-N-acetyltransferase. Pineal activity may be disturbed by circulating LPS and proinflammatory cytokines because the expression of mRNAs encoding their corresponding receptors was determined in this gland. Conclusion The present study showed that peripheral

  20. Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis

    OpenAIRE

    Heijden, R.A. van der; Bijzet, J.; Meijers, W.C.; Yakala, G.K.; Kleemann, R.; Nguyen, T.Q.; Boer, R.A. de; Schalkwijk, C.G.; Hazenberg, B.P.C.; Tietge, U.J.F.; Heeringa, P.

    2015-01-01

    Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features i...

  1. Shaofu Zhuyu decoction ameliorates obesity-mediated hepatic steatosis and systemic inflammation by regulating metabolic pathways.

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    Moonju Hong

    Full Text Available Shaofu Zhuyu decoction (SFZYD, also known as Sobokchugeo-tang, a classical prescription drug in traditional East Asian medicine, has been used to treat blood stasis syndrome (BSS. Hepatic steatosis is the result of excess caloric intake, and its pathogenesis involves internal retention of phlegm and dampness, blood stasis, and liver Qi stagnation. To evaluate the effects of treatment with SFZYD on obesity-induced inflammation and hepatic steatosis, we fed male C57BL/6N mice a high fat diet (HFD for 8 weeks and then treated them with SFZYD by oral gavage for an additional 4 weeks. The results of histological and biochemical examinations indicated that SFZYD treatment ameliorates systemic inflammation and hepatic steatosis. A partial least squares-discriminant analysis (PLS-DA scores plot of serum metabolites showed that HFD mice began to produce metabolites similar to those of normal chow (NC mice after SFZYD administration. We noted significant alterations in the levels of twenty-seven metabolites, alterations indicating that SFZYD regulates the TCA cycle, the pentose phosphate pathway and aromatic amino acid metabolism. Increases in the levels of TCA cycle intermediate metabolites, such as 2-oxoglutaric acid, isocitric acid, and malic acid, in the serum of obese mice were significantly reversed after SFZYD treatment. In addition to inducing changes in the above metabolites, treatment with SFZYD also recovered the expression of genes related to hepatic mitochondrial dysfunction, including Ucp2, Cpt1α, and Ppargc1α, as well as the expression of genes involved in lipid metabolism and inflammation, without affecting glucose uptake or insulin signaling. Taken together, these findings suggest that treatment with SFZYD ameliorated obesity-induced systemic inflammation and hepatic steatosis by regulating inflammatory cytokine and adipokine levels in the circulation and various tissues. Moreover, treatment with SFZYD also reversed alterations in the

  2. A novel gingival overgrowth mouse model induced by the combination of CsA and ligature-induced inflammation.

    Science.gov (United States)

    Okanobu, Ai; Matsuda, Shinji; Kajiya, Mikihito; Fujita, Tsuyoshi; Kittaka, Mizuho; Shiba, Hideki; Kurihara, Hidemi

    2017-06-01

    Drug-induced gingival overgrowth (DIGO) is a side effect of the enlargement of gingival tissue by phenytoin, nifedipine, and cyclosporine A (CsA). Gingival inflammation has been identified as a key factor that initiates DIGO. However, a sufficient animal model for clarifying the role of inflammation in DIGO has not yet been generated. We herein describe a novel CsA-induced gingival overgrowth mouse model to evaluate the role of inflammation. A ligature was placed around the second molar in maxillae for 7days to induce gingival inflammation, and CsA (50mg/kg/day) was administered to mice during each experimental period. The severity of gingival overgrowth and mRNA expression of inflammatory cytokines in gingiva were assessed by the gingival overgrowth degree, histological analyses, and RT-PCR. The administration of CsA for 28days in combination with ligation significantly increased the gingival overgrowth degree and expanded the connective tissue area. Increases in the gingival overgrowth degree continued in a time-dependent manner until 21days. Furthermore, the cessation of CsA reduced gingival overgrowth. Thin ligatures (7-0 size) induced weaker tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 mRNA expression and less gingival overgrowth than thick ligatures (5-0 ligature). Moreover, the administration of an antibiotic cocktail, which suppressed the expression of these inflammatory cytokines in gingiva, attenuated gingival overgrowth induced by ligatures and CsA. These results suggest that inflammation in gingival tissue plays a role in initiating CsA-induced gingival overgrowth. This gingival overgrowth mouse model has potential for elucidating the etiology of DIGO from the view point of gingival inflammation. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation

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    Joshua B. Lewis

    2016-10-01

    Full Text Available It has long been understood that increased epithelial permeability contributes to inflammation observed in many respiratory diseases. Recently, evidence has revealed that environmental exposure to noxious material such as cigarette smoke reduces tight junction barrier integrity, thus enhancing inflammatory conditions. Claudin-6 (Cldn6 is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To test the hypothesis that increased Cldn6 ameliorates inflammation at the respiratory barrier, we utilized the Tet-On inducible transgenic system to conditionally over-express Clnd6 in the distal lung. Cldn6 transgenic (TG and control mice were continuously provided doxycycline from postnatal day (PN 30 until euthanasia date at PN90. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS via a nose only inhalation system from PN30-90 and compared to room air (RA controls. Animals were euthanized on PN90 and lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF was procured for the assessment of inflammatory cells and molecules. Quantitative RT-PCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up-regulation. Histological evaluations revealed no adverse pulmonary remodeling via Hematoxylin and Eosin (H&E staining or any qualitative alterations in the abundance of type II pneumocytes or proximal non-ciliated epithelial cells via staining for cell specific propeptide of Surfactant Protein-C (proSP-C or Club Cell Secretory Protein (CCSP, respectively. Immunoblotting and qRT-PCR confirmed the differential expression of Cldn6 and the pro-inflammatory cytokines TNF-α and IL-1β. As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal

  4. Up-Regulation of Claudin-6 in the Distal Lung Impacts Secondhand Smoke-Induced Inflammation.

    Science.gov (United States)

    Lewis, Joshua B; Milner, Dallin C; Lewis, Adam L; Dunaway, Todd M; Egbert, Kaleb M; Albright, Scott C; Merrell, Brigham J; Monson, Troy D; Broberg, Dallin S; Gassman, Jason R; Thomas, Daniel B; Arroyo, Juan A; Reynolds, Paul R

    2016-10-17

    It has long been understood that increased epithelial permeability contributes to inflammation observed in many respiratory diseases. Recently, evidence has revealed that environmental exposure to noxious material such as cigarette smoke reduces tight junction barrier integrity, thus enhancing inflammatory conditions. Claudin-6 (Cldn6) is a tetraspanin transmembrane protein found within the tight junctional complex and is implicated in maintaining lung epithelial barriers. To test the hypothesis that increased Cldn6 ameliorates inflammation at the respiratory barrier, we utilized the Tet-On inducible transgenic system to conditionally over-express Clnd6 in the distal lung. Cldn6 transgenic (TG) and control mice were continuously provided doxycycline from postnatal day (PN) 30 until euthanasia date at PN90. A subset of Cldn6 TG and control mice were also subjected to daily secondhand tobacco smoke (SHS) via a nose only inhalation system from PN30-90 and compared to room air (RA) controls. Animals were euthanized on PN90 and lungs were harvested for histological and molecular characterization. Bronchoalveolar lavage fluid (BALF) was procured for the assessment of inflammatory cells and molecules. Quantitative RT-PCR and immunoblotting revealed increased Cldn6 expression in TG vs. control animals and SHS decreased Cldn6 expression regardless of genetic up-regulation. Histological evaluations revealed no adverse pulmonary remodeling via Hematoxylin and Eosin (H&E) staining or any qualitative alterations in the abundance of type II pneumocytes or proximal non-ciliated epithelial cells via staining for cell specific propeptide of Surfactant Protein-C (proSP-C) or Club Cell Secretory Protein (CCSP), respectively. Immunoblotting and qRT-PCR confirmed the differential expression of Cldn6 and the pro-inflammatory cytokines TNF-α and IL-1β. As a general theme, inflammation induced by SHS exposure was influenced by the availability of Cldn6. These data reveal captivating

  5. Systemic inflammation decreases pain threshold in humans in vivo.

    Science.gov (United States)

    de Goeij, Moniek; van Eijk, Lucas T; Vanelderen, Pascal; Wilder-Smith, Oliver H; Vissers, Kris C; van der Hoeven, Johannes G; Kox, Matthijs; Scheffer, Gert Jan; Pickkers, Peter

    2013-01-01

    Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods. Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20 ± 4 % and 13 ± 3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7 ± 3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques. In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.

  6. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

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    Wei-Chi Chou

    2015-01-01

    Full Text Available Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group, sham-operation (Sham, or sham plus caffeine (n=12 in each group. To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P<0.001 and P=0.008, resp.. Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2 and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P<0.05. These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  7. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury.

    Science.gov (United States)

    Ribeiro, A; Almeida, V I; Costola-de-Souza, C; Ferraz-de-Paula, V; Pinheiro, M L; Vitoretti, L B; Gimenes-Junior, J A; Akamine, A T; Crippa, J A; Tavares-de-Lima, W; Palermo-Neto, J

    2015-02-01

    We have previously shown that the prophylactic treatment with cannabidiol (CBD) reduces inflammation in a model of acute lung injury (ALI). In this work we analyzed the effects of the therapeutic treatment with CBD in mice subjected to the model of lipopolysaccharide (LPS)-induced ALI on pulmonary mechanics and inflammation. CBD (20 and 80 mg/kg) was administered (i.p.) to mice 6 h after LPS-induced lung inflammation. One day (24 h) after the induction of inflammation the assessment of pulmonary mechanics and inflammation were analyzed. The results show that CBD decreased total lung resistance and elastance, leukocyte migration into the lungs, myeloperoxidase activity in the lung tissue, protein concentration and production of pro-inflammatory cytokines (TNF and IL-6) and chemokines (MCP-1 and MIP-2) in the bronchoalveolar lavage supernatant. Thus, we conclude that CBD administered therapeutically, i.e. during an ongoing inflammatory process, has a potent anti-inflammatory effect and also improves the lung function in mice submitted to LPS-induced ALI. Therefore the present and previous data suggest that in the future cannabidiol might become a useful therapeutic tool for the attenuation and treatment of inflammatory lung diseases.

  8. Altered detrusor gap junction communications induce storage symptoms in bladder inflammation: a mouse cyclophosphamide-induced model of cystitis.

    Directory of Open Access Journals (Sweden)

    Takeshi Okinami

    Full Text Available Lower urinary tract symptoms (LUTS include storage, voiding and post-micturition symptoms, featuring many urological diseases. Storage symptoms are the most frequent among these and associated with overactive bladder and non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS. Gap junction, a key regulator of hyperactive conditions in the bladder, has been reported to be involved in pathological bladder inflammation. Here we report involvement of gap junction in the etiology of storage symptoms in bladder inflammation. In this study, cyclophosphamide-induced cystitis was adapted as a model of bladder inflammation. Cyclophosphamide-treated mice showed typical storage symptoms including increased urinary frequency and reduced bladder capacity, with concurrent up-regulation of connexin 43 (GJA1, one of the major gap junction proteins in the bladder. In isometric tension study, bladder smooth muscle strips taken from the treated mice showed more pronounced spontaneous contraction than controls, which was attenuated by carbenoxolone, a gap junction inhibitor. In voiding behavior studies, the storage symptoms in the treated mice characterized by frequent voiding were alleviated by 18α-glycyrrhetinic acid, another gap junction inhibitor. These results demonstrate that cyclophosphamide-induced mouse model of cystitis shows clinical storage symptoms related with bladder inflammation and that gap junction in the bladder may be a key molecule of these storage symptoms. Therefore, gap junction in the bladder might be an alternative therapeutic target for storage symptoms in bladder inflammation.

  9. Detection of local inflammation induced by repeated exposure to contact allergens by use of IVIS SpectrumCT analyses

    DEFF Research Database (Denmark)

    Nielsen, Morten M.; Schmidt, Jonas D.; Christensen, Jan P.

    2017-01-01

    Background: Contact allergy is characterized by local skin inflammation that, in some cases, can result in systemic immune activation. Objectives: To investigate whether IVIS SpectrumCT analyses can be used to detect the immune response induced by contact allergens. Methods: Mice were repeatedly...... exposed to vehicle or allergens on the ears. The local and systemic responses were analysed at different times with the ProSense 750 FAST probe in IVIS SpectrumCT measurements. In addition, changes in ear thickness, cytokine profile in the skin and immunological phenotype in the draining lymph nodes...... and spleen were determined. Results: Local inflammation was detected by ProSense 750 FAST and correlated with changes in ear thickness, cytokine profile and immunological phenotype following exposure to the strong contact allergen 2,4-dinitrofluorobenzene. Analysis of the systemic response with ProSense 750...

  10. Tumor necrosis factor is not required for particle-induced genotoxicity and pulmonary inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Saber, Anne T.; Bornholdt, Jette; Dybdahl, Marianne; Sharma, Anoop K.; Vogel, Ulla; Wallin, Haakan [National Institute of Occupational Health, Copenhagen (Denmark); Loft, Steffen [Copenhagen University, Institute of Public Health, Copenhagen (Denmark)

    2005-03-01

    Particle-induced carcinogenicity is not well understood, but might involve inflammation. The proinflammatory cytokine tumor necrosis factor (TNF) is considered to be an important mediator in inflammation. We investigated its role in particle-induced inflammation and DNA damage in mice with and without TNF signaling. TNF-/- mice and TNF+/+ mice were exposed by inhalation to 20 mg m{sup -3} carbon black (CB), 20 mg m{sup -3} diesel exhaust particles (DEP), or filtered air for 90 min on each of four consecutive days. DEP, but not CB particles, induced infiltration of neutrophilic granulocutes into the lung lining fluid (by the cellular fraction in the bronchoalveolar lavage fluid), and both particle types induced interleukin-6 mRNA in the lung tissue. Surprisingly, TNF-/- mice were intact in these inflammatory responses. There were more DNA strand breaks in the BAL cells of DEP-exposed TNF-/- mice and CB-exposed mice compared with the air-exposed mice. Thus, the CB-induced DNA damage in BAL-cells was independent of neutrophil infiltration. The data indicate that an inflammatory response was not a prerequisite for DNA damage, and TNF was not required for the induction of inflammation by DEP and CB particles. (orig.)

  11. Oral Administration of Vanillin Improves Imiquimod-Induced Psoriatic Skin Inflammation in Mice.

    Science.gov (United States)

    Cheng, Hui-Man; Chen, Feng-Yuan; Li, Chia-Cheng; Lo, Hsin-Yi; Liao, Yi-Fang; Ho, Tin-Yun; Hsiang, Chien-Yun

    2017-11-29

    Vanillin is one of the most widely used flavoring products worldwide. Psoriasis is a chronic inflammatory skin disorder. The interleukin-23 (IL-23)/interleukin-17 (IL-17) axis plays a critical role in psoriasis. Here, we analyzed the effect of vanillin on imiquimod (IMQ)-induced psoriatic skin inflammation in mice. Mice were treated topically with IMQ on the back skin and orally with various amounts of vanillin for 7 consecutive days. Vanillin significantly improved IMQ-induced histopathological changes of skin in a dose-dependent manner. The thickness and number of cell layers of epidermis were reduced by 29 ± 14.4 and 27.8 ± 11%, respectively, in mice given 100 mg/kg of vanillin. A microarray showed that a total of 9042 IMQ-upregulated genes were downregulated by vanillin, and the biological pathways involved in the immune system and metabolism were significantly altered by vanillin. The upregulated expressions of IL-23, IL-17A, and IL-17F genes were suppressed by vanillin, with fold changes of -3.07 ± 0.08, -2.06 ± 0.21, and -1.62 ± 0.21, respectively. Moreover, vanillin significantly decreased both the amounts of IL-17A and IL-23 and the infiltration of immune cells in the skin tissues of IMQ-treated mice. In conclusion, our findings suggested that vanillin was an effective bioactive compound against psoriatic skin inflammation. Moreover, the downregulation of IL-23 and IL-17 expression suggested that vanillin was a novel regulator of the IL-23/IL-17 axis.

  12. Clarithromycin ameliorates pulmonary inflammation induced by short term cigarette smoke exposure in mice.

    Science.gov (United States)

    Nakamura, Masuo; Wada, Hiroo; Honda, Kojiro; Nakamoto, Keitaro; Inui, Toshiya; Sada, Mitsuru; Watanabe, Masato; Takata, Saori; Yokoyama, Takuma; Saraya, Takeshi; Kurai, Daisuke; Ishii, Haruyuki; Goto, Hajime; Kamma, Hiroshi; Takizawa, Hajime

    2015-12-01

    Cigarette smoking is considered to be one of major causes of acute worsening of asthma as well as chronic obstructive pulmonary disease (COPD). Macrolide antibiotics have been reported to reduce the risk of exacerbations of COPD, and possibly neutrophilic asthma. However, the effect of clarithromycin (CAM) on pulmonary inflammation caused by short term exposure to cigarette smoke still remains to be investigated. C57BL/6J female mice were daily exposed to tobacco smoke using a tobacco smoke exposure system, or clean air for 8 days, while simultaneously treated with either oral CAM or vehicles. Twenty four hours after the last exposure, mice were anaesthetized and sacrificed, and bronchoalveolar lavage (BAL) fluids were collected. Cellular responses in BAL fluids were evaluated. Levels of cytokine mRNA in the lung tissues were measured by quantitative RT-PCR. Paraffin-embedded lung tissues were evaluated to quantitate degree of neutrophil infiltration. The numbers of total cells, macrophages and neutrophils in the BAL fluid of smoke-exposed mice were significantly increased as compared to clean air group. These changes were significantly ameliorated in CAM-treated mice. The lung morphological analysis confirmed decrease of neutrophils by CAM treatment. Studies by quantitative PCR demonstrated CAM treatment significantly reduced lung expression levels of IL-17A, keratinocyte-derived chemokine (KC), granulocyte-macrophage colony stimulating factor (GM-CSF) and MMP-9 induced by cigarette smoke. We demonstrate that CAM administration resolves enhanced pulmonary inflammation induced by short term cigarette smoke exposure in mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Leptin deficiency in mice counteracts imiquimod (IMQ)-induced psoriasis-like skin inflammation while leptin stimulation induces inflammation in human keratinocytes.

    Science.gov (United States)

    Stjernholm, Theresa; Ommen, Pernille; Langkilde, Ane; Johansen, Claus; Iversen, Lars; Rosada, Cecilia; Stenderup, Karin

    2017-04-01

    Leptin is an adipocyte-derived cytokine secreted mostly by adipose tissue. Serum leptin levels are elevated in obese individuals and correlate positively with body mass index (BMI). Interestingly, serum leptin levels are also elevated in patients with psoriasis and correlate positively with disease severity. Psoriasis is associated with obesity; patients with psoriasis have a higher incidence of obesity, and obese individuals have a higher risk of developing psoriasis. Additionally, obese patients with psoriasis experience a more severe degree of psoriasis. In this study, we hypothesised that leptin may link psoriasis and obesity and plays an aggravating role in psoriasis. To investigate leptin's role in psoriasis, we applied the widely accepted imiquimod (IMQ)-induced psoriasis-like skin inflammation mouse model on leptin-deficient (ob/ob) mice and evaluated psoriasis severity. Moreover, we stimulated human keratinocytes with leptin and investigated the effect on proliferation and expression of pro-inflammatory proteins. In ob/ob mice, clinical signs of erythema, infiltration and scales in dorsal skin and inflammation in ear skin, as measured by ear thickness, were attenuated and compared with wt mice. Moreover, IL-17A and IL-22 mRNA expression levels, as well as increased epidermal thickness, were significantly less induced. In vitro, the effect of leptin stimulation on human keratinocytes demonstrated increased proliferation and induced secretion of several pro-inflammatory proteins; two hallmarks of psoriasis. In conclusion, leptin deficiency attenuated IMQ-induced psoriasis-like skin inflammation in a mouse model, and leptin stimulation induced a pro-inflammatory phenotype in human keratinocytes, thus, supporting an aggravating role of leptin in psoriasis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Grouping nanomaterials to predict their potential to induce pulmonary inflammation

    International Nuclear Information System (INIS)

    Braakhuis, Hedwig M.; Oomen, Agnes G.; Cassee, Flemming R.

    2016-01-01

    The rapidly expanding manufacturing, production and use of nanomaterials have raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Currently, efforts are made to increase the knowledge on the characteristics of nanomaterials that can be used to categorise them into hazard groups according to these characteristics. Grouping helps to gather information on nanomaterials in an efficient way with the aim to aid risk assessment. Here, we discuss different ways of grouping nanomaterials for their risk assessment after inhalation. Since the relation between single intrinsic particle characteristics and the severity of pulmonary inflammation is unknown, grouping of nanomaterials by their intrinsic characteristics alone is not sufficient to predict their risk after inhalation. The biokinetics of nanomaterials should be taken into account as that affects the dose present at a target site over time. The parameters determining the kinetic behaviour are not the same as the hazard-determining parameters. Furthermore, characteristics of nanomaterials change in the life-cycle, resulting in human exposure to different forms and doses of these nanomaterials. As information on the biokinetics and in situ characteristics of nanomaterials is essential but often lacking, efforts should be made to include these in testing strategies. Grouping nanomaterials will probably be of the most value to risk assessors when information on intrinsic characteristics, life-cycle, biokinetics and effects are all combined. - Highlights: • Grouping of nanomaterials helps to gather information in an efficient way with the aim to aid risk assessment. • Different ways of grouping nanomaterials for their risk assessment after inhalation are

  15. Systemic inflammation in COPD in relation to smoking status

    Directory of Open Access Journals (Sweden)

    Serapinas Danielius

    2011-08-01

    Full Text Available Abstract Background and aims Smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD that has been recently defined as a systemic pulmonary inflammatory disease. However, the impact of smoking itself on systemic inflammation in COPD patients has not yet been well established. The aim of our study was to investigate the association between inflammatory markers and smoking status. Materials and methods We compared 202 current smokers, 61 ex-smokers and 57 never-smokers, all COPD patients. Assessments included medical history, spirometry, alpha-1 antitrypsin (AAT genotyping, serum AAT, C-reactive protein (CRP, tumor necrosis factor (TNF-α, and soluble tumor necrosis factor receptor (sTNFR-1 and sTNFR-2 concentrations. Results AAT and CRP concentrations in smokers (1.75 ± 0.51 g/L and 14.4 [9.5-20.5] mg/L and ex-smokers (1.69 ± 0.43 g/L and 12.3 [8.7-16.3] mg/L were higher than in never-smokers (1.49 ± 0.38 g/L and 5.1 [2.5-8.7] mg/L; p Conclusions Our data confirm that smoking is associated with increased levels of AAT, CRP, and sTNFR-1 in COPD patients, an array of systemic inflammation markers that continue to be active even after smoking cessation.

  16. Pathogenic Inflammation and Its Therapeutic Targeting in Systemic Lupus Erythematosus

    Science.gov (United States)

    Gottschalk, Timothy A.; Tsantikos, Evelyn; Hibbs, Margaret L.

    2015-01-01

    Systemic lupus erythematosus (SLE, lupus) is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues, including skin, kidneys, and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B- and T-lymphocyte activation, and, with the single exception of an agent known as belimumab which targets the B-cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immunosuppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B-cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here, we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and review the known

  17. Pathogenic inflammation and its therapeutic targeting in systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Timothy Andrew Gottschalk

    2015-10-01

    Full Text Available Systemic Lupus Erythematosus (SLE, lupus is a highly complex and heterogeneous autoimmune disease that most often afflicts women in their child-bearing years. It is characterized by circulating self-reactive antibodies that deposit in tissues including skin, kidneys and brain, and the ensuing inflammatory response can lead to irreparable tissue damage. Over many years, clinical trials in SLE have focused on agents that control B and T lymphocyte activation, and, with the single exception of an agent known as Belimumab which targets the B cell survival factor BAFF, they have been disappointing. At present, standard therapy for SLE with mild disease is the agent hydroxychloroquine. During disease flares, steroids are often used, while the more severe manifestations with major organ involvement warrant potent, broad-spectrum immuno-suppression with cyclophosphamide or mycophenolate. Current treatments have severe and dose-limiting toxicities and thus a more specific therapy targeting a causative factor or signaling pathway would be greatly beneficial in SLE treatment. Moreover, the ability to control inflammation alongside B cell activation may be a superior approach for disease control. There has been a recent focus on the innate immune system and associated inflammation, which has uncovered key players in driving the pathogenesis of SLE. Delineating some of these intricate inflammatory mechanisms has been possible with studies using spontaneous mouse mutants and genetically engineered mice. These strains, to varying degrees, exhibit hallmarks of the human disease and therefore have been utilized to model human SLE and to test new drugs. Developing a better understanding of the initiation and perpetuation of disease in SLE may uncover suitable novel targets for therapeutic intervention. Here we discuss the involvement of inflammation in SLE disease pathogenesis, with a focus on several key proinflammatory cytokines and myeloid growth factors, and

  18. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ae Sin; Jung, Yu Jin; Kim, Dal; Nguyen-Thanh, Tung [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Kang, Kyung Pyo [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Lee, Sik [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Park, Sung Kwang [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of); Kim, Won, E-mail: kwon@jbnu.ac.kr [Department of Internal Medicine, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Research Institute of Clinical Medicine of Chonbuk National University, Chonbuk National University Hospital, Jeonju (Korea, Republic of)

    2014-08-08

    Highlights: • Knockout of SIRT2 attenuates lipopolysaccharide-induced iNOS expression. • Lipopolysaccharide-induced NO production is decreased in SIRT2 KO macrophage. • SIRT2 deficiency suppresses lipopolysaccharide-induced ROS production in macrophage. • M1-macrophage related factors are decreased in SIRT2 deficient cells. • SIRT2 deficiency decreases lipopolysaccharide-induced activation of NFκB. - Abstract: Introduction: SIRT2 is a NAD(+)-dependent deacetylases and associated with numerous processes such as infection, carcinogenesis, DNA damage and cell cycle regulation. However, the role of SIRT2 in inflammatory process in macrophage remains unclear. Materials and methods: In the present study, we have evaluated the regulatory effects of SIRT2 in lipopolysaccharide (LPS)-stimulated macrophages isolated from SIRT2 knockout (KO) and wild type (WT) mice or Raw264.7 macrophage cells. As inflammatory parameters, expression of inducible nitric oxide synthase (iNOS), the productions of nitric oxide, reactive oxygen species (ROS) and M1-macrophage-related factors were evaluated. We also examined the effects of SIRT2 on activation of nuclear factor-kappaB (NFκB) signaling. Results: SIRT2 deficiency inhibits LPS-induced iNOS mRNA and protein expression in bone marrow derived macrophages. SIRT2-siRNA transfection also suppressed LPS-induced iNOS expression in Raw264.7 macrophage cells. Bone marrow derived macrophages isolated from SIRT2 KO mice produced lower nitric oxide and expressed lower levels of M1-macrophage related markers including iNOS and CD86 in response to LPS than WT mice. Decrease of SIRT2 reduced the LPS-induced reactive oxygen species production. Deficiency of SIRT2 resulted in inhibition of NFκB activation through reducing the phosphorylation and degradation of IκBα. The phosphorylation and nuclear translocation of p65 was significantly decreased in SIRT2-deficient macrophages after LPS stimulation. Discussion: Our data suggested that

  19. Allergic inflammation does not impact chemical-induced carcinogenesis in the lungs of mice

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    Doris Konstantinos

    2010-08-01

    Full Text Available Abstract Background Although the relationship between allergic inflammation and lung carcinogenesis is not clearly defined, several reports suggest an increased incidence of lung cancer in patients with asthma. We aimed at determining the functional impact of allergic inflammation on chemical carcinogenesis in the lungs of mice. Methods Balb/c mice received single-dose urethane (1 g/kg at day 0 and two-stage ovalbumin during tumor initiation (sensitization: days -14 and 0; challenge: daily at days 6-12, tumor progression (sensitization: days 70 and 84; challenge: daily at days 90-96, or chronically (sensitization: days -14 and 0; challenge: daily at days 6-12 and thrice weekly thereafter. In addition, interleukin (IL-5 deficient and wild-type C57BL/6 mice received ten weekly urethane injections. All mice were sacrificed after four months. Primary end-points were number, size, and histology of lung tumors. Secondary end-points were inflammatory cells and mediators in the airspace compartment. Results Ovalbumin provoked acute allergic inflammation and chronic remodeling of murine airways, evident by airspace eosinophilia, IL-5 up-regulation, and airspace enlargement. Urethane resulted in formation of atypical alveolar hyperplasias, adenomas, and adenocarcinomas in mouse lungs. Ovalbumin-induced allergic inflammation during tumor initiation, progression, or continuously did not impact the number, size, or histologic distribution of urethane-induced pulmonary neoplastic lesions. In addition, genetic deficiency in IL-5 had no effect on urethane-induced lung tumorigenesis. Conclusions Allergic inflammation does not impact chemical-induced carcinogenesis of the airways. These findings suggest that not all types of airway inflammation influence lung carcinogenesis and cast doubt on the idea of a mechanistic link between asthma and lung cancer.

  20. Increased adiposity, dysregulated glucose metabolism and systemic inflammation in Galectin-3 KO mice.

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    Jingbo Pang

    Full Text Available Obesity and type 2 diabetes are associated with increased production of Galectin-3 (Gal-3, a protein that modulates inflammation and clearance of glucose adducts. We used Lean and Diet-induced Obese (DIO WT and Gal-3 KO mice to investigate the role of Gal-3 in modulation of adiposity, glucose metabolism and inflammation. Deficiency of Gal-3 lead to age-dependent development of excess adiposity and systemic inflammation, as indicated by elevated production of acute-phase proteins, number of circulating pro-inflammatory Ly6C(high monocytes and development of neutrophilia, microcytic anemia and thrombocytosis in 20-week-old Lean and DIO male Gal-3 KO mice. This was associated with impaired fasting glucose, heightened response to a glucose tolerance test and reduced adipose tissue expression of adiponectin, Gal-12, ATGL and PPARγ, in the presence of maintained insulin sensitivity and hepatic expression of gluconeogenic enzymes in 20-week-old Gal-3 KO mice compared to their diet-matched WT controls. Expression of PGC-1α and FGF-21 in the liver of Lean Gal-3 KO mice was comparable to that observed in DIO animals. Impaired fasting glucose and altered responsiveness to a glucose load preceded development of excess adiposity and systemic inflammation, as demonstrated in 12-week-old Gal-3 KO mice. Finally, a role for the microflora in mediating the fasting hyperglycemia, but not the excessive response to a glucose load, of 12-week-old Gal-3 KO mice was demonstrated by administration of antibiotics. In conclusion, Gal-3 is an important modulator of glucose metabolism, adiposity and inflammation.

  1. [Change in gene expression of inflammation-related genes induced in multiple organ dysfunction syndrome induced by infection of injuries in rat].

    Science.gov (United States)

    Ban, Yu; Shen, Hong; Li, Tan-shi

    2007-03-01

    To study the changes in inflammation-related gene expression in liver tissue during the course of multiple organ dysfunction syndrome (MODS) induced by infection of injuries and its implication. The rats model with MODS following trauma and infection was reproduced in rat. Liver tissue was harvested. The differences of gene expressions between the simple trauma group and MODS group were detected by means of cDNA microarray. Comparison between the two groups, differentially expressed genes included enhanced expression of genes related both of tissue damage and repair. There was also up-regulation of expression of both inflammation-related and anti-inflammation related genes. A few genes appeared down-regulated. The differences of expression extent were significant. There were up-regulation of some genes related to apoptosis and fibrosis. Differential expressions of genes in the liver tissue include both that related to the inflammation and anti-inflammation, with down-regulation and up-regulation at the same time. There is a difference in the intensity. There is also an expression of genes related to intrinsic protection, as manifested by co-existence of systemic inflammatory response syndrome (SIRS) and compensation anti-inflammatory response syndrome (CARS) under the condition of MODS. There is an imbalance in inflammatory reaction. The simultaneous up-regulation of the tissue damage and repair related genes suggests that cellular injury is accompanied by repair in the organs during the course of MODS.

  2. Time-response relationship of nano and micro particle induced lung inflammation. Quartz as reference compound

    DEFF Research Database (Denmark)

    Roursgaard, Martin; Poulsen, Steen Seier; Poulsen, Lars K.

    2010-01-01

    An increasing number of engineered particles, including nanoparticles, are being manufactured, increasing the need for simple low-dose toxicological screening methods. This study aimed to investigate the kinetics of biomarkers related to acute and sub-chronic particle-induced lung inflammation of...

  3. Cigarette Smoke-Induced Collagen Destruction; Key to Chronic Neutrophilic Airway Inflammation?

    NARCIS (Netherlands)

    Overbeek, Saskia A.; Braber, Saskia; Koelink, Pim J.; Henricks, Paul A. J.; Mortaz, Esmaeil; Loi, Adele T. LoTam; Jackson, Patricia L.; Garssen, Johan; Wagenaar, Gerry T. M.; Timens, Wim; Koenderman, Leo; Blalock, J. Edwin; Kraneveld, Aletta D.; Folkerts, Gert

    2013-01-01

    Background: Cigarette smoking induces inflammatory responses in all smokers and is the major risk factor for lung disease such as chronic obstructive pulmonary disease (COPD). In this progressive disease, chronic inflammation in the lung contributes to lung tissue destruction leading to the

  4. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance

    Science.gov (United States)

    Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammat...

  5. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID during Inflammation-Associated Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Tsutomu Chiba

    2011-06-01

    Full Text Available Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID, a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  6. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Takai, Atsushi; Marusawa, Hiroyuki, E-mail: maru@kuhp.kyoto-u.ac.jp; Chiba, Tsutomu [Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507 (Japan)

    2011-06-22

    Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis.

  7. Acquisition of Genetic Aberrations by Activation-Induced Cytidine Deaminase (AID) during Inflammation-Associated Carcinogenesis

    International Nuclear Information System (INIS)

    Takai, Atsushi; Marusawa, Hiroyuki; Chiba, Tsutomu

    2011-01-01

    Genetic abnormalities such as nucleotide alterations and chromosomal disorders that accumulate in various tumor-related genes have an important role in cancer development. The precise mechanism of the acquisition of genetic aberrations, however, remains unclear. Activation-induced cytidine deaminase (AID), a nucleotide editing enzyme, is essential for the diversification of antibody production. AID is expressed only in activated B lymphocytes under physiologic conditions and induces somatic hypermutation and class switch recombination in immunoglobulin genes. Inflammation leads to aberrant AID expression in various gastrointestinal organs and increased AID expression contributes to cancer development by inducing genetic alterations in epithelial cells. Studies of how AID induces genetic disorders are expected to elucidate the mechanism of inflammation-associated carcinogenesis

  8. Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: II. Effects on skeletal muscle atrophy.

    Science.gov (United States)

    Verhees, Koen J P; Pansters, Nicholas A M; Baarsma, Hoeke A; Remels, Alexander H V; Haegens, Astrid; de Theije, Chiel C; Schols, Annemie M W J; Gosens, Reinoud; Langen, Ramon C J

    2013-11-01

    Chronic obstructive pulmonary disease (COPD) is accompanied by pulmonary inflammation and associated with extra-pulmonary manifestations, including skeletal muscle atrophy. Glycogen synthase kinase-3 (GSK-3) has been implicated in the regulation of muscle protein- and myonuclear turnover; two crucial processes that determine muscle mass. In the present study we investigated the effect of the selective GSK-3 inhibitor SB216763 on muscle mass in a guinea pig model of lipopolysaccharide (LPS)-induced pulmonary inflammation-associated muscle atrophy. Guinea pigs were pretreated with either intranasally instilled SB216763 or corresponding vehicle prior to each LPS/saline challenge twice weekly. Pulmonary inflammation was confirmed and indices of muscle mass were determined after 12 weeks. Additionally, cultured skeletal muscle cells were incubated with tumor necrosis factor α (TNF-α) or glucocorticoids (GCs) to model the systemic effects of pulmonary inflammation on myogenesis, in the presence or absence of GSK-3 inhibitors. Repeated LPS instillation induced muscle atrophy based on muscle weight and muscle fiber cross sectional area. Intriguingly, GSK-3 inhibition using SB216763 prevented the LPS-induced muscle mass decreases and myofiber atrophy. Indices of protein turnover signaling were unaltered in guinea pig muscle. Interestingly, inhibition of myogenesis of cultured muscle cells by TNF-α or synthetic GCs was prevented by GSK-3 inhibitors. In a guinea pig model of LPS-induced pulmonary inflammation, GSK-3 inhibition prevents skeletal muscle atrophy without affecting pulmonary inflammation. Resistance to inflammation- or GC-induced impairment of myogenic differentiation, imposed by GSK-3 inhibition, suggests that sustained myogenesis may contribute to muscle mass maintenance despite persistent pulmonary inflammation. Collectively, these results warrant further exploration of GSK-3 as a potential novel drug target to prevent or reverse muscle wasting in COPD.

  9. Silica-induced Chronic Inflammation Promotes Lung Carcinogenesis in the Context of an Immunosuppressive Microenvironment

    Directory of Open Access Journals (Sweden)

    Javier Freire

    2013-08-01

    Full Text Available The association between inflammation and lung tumor development has been clearly demonstrated. However, little is known concerning the molecular events preceding the development of lung cancer. In this study, we characterize a chemically induced lung cancer mouse model in which lung cancer developed in the presence of silicotic chronic inflammation. Silica-induced lung inflammation increased the incidence and multiplicity of lung cancer in mice treated with N-nitrosodimethylamine, a carcinogen found in tobacco smoke. Histologic and molecular analysis revealed that concomitant chronic inflammation contributed to lung tumorigenesis through induction of preneoplastic changes in lung epithelial cells. In addition, silica-mediated inflammation generated an immunosuppressive microenvironment in which we observed increased expression of programmed cell death protein 1 (PD-1, transforming growth factor-β1, monocyte chemotactic protein 1 (MCP-1, lymphocyte-activation gene 3 (LAG3, and forkhead box P3 (FOXP3, as well as the presence of regulatory T cells. Finally, the K-RAS mutational profile of the tumors changed from Q61R to G12D mutations in the inflammatory milieu. In summary, we describe some of the early molecular changes associated to lung carcinogenesis in a chronic inflammatory microenvironment and provide novel information concerning the mechanisms underlying the formation and the fate of preneoplastic lesions in the silicotic lung.

  10. Moderate Exercise Attenuates Lipopolysaccharide-Induced Inflammation and Associated Maternal and Fetal Morbidities in Pregnant Rats.

    Directory of Open Access Journals (Sweden)

    Karina T Kasawara

    Full Text Available Fetal growth restriction (FGR and coagulopathies are often associated with aberrant maternal inflammation. Moderate-intensity exercise during pregnancy has been shown to increase utero-placental blood flow and to enhance fetal nutrition as well as fetal and placental growth. Furthermore, exercise is known to reduce inflammation. To evaluate the effect of moderate-intensity exercise on inflammation associated with the development of maternal coagulopathies and FGR, Wistar rats were subjected to an exercise regime before and during pregnancy. To model inflammation-induced FGR, pregnant rats were administered daily intraperitoneal injections of E. coli lipopolysaccharide (LPS on gestational days (GD 13.5-16.5 and sacrificed at GD 17.5. Control rats were injected with saline. Maternal hemostasis was assessed by thromboelastography. Moderate-intensity exercise prevented LPS-mediated increases in white blood cell counts measured on GD 17.5 and improved maternal hemostasis profiles. Importantly, our data reveal that exercise prevented LPS-induced FGR. Moderate-intensity exercise initiated before and maintained during pregnancy may decrease the severity of maternal and perinatal complications associated with abnormal maternal inflammation.

  11. Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway.

    Directory of Open Access Journals (Sweden)

    Wook-Bin Lee

    Full Text Available Trehalose 6,6'-dimycolate (TDM, a cord factor of Mycobacterium tuberculosis (Mtb, is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM-induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM-coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK. Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFα production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle⁻/⁻ mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils

  12. Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation.

    Science.gov (United States)

    Behrends, D A; Hui, D; Gao, C; Awlia, A; Al-Saran, Y; Li, A; Henderson, J E; Martineau, P A

    2017-03-01

    Bone repair is initiated with a local inflammatory response to injury. The presence of systemic inflammation impairs bone healing and often leads to malunion, although the underlying mechanisms remain poorly defined. Our research objective was to use a mouse model of cortical bone repair to determine the effect of systemic inflammation on cells in the bone healing microenvironment. QUESTION/PURPOSES: (1) Does systemic inflammation, induced by lipopolysaccharide (LPS) administration affect the quantity and quality of regenerating bone in primary bone healing? (2) Does systemic inflammation alter vascularization and the number or activity of inflammatory cells, osteoblasts, and osteoclasts in the bone healing microenvironment? Cortical defects were drilled in the femoral diaphysis of female and male C57BL/6 mice aged 5 to 9 months that were treated with daily systemic injections of LPS or physiologic saline as control for 7 days. Mice were euthanized at 1 week (Control, n = 7; LPS, n = 8), 2 weeks (Control, n = 7; LPS, n = 8), and 6 weeks (Control, n = 9; LPS, n = 8) after surgery. The quantity (bone volume per tissue volume [BV/TV]) and microarchitecture (trabecular separation and thickness, porosity) of bone in the defect were quantified with time using microCT. The presence or activity of vascular endothelial cells (CD34), macrophages (F4/80), osteoblasts (alkaline phosphatase [ALP]), and osteoclasts (tartrate-resistant acid phosphatase [TRAP]) were evaluated using histochemical analyses. Only one of eight defects was bridged completely 6 weeks after surgery in LPS-injected mouse bones compared with seven of nine defects in the control mouse bones (odds ratio [OR], 0.04; 95% CI, 0.003-0.560; p = 0.007). The decrease in cortical bone in LPS-treated mice was reflected in reduced BV/TV (21% ± 4% vs 39% ± 10%; p inflammation reduced the amount and impaired the quality of bone regenerated in mouse femurs. The effects were associated with impaired revascularization

  13. 5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production.

    Science.gov (United States)

    Voronova, Irina P; Khramova, Galina M; Kulikova, Elizabeth A; Petrovskii, Dmitrii V; Bazovkina, Daria V; Kulikov, Alexander V

    2016-01-01

    G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. A murine model of inflammation-induced cerebral microbleeds

    OpenAIRE

    Sumbria, Rachita K.; Grigoryan, Mher Mahoney; Vasilevko, Vitaly; Krasieva, Tatiana B.; Scadeng, Miriam; Dvornikova, Alexandra K.; Paganini-Hill, Annlia; Kim, Ronald; Cribbs, David H.; Fisher, Mark J.

    2016-01-01

    Background Cerebral microhemorrhages (CMH) are tiny deposits of blood degradation products in the brain and are pathological substrates of cerebral microbleeds. The existing CMH animal models are ?-amyloid-, hypoxic brain injury-, or hypertension-induced. Recent evidence shows that CMH develop independently of hypoxic brain injury, hypertension, or amyloid deposition and CMH are associated with normal aging, sepsis, and neurodegenerative conditions. One common factor among the above pathologi...

  15. Pain perception in healthy volunteers: effect of repeated exposure to experimental systemic inflammation.

    Science.gov (United States)

    Janum, Susanne; Nielsen, Signe T; Werner, Mads U; Mehlsen, Jesper; Kehlet, Henrik; Møller, Kirsten

    2016-10-01

    We aimed to study the relationship between pain perception and cytokine release during systemic inflammation. We present a randomized crossover trial in healthy volunteers (n = 17) in 37 individual trials. Systemic inflammation was induced by an i.v. bolus of Escherichia coli LPS (2 ng/kg) on two separate trial days, with or without a nicotine patch applied 10 h previously. Pain perception at baseline, and 2 and 6 h after LPS was assessed by pressure algometry and tonic heat stimulation at an increasing temperature (45-48℃) during both trials. Compared with baseline, pain pressure threshold was reduced 2 and 6 h after LPS, while heat pain perception was accentuated at all testing temperatures after 2 but not 6 h. The magnitude of changes in pain perception did not correlate to cytokine release. No effect of transdermal nicotine or training status was observed. In conclusion, LPS administration in healthy human volunteers leads to reduction in pain pressure threshold and an increase in pain perception to heat stimuli, supporting a relationship between acute systemic inflammation and pain perception. © The Author(s) 2016.

  16. Development of Sensor Cells Using NF-κB Pathway Activation for Detection of Nanoparticle-Induced Inflammation

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    Akiyoshi Taniguchi

    2011-07-01

    Full Text Available The increasing use of nanomaterials in consumer and industrial products has aroused concerns regarding their fate in biological systems. An effective detection method to evaluate the safety of bio-nanomaterials is therefore very important. Titanium dioxide (TiO2, which is manufactured worldwide in large quantities for use in a wide range of applications, including pigment and cosmetic manufacturing, was once thought to be an inert material, but recently, more and more studies have indicated that TiO2 nanoparticles (TiO2 NPs can cause inflammation and be harmful to humans by causing lung and brain problems. In order to evaluate the safety of TiO2 NPs for the environment and for humans, sensor cells for inflammation detection were developed, and these were transfected with the Toll-like receptor 4 (TLR4 gene and Nuclear Factor Kappa B (NF-κB reporter gene. NF-κB as a primary cause of inflammation has received a lot of attention, and it can be activated by a wide variety of external stimuli. Our data show that TiO2 NPs-induced inflammation can be detected by our sensor cells through NF-κB pathway activation. This may lead to our sensor cells being used for bio-nanomaterial safety evaluation.

  17. The effect of PPE-induced emphysema and chronic LPS-induced pulmonary inflammation on atherosclerosis development in APOE*3-LEIDEN mice.

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    P Padmini S J Khedoe

    Full Text Available BACKGROUND: Chronic obstructive pulmonary disease (COPD is characterized by pulmonary inflammation, airways obstruction and emphysema, and is a risk factor for cardiovascular disease (CVD. However, the contribution of these individual COPD components to this increased risk is unknown. Therefore, the aim of this study was to determine the contribution of emphysema in the presence or absence of pulmonary inflammation to the increased risk of CVD, using a mouse model for atherosclerosis. Because smoke is a known risk factor for both COPD and CVD, emphysema was induced by intratracheal instillation of porcine pancreatic elastase (PPE. METHODS: Hyperlipidemic APOE*3-Leiden mice were intratracheally instilled with vehicle, 15 or 30 µg PPE and after 4 weeks, mice received a Western-type diet (WTD. To study the effect of emphysema combined with pulmonary inflammation on atherosclerosis, mice received 30 µg PPE and during WTD feeding, mice were intranasally instilled with vehicle or low-dose lipopolysaccharide (LPS; 1 µg/mouse, twice weekly. After 20 weeks WTD, mice were sacrificed and emphysema, pulmonary inflammation and atherosclerosis were analysed. RESULTS: Intratracheal PPE administration resulted in a dose-dependent increase in emphysema, whereas atherosclerotic lesion area was not affected by PPE treatment. Additional low-dose intranasal LPS administration induced a low-grade systemic IL-6 response, as compared to vehicle. Combining intratracheal PPE with intranasal LPS instillation significantly increased the number of pulmonary macrophages and neutrophils. Plasma lipids during the study were not different. LPS instillation caused a limited, but significant increase in the atherosclerotic lesion area. This increase was not further enhanced by PPE. CONCLUSION: This study shows for the first time that PPE-induced emphysema both in the presence and absence of pulmonary inflammation does not affect atherosclerotic lesion development.

  18. The effect of PPE-induced emphysema and chronic LPS-induced pulmonary inflammation on atherosclerosis development in APOE*3-LEIDEN mice.

    Science.gov (United States)

    Khedoe, P Padmini S J; Wong, Man C; Wagenaar, Gerry T M; Plomp, Jaap J; van Eck, Miranda; Havekes, Louis M; Rensen, Patrick C N; Hiemstra, Pieter S; Berbée, Jimmy F P

    2013-01-01

    Chronic obstructive pulmonary disease (COPD) is characterized by pulmonary inflammation, airways obstruction and emphysema, and is a risk factor for cardiovascular disease (CVD). However, the contribution of these individual COPD components to this increased risk is unknown. Therefore, the aim of this study was to determine the contribution of emphysema in the presence or absence of pulmonary inflammation to the increased risk of CVD, using a mouse model for atherosclerosis. Because smoke is a known risk factor for both COPD and CVD, emphysema was induced by intratracheal instillation of porcine pancreatic elastase (PPE). Hyperlipidemic APOE*3-Leiden mice were intratracheally instilled with vehicle, 15 or 30 µg PPE and after 4 weeks, mice received a Western-type diet (WTD). To study the effect of emphysema combined with pulmonary inflammation on atherosclerosis, mice received 30 µg PPE and during WTD feeding, mice were intranasally instilled with vehicle or low-dose lipopolysaccharide (LPS; 1 µg/mouse, twice weekly). After 20 weeks WTD, mice were sacrificed and emphysema, pulmonary inflammation and atherosclerosis were analysed. Intratracheal PPE administration resulted in a dose-dependent increase in emphysema, whereas atherosclerotic lesion area was not affected by PPE treatment. Additional low-dose intranasal LPS administration induced a low-grade systemic IL-6 response, as compared to vehicle. Combining intratracheal PPE with intranasal LPS instillation significantly increased the number of pulmonary macrophages and neutrophils. Plasma lipids during the study were not different. LPS instillation caused a limited, but significant increase in the atherosclerotic lesion area. This increase was not further enhanced by PPE. This study shows for the first time that PPE-induced emphysema both in the presence and absence of pulmonary inflammation does not affect atherosclerotic lesion development.

  19. Systemic inflammation and COPD: the Framingham Heart Study.

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    Walter, Robert E; Wilk, Jemma B; Larson, Martin G; Vasan, Ramachandran S; Keaney, John F; Lipinska, Izabella; O'Connor, George T; Benjamin, Emelia J

    2008-01-01

    The current paradigm for the pathogenesis of COPD includes an ultimately maladaptive local inflammatory response to environmental stimuli. We examined the hypothesis that systemic inflammatory biomarkers are associated with impaired lung function, particularly among those with extensive cigarette smoking. Using data from the Framingham Heart Study, we examined cross-sectional associations of systemic inflammatory biomarkers (CD40 ligand [CD40L], intercellular adhesion molecule [ICAM]-1, interleukin [IL]-6, monocyte chemoattractant protein-1, P-selectin, and myeloperoxidase, in addition to C-reactive protein) to impaired lung function. IL-6 was consistently associated with impaired lung function; a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV(1) (95% confidence interval [CI], - 61 to - 20) and a borderline 15% higher odds of COPD (odds ratio, 1.15; 95% CI, 0.99 to 1.34). Additionally, P-selectin was associated with lower FEV(1) levels; after adjusting for the other biomarkers, a 1-SD higher concentration of P-selectin predicted an FEV(1) that was on average 19 mL lower (95% CI, - 37 to 0). Including the biomarkers individually as sole exposures in the models generally strengthened the impaired lung function/biomarker association; the relations of ICAM-1 to FEV(1), and ICAM and CD40L to COPD became significant. The observed associations did not vary significantly with smoking history, except that the association between CD40L and COPD appeared greater in individuals with more extensive smoking histories. Among participants in the Framingham Heart Study, systemic inflammation was associated with lower levels of pulmonary function. Further research into the role of systemic inflammation in the development of pulmonary dysfunction is merited.

  20. LTB4 causes macrophage–mediated inflammation and directly induces insulin resistance in obesity

    Science.gov (United States)

    Bandyopadhyay, Gautam; Lagakos, William S.; Talukdar, Saswata; Osborn, Olivia; Johnson, Andrew; Chung, Heekyung; Maris, Michael; Ofrecio, Jachelle M.; Taguchi, Sayaka; Lu, Min; Olefsky, Jerrold M.

    2015-01-01

    Chronic inflammation is a key component of obesity–induced insulin resistance and plays a central role in metabolic disease. In this study, we found that the major insulin target tissues, liver, muscle and adipose tissue exhibit increased levels of the chemotactic eicosanoid LTB4 in obese high fat diet (HFD) mice compared to lean chow fed mice. Inhibition of the LTB4 receptor, Ltb4r1, through either genetic or pharmacologic loss of function results in an anti–inflammatory phenotype with protection from systemic insulin resistance and hepatic steatosis in the setting of both HFD–induced and genetic obesity. Importantly, in vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways in macrophages, promoted de novo hepatic lipogenesis, decreased insulin stimulated glucose uptake in L6 myocytes, increased gluconeogenesis, and impaired insulin–mediated suppression of hepatic glucose output (HGO) in primary mouse hepatocytes. This was accompanied by decreased insulin stimulated Akt phosphorylation and increased Irs1 and Irs2 serine phosphorylation and all of these events were Gαi and Jnk dependent. Taken together, these observations elucidate a novel role of LTB4/Ltb4r1 in the etiology of insulin resistance in hepatocytes and myocytes, and shows that in vivo inhibition of Ltb4r1 leads to robust insulin sensitizing effects. PMID:25706874

  1. Single and Combined Exposure to Zinc- and Copper-Containing Welding Fumes Lead to Asymptomatic Systemic Inflammation.

    Science.gov (United States)

    Markert, Agnieszka; Baumann, Ralf; Gerhards, Benjamin; Gube, Monika; Kossack, Veronika; Kraus, Thomas; Brand, Peter

    2016-02-01

    Recently, it has been shown that exposure to welding fumes containing both zinc and copper leads to asymptomatic systemic inflammation in humans as shown by an increase of blood C-reactive protein. In the present study, it was investigated which metal is responsible for this effect. Fifteen healthy male subjects were exposed under controlled conditions to welding fumes containing either zinc, or copper, or copper and zinc. For each exposure blood C-reactive protein increased. Copper- and zinc-containing welding fumes are able to induce systemic inflammation.

  2. Stress and Systemic Inflammation: Yin-Yang Dynamics in Health and Diseases.

    Science.gov (United States)

    Yan, Qing

    2018-01-01

    Studies in psychoneuroimmunology (PNI) would provide better insights into the "whole mind-body system." Systems biology models of the complex adaptive systems (CASs), such as a conceptual framework of "Yin-Yang dynamics," may be helpful for identifying systems-based biomarkers and targets for more effective prevention and treatment. The disturbances in the Yin-Yang dynamical balance may result in stress, inflammation, and various disorders including insomnia, Alzheimer's disease, obesity, diabetes, cardiovascular diseases, skin disorders, and cancer. At the molecular and cellular levels, the imbalances in the cytokine pathways, mitochondria networks, redox systems, and various signaling pathways may contribute to systemic inflammation. In the nervous system, Yin and Yang may represent the dynamical associations between the progressive and regressive processes in aging and neurodegenerative diseases. In response to the damages to the heart, the Yin-Yang dynamical balance between proinflammatory and anti-inflammatory cytokine networks is crucial. The studies of cancer have revealed the importance of the Yin-Yang dynamics in the tumoricidal and tumorigenic activities of the immune system. Stress-induced neuroimmune imbalances are also essential in chronic skin disorders including atopic dermatitis and psoriasis. With the integrative framework, the restoration of the Yin-Yang dynamics can become the objective of dynamical systems medicine.

  3. Secretoglobin Superfamily Protein SCGB3A2 Deficiency Potentiates Ovalbumin-Induced Allergic Pulmonary Inflammation

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    Taketomo Kido

    2014-01-01

    Full Text Available Secretoglobin (SCGB 3A2, a cytokine-like secretory protein of small molecular weight, which may play a role in lung inflammation, is predominantly expressed in airway epithelial cells. In order to understand the physiological role of SCGB3A2, Scgb3a2−/− mice were generated and characterized. Scgb3a2−/− mice did not exhibit any overt phenotypes. In ovalbumin- (OVA- induced airway allergy inflammation model, Scgb3a2−/− mice in mixed background showed a decreased OVA-induced airway inflammation, while six times C57BL/6NCr backcrossed congenic Scgb3a2−/− mice showed a slight exacerbation of OVA-induced airway inflammation as compared to wild-type littermates. These results indicate that the loss of SCGB3A2 function was influenced by a modifier gene(s in mixed genetic background and suggest that SCGB3A2 has anti-inflammatory property. The results further suggest the possible use of recombinant human SCGB3A2 as an anti-inflammatory agent.

  4. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice.

    Science.gov (United States)

    Meira, Lisiane B; Bugni, James M; Green, Stephanie L; Lee, Chung-Wei; Pang, Bo; Borenshtein, Diana; Rickman, Barry H; Rogers, Arlin B; Moroski-Erkul, Catherine A; McFaline, Jose L; Schauer, David B; Dedon, Peter C; Fox, James G; Samson, Leona D

    2008-07-01

    Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.

  5. Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats.

    Science.gov (United States)

    Wang, T; Liu, Y; Chen, L; Wang, X; Hu, X-R; Feng, Y-L; Liu, D-S; Xu, D; Duan, Y-P; Lin, J; Ou, X-M; Wen, F-Q

    2009-05-01

    Airway inflammation with mucus overproduction is a distinguishing pathophysiological feature of many chronic respiratory diseases. Phosphodiesterase (PDE) inhibitors have shown anti-inflammatory properties. In the present study, the effect of sildenafil, a potent inhibitor of PDE5 that selectively degrades cyclic guanosine 3',5'-monophosphate (cGMP), on acrolein-induced inflammation and mucus production in rat airways was examined. Rats were exposed to acrolein for 14 and 28 days. Sildenafil or distilled saline was administered intragastrically prior to acrolein exposure. Bronchoalveolar lavage fluid (BALF) was acquired for cell count and the detection of pro-inflammatory cytokine levels. Lung tissue was examined for cGMP content, nitric oxide (NO)-metabolite levels, histopathological lesion scores, goblet cell metaplasia and mucin production. The results suggested that sildenafil pretreatment reversed the significant decline of cGMP content in rat lungs induced by acrolein exposure, and suppressed the increase of lung NO metabolites, the BALF leukocyte influx and pro-inflammatory cytokine release. Moreover, sildenafil pretreatment reduced acrolein-induced Muc5ac mucin synthesis at both mRNA and protein levels, and attenuated airway inflammation, as well as epithelial hyperplasia and metaplasia. In conclusion, sildenafil could attenuate airway inflammation and mucus production in the rat model, possibly through the nitric oxide/cyclic guanosine 3',5'-monophosphate pathway, and, thus, might have a therapeutic potential for chronic airway diseases.

  6. Innate type 2 response to Alternaria extract enhances ryegrass-induced lung inflammation.

    Science.gov (United States)

    Kim, Hee-Kyoo; Lund, Sean; Baum, Rachel; Rosenthal, Peter; Khorram, Naseem; Doherty, Taylor A

    2014-01-01

    Exposure to the fungal allergen Alternaria alternata as well as ryegrass pollen has been implicated in severe asthma symptoms during thunderstorms. We have previously shown that Alternaria extract induces innate type 2 lung inflammation in mice. We hypothesized that the innate eosinophilic response to Alternaria extract may enhance lung inflammation induced by ryegrass. Mice were sensitized to ryegrass allergen and administered a single challenge with A. alternata extract before or after final ryegrass challenges. Levels of eosinophils, neutrophils, Th2 cells, innate lymphoid cells (ILC2), interleukin (IL)-5 and IL-13 in bronchoalveolar lavage (BAL) as well as inflammation and mucus were assessed. Mice receiving ryegrass sensitization and challenge developed an eosinophilic lung response. A single challenge with Alternaria extract given 3 days before or 3 days after ryegrass challenges resulted in increased eosinophils, peribronchial inflammation and mucus production in the airways compared with ryegrass-only challenges. Type 2 ILC2 and Th2 cell recruitment to the airways was increased after Alternaria extract exposure in ryegrass-challenged mice. Innate immune challenges with Alternaria extract induced BAL eosinophilia, Th2 cell recruitment as well as ILC2 expansion and proliferation. A single exposure to Alternaria extract in ryegrass-sensitized and -challenged mice enhances the type 2 lung inflammatory response, including airway eosinophilia, peribronchial infiltrate, and mucus production, possibly through Th2 cell recruitment and ILC2 expansion. If translated to humans, exposure to both grass pollen and Alternaria may be a potential cause of thunderstorm-related asthma.

  7. Innate Type-2 Response to Alternaria Extract Enhances Ryegrass-induced Lung Inflammation

    Science.gov (United States)

    Kim, Hee-Kyoo; Lund, Sean; Baum, Rachel; Rosenthal, Peter; Khorram, Naseem; Doherty, Taylor A.

    2014-01-01

    Background Exposure to the fungal allergen Alternaria alternata as well as ryegrass pollen has been implicated in severe asthma symptoms during thunderstorms. We have previously shown that Alternaria extract induces innate type 2 lung inflammation in mice. We hypothesized that the innate eosinophilic response to Alternaria extract may enhance lung inflammation induced by ryegrass. Methods Mice were sensitized to ryegrass allergen and administered a single challenge with Alternaria alternata extract before or after final ryegrass challenges. Levels of BAL eosinophils, neutrophils, Th2 cells, innate lymphoid cells (ILC2), IL-5 and IL-13 as well as inflammation and mucus were assessed. Results Mice receiving ryegrass sensitization and challenge developed an eosinophilic lung response. A single challenge with Alternaria extract given 3 days before or 3 days after ryegrass challenges resulted in increased eosinophils, peribronchial inflammation and mucus production in the airway compared with ryegrass only challenges. Type 2 innate lymphoid cell (ILC2) and Th2 cell recruitment to the airway was increased after Alternaria extract exposure in ryegrass challenged mice. Innate challenges with Alternaria extract induced BAL eosinophilia, Th2 cell recruitment as well as ILC2 expansion and proliferation. Conclusions A single exposure of Alternaria extract in ryegrass sensitized and challenged mice enhances the type-2 lung inflammatory response including airway eosinophilia, peribronchial infiltrate, and mucus production possibly through Th2 cell recruitment and ILC2 expansion. If translated to humans, exposures to both grass pollen and Alternaria may be a potential cause of thunderstorm-related asthma. PMID:24296722

  8. Characterization and pharmacological modulation of intestinal inflammation induced by ionizing radiation; Caracterisation et modulation pharmacologique de l'inflammation intestinale induite par les rayonnements ionisants

    Energy Technology Data Exchange (ETDEWEB)

    Gremy, O

    2006-12-15

    The use of radiation therapy to treat abdominal and pelvic malignancies inevitably involves exposure of healthy intestinal tissues which are very radiosensitive. As a result, most patients experience symptoms such as abdominal pain, nausea and diarrhea. Such symptoms are associated with acute damage to intestine mucosa including radio-induced inflammatory processes. With a rat model of colorectal fractionated radiation, we have shown a gradual development of a colonic inflammation during radiation planning, without evident tissue injury. This radio-induced inflammation is characterized not only by the sur expressions of pro-inflammatory cytokines and chemokines, a NF-kB activation, but also by a repression of anti-inflammatory cytokines and the nuclear receptors PPARa and RXRa, both involved in inflammation control. This early inflammation is associated with a discreet neutrophil recruitment and a macrophage accumulation. Macrophages are still abnormally numerous in tissue 27 weeks after the last day of irradiation. Inflammatory process is the most often related to a specific immune profile, either a type Th1 leading to a cellular immune response, or a type Th2 for humoral immunity. According to our studies, a unique abdominal radiation in the rat induces an ileum inflammation and an immune imbalance resulting in a Th2-type profile. Inhibiting this profile is important as its persistence promotes chronic inflammation, predisposition to bacterial infections and fibrosis which is the main delayed side-effect of radiotherapy. The treatment of rats with an immuno-modulator compound, the caffeic acid phenethyl ester (C.A.P.E.), have the potential to both reduce ileal mucosal inflammation and inhibit the radio-induced Th2 status. In order to search new therapeutic molecular target, we has been interested in the PPARg nuclear receptor involved in the maintenance of colon mucosal integrity. In our abdominal irradiation model, we have demonstrated that the prophylactic

  9. Exposure-dependent control of malaria-induced inflammation in children.

    Science.gov (United States)

    Portugal, Silvia; Moebius, Jacqueline; Skinner, Jeff; Doumbo, Safiatou; Doumtabe, Didier; Kone, Younoussou; Dia, Seydou; Kanakabandi, Kishore; Sturdevant, Daniel E; Virtaneva, Kimmo; Porcella, Stephen F; Li, Shanping; Doumbo, Ogobara K; Kayentao, Kassoum; Ongoiba, Aissata; Traore, Boubacar; Crompton, Peter D

    2014-04-01

    In malaria-naïve individuals, Plasmodium falciparum infection results in high levels of parasite-infected red blood cells (iRBCs) that trigger systemic inflammation and fever. Conversely, individuals in endemic areas who are repeatedly infected are often asymptomatic and have low levels of iRBCs, even young children. We hypothesized that febrile malaria alters the immune system such that P. falciparum re-exposure results in reduced production of pro-inflammatory cytokines/chemokines and enhanced anti-parasite effector responses compared to responses induced before malaria. To test this hypothesis we used a systems biology approach to analyze PBMCs sampled from healthy children before the six-month malaria season and the same children seven days after treatment of their first febrile malaria episode of the ensuing season. PBMCs were stimulated with iRBC in vitro and various immune parameters were measured. Before the malaria season, children's immune cells responded to iRBCs by producing pro-inflammatory mediators such as IL-1β, IL-6 and IL-8. Following malaria there was a marked shift in the response to iRBCs with the same children's immune cells producing lower levels of pro-inflammatory cytokines and higher levels of anti-inflammatory cytokines (IL-10, TGF-β). In addition, molecules involved in phagocytosis and activation of adaptive immunity were upregulated after malaria as compared to before. This shift was accompanied by an increase in P. falciparum-specific CD4+Foxp3- T cells that co-produce IL-10, IFN-γ and TNF; however, after the subsequent six-month dry season, a period of markedly reduced malaria transmission, P. falciparum-inducible IL-10 production remained partially upregulated only in children with persistent asymptomatic infections. These findings suggest that in the face of P. falciparum re-exposure, children acquire exposure-dependent P. falciparum-specific immunoregulatory responses that dampen pathogenic inflammation while enhancing anti

  10. Ex-Vivo Uterine Environment (EVE Therapy Induced Limited Fetal Inflammation in a Premature Lamb Model.

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    Yuichiro Miura

    Full Text Available Ex-vivo uterine environment (EVE therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume.Ewes underwent surgical delivery at 115 days of gestation (term is 150 days, and fetuses were transferred to EVE therapy (EVE group; n = 5. Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6 were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups.Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p0.05 in surfactant protein mRNA expression level between the two groups.In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of future studies.

  11. Subacute endotoxemia induces adipose inflammation and changes in lipid and lipoprotein metabolism in cats.

    Science.gov (United States)

    Osto, M; Zini, E; Franchini, M; Wolfrum, C; Guscetti, F; Hafner, M; Ackermann, M; Reusch, C E; Lutz, T A

    2011-03-01

    Acute inflammation in humans is associated with transient insulin resistance (IR) and dyslipidemia. Chronic low-grade inflammation is a pathogenic component of IR and adipose tissue dysfunction in obesity-induced type 2 diabetes. Because feline diabetes closely resembles human type 2 diabetes, we studied whether lipopolysaccharide (LPS)-induced subacute inflammation, in the absence of obesity, is the potential primary cause of IR and metabolic disorders. Cats received increasing iv doses (10-1000 ng/kg(-1) · h(-1)) of LPS (n = 5) or saline (n = 5) for 10 d. Body temperature, proinflammatory and metabolic markers, and insulin sensitivity were measured daily. Tissue mRNA and protein expression were quantified on d 10. LPS infusion increased circulating and tissue markers of inflammation. Based on the homeostasis model assessment, endotoxemia induced transient IR and β-cell dysfunction. At the whole-body level, IR reverted after the 10-d treatment; however, tissue-specific indications of IR were observed, such as down-regulation of adipose glucose transporter 4, hepatic peroxisome proliferative activated receptor-γ1 and -2, and muscle insulin receptor substrate-1. In adipose tissue, increased hormone-sensitive lipase activity led to reduced adipocyte size, concomitant with increased plasma and hepatic triglyceride content and decreased total and high-density lipoprotein cholesterol levels. Prolonged LPS-induced inflammation caused acute IR, followed by long-lasting tissue-specific dysfunctions of lipid-, glucose-, and insulin metabolism-related targets; this ultimately resulted in dyslipidemia but not whole-body IR. Endotoxemia in cats may provide a promising model to study the cross talk between metabolic and inflammatory responses in the development of adipose tissue dysfunction and IR.

  12. Protective effect of sugar cane extract against dextran sulfate sodium-induced colonic inflammation in mice.

    Science.gov (United States)

    Wang, Bin; Li, Yansen; Mizu, Masami; Furuta, Toma; Li, ChunMei

    2017-02-01

    Sugar cane extract (SCE) exhibits various biological effects and has been reported to enhance animal growth performance. However, the effect of SCE on inflammation in animals is still obscure. To study the effects and underlying mechanism of SCE on dextran sulfate sodium (DSS)-induced colonic inflammation, forty female ICR mice (26.63±0.19g, 6-week-old) were assigned into four groups: a control group (Cont), a DSS-challenged group (DSS), a SCE-supplemented group (SCE), and a DSS+SCE group (DSS+SCE). Mice in Cont group and DSS group were fed basic diet and other mice received 1% SCE supplemented in basic diet from 6-week to 8-week-old. Mice in DSS and DSS+SCE groups were also given a 4% DSS solution from 7-week to 8-week-old via drinking water to induce colonic inflammation. After 2 weeks, mice were sacrificed and samples were collected. The results showed that dietary SCE alleviated DSS induced growth suppression, splenic damage, colonic histological changes, colonic inflammation, oxidative stress, and colonic dysfunction of tight junctions. Meanwhile, the DSS exposure activated nuclear transcription factor kappa B p65 and inhibited nuclear factor E2-related factor 2 (Nrf2), while SCE markedly attenuated the DSS-promoted effect on the p65 nuclear accumulation and the DSS-inhibited effect on the Nrf2 nuclear accumulation. In conclusion, SCE conferred a protective role in the DSS-induced inflammation and the mechanism might be associated with the activated signals of the nuclear factor kappa B p65 and Nrf2. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Dietary soy isoflavones alleviate dextran sulfate sodium-induced inflammation and oxidative stress in mice.

    Science.gov (United States)

    Wang, Bin; Wu, Cunbing

    2017-07-01

    It has been hypothesized that soy isoflavones exhibit anti-oxidative and anti-inflammatory functions, however, the effects of soy isoflavones on inflammatory bowel diseases remain unknown. Therefore, the present study aimed to investigate the effect and underlying mechanism of dietary soy isoflavones on dextran sulfate sodium (DSS)-induced colitis. Mice were administered DSS and soy isoflavones, and histomorphometry, oxidative stress, inflammation and intestinal tight junctions were determined. The current study demonstrated that dietary soy isoflavones alleviated DSS-induced growth suppression, colonic inflammatory response, oxidative stress and colonic barrier dysfunction. DSS treatment was indicated to activate Toll-like receptor 4 (TRL4) and myeloid differentiation protein 88 (MyD88) in mice, whereas dietary soy isoflavones inhibited Myd88 expression in DSS-challenged mice. In conclusion, dietary soy isoflavones alleviate DSS-induced inflammation in mice, which may be associated with enhancing antioxidant function and inhibiting the TLR4/MyD88 signal.

  14. A hepatic protein, fetuin-A, occupies a protective role in lethal systemic inflammation.

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    Wei Li

    2011-02-01

    Full Text Available A liver-derived protein, fetuin-A, was first purified from calf fetal serum in 1944, but its potential role in lethal systemic inflammation was previously unknown. This study aims to delineate the molecular mechanisms underlying the regulation of hepatic fetuin-A expression during lethal systemic inflammation (LSI, and investigated whether alterations of fetuin-A levels affect animal survival, and influence systemic accumulation of a late mediator, HMGB1.LSI was induced by endotoxemia or cecal ligation and puncture (CLP in fetuin-A knock-out or wild-type mice, and animal survival rates were compared. Murine peritoneal macrophages were challenged with exogenous (endotoxin or endogenous (IFN-γ stimuli in the absence or presence of fetuin-A, and HMGB1 expression and release was assessed. Circulating fetuin-A levels were decreased in a time-dependent manner, starting between 26 h, reaching a nadir around 24-48 h, and returning towards base-line approximately 72 h post onset of endotoxemia or sepsis. These dynamic changes were mirrored by an early cytokine IFN-γ-mediated inhibition (up to 50-70% of hepatic fetuin-A expression. Disruption of fetuin-A expression rendered animals more susceptible to LSI, whereas supplementation of fetuin-A (20-100 mg/kg dose-dependently increased animal survival rates. The protection was associated with a significant reduction in systemic HMGB1 accumulation in vivo, and parallel inhibition of IFN-γ- or LPS-induced HMGB1 release in vitro.These experimental data suggest that fetuin-A is protective against lethal systemic inflammation partly by inhibiting active HMGB1 release.

  15. Galangin Abrogates Ovalbumin-Induced Airway Inflammation via Negative Regulation of NF-κB

    Directory of Open Access Journals (Sweden)

    Wang-Jian Zha

    2013-01-01

    Full Text Available Persistent activation of nuclear factor κB (NF-κB has been associated with the development of asthma. Galangin, the active pharmacological ingredient from Alpinia galanga, is reported to have a variety of anti-inflammatory properties in vitro via negative regulation of NF-κB. This study aimed to investigate whether galangin can abrogate ovalbumin- (OVA- induced airway inflammation by negative regulation of NF-κB. BALB/c mice sensitized and challenged with OVA developed airway hyperresponsiveness (AHR and inflammation. Galangin dose dependently inhibited OVA-induced increases in total cell counts, eosinophil counts, and interleukin-(IL- 4, IL-5, and IL-13 levels in bronchoalveolar lavage fluid, and reduced serum level of OVA-specific IgE. Galangin also attenuated AHR, reduced eosinophil infiltration and goblet cell hyperplasia, and reduced expression of inducible nitric oxide synthase and vascular cell adhesion protein-1 (VCAM-1 levels in lung tissue. Additionally, galangin blocked inhibitor of κB degradation, phosphorylation of the p65 subunit of NF-κB, and p65 nuclear translocation from lung tissues of OVA-sensitized mice. Similarly, in normal human airway smooth muscle cells, galangin blocked tumor necrosis factor-α induced p65 nuclear translocation and expression of monocyte chemoattractant protein-1, eotaxin, CXCL10, and VCAM-1. These results suggest that galangin can attenuate ovalbumin-induced airway inflammation by inhibiting the NF-κB pathway.

  16. Effects of Papaver rhoeas (L.) extract on formalin-induced pain and inflammation in mice.

    Science.gov (United States)

    Saeed-Abadi, S; Ranjbaran, M; Jafari, F; Najafi-Abedi, A; Rahmani, B; Esfandiari, B; Delfan, B; Mojabi, N; Ghahramani, M; Sahraei, H

    2012-11-01

    Stress amelioration can improve its metabolic as well as other side effects. In the present study, the effects of hydro-alcoholic extract of Papver rhoeas (L.) on formalin-induced pain and inflammation were investigated in male Swiss-Webster mice (20-25 g). Formalin injects in the plantar portion of mice hind paw and pain was studied for 60 min. The plant extract and other drugs were administered intraperitoneally 30 min before formalin. Experiments showed that administration of extract (25, 50 and 100 mg kg(-1)) could induced analgesia in a dose-response manner in both phases of formalin test. More over, the extract inhibits inflammation induced by formalin injection. Naloxone (4 mg kg(-1)), dextromethorphan (20 mg kg(-1)) and NG-nitro-L-arginine-methylester (L-NAME; 10 mg kg(-1)) reduced the extract analgesia in first but not late phase. Extract administration also increased plasma corticosterone level in dose-dependent manner. It could be concluded that Papaver rhoeas (L.) extract could inhibits acute phase of formalin test in mice by opioidergic, glutamatergic and nitricergic mechanisms. In addition, the extract can induce corticosterone plasma level which may be responsible for inhibition of inflammation and chronic phase of pain induced by formalin.

  17. Cadmium induces lung inflammation independent of lung cell proliferation: a molecular approach

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    Kundu Subhadip

    2009-06-01

    Full Text Available Abstract Background Cadmium is one of the inflammation-related xenobiotics and has been regarded as a potent carcinogen. The relationship between inflammation and cell proliferation due to chronic infection has been studied, but the mechanism is not fully clear. Though the mode of cadmium toxicity is well characterized in animal cells, still it requires some further investigations. Previously we reported that cadmium induces immune cell death in Swiss albino mice. In the present study we showed that instead of inducing cell death mechanism, cadmium in low concentration triggers proliferation in mice lung cell and our results reveals that prior to the induction of proliferation it causes severe inflammation. Methods Swiss albino mice were treated with different concentrations of cadmium to determine the LD50. Mice were subdivided (5 mice each according to the exposure period (15, 30, 45, 60 days and were given sub lethal dose (5 mg/Kg body weight of cadmium chloride and ibuprofen (50 mg/Kg body weight, recommended dose once in a week. SEM and histology were performed as evidence of changes in cellular morphology. Inflammation was measured by the expression of Cox-2 and MMPs. Expression of proinflammatory cytokines (Cox-2, IL-6, signaling and cell cycle regulatory molecules (STAT3, Akt, CyclinD1 were measured by western blot, ELISA and immunoprecipitation. Mutagenecity was evidenced by comet assay. Cell proliferation was determined by cell count, cell cycle and DNA analysis. Results Prolonged exposure of low concentration of cadmium resulted in up regulation of proinflammatory cytokines and cell cycle regulatory molecules. Though NSAIDs like Ibuprofen reduces the expression of inflammatory cytokines, but it did not show any inhibitory effect on cadmium adopted lung cell proliferation. Conclusion Our results prove that cadmium causes both inflammation and cell proliferation when applied in a low dose but proliferative changes occur independent of

  18. Unsaturated Fatty Acids Revert Diet-Induced Hypothalamic Inflammation in Obesity

    Science.gov (United States)

    Cintra, Dennys E.; Ropelle, Eduardo R.; Moraes, Juliana C.; Pauli, José R.; Morari, Joseane; de Souza, Claudio T.; Grimaldi, Renato; Stahl, Marcela; Carvalheira, José B.; Saad, Mario J.; Velloso, Licio A.

    2012-01-01

    Background In experimental models, hypothalamic inflammation is an early and determining factor in the installation and progression of obesity. Pharmacological and gene-based approaches have proven efficient in restraining inflammation and correcting the obese phenotypes. However, the role of nutrients in the modulation of hypothalamic inflammation is unknown. Methodology/Principal Findings Here we show that, in a mouse model of diet-induced obesity, partial substitution of the fatty acid component of the diet by flax seed oil (rich in C18:3) or olive oil (rich in C18:1) corrects hypothalamic inflammation, hypothalamic and whole body insulin resistance, and body adiposity. In addition, upon icv injection in obese rats, both ω3 and ω9 pure fatty acids reduce spontaneous food intake and body mass gain. These effects are accompanied by the reversal of functional and molecular hypothalamic resistance to leptin/insulin and increased POMC and CART expressions. In addition, both, ω3 and ω9 fatty acids inhibit the AMPK/ACC pathway and increase CPT1 and SCD1 expression in the hypothalamus. Finally, acute hypothalamic injection of ω3 and ω9 fatty acids activate signal transduction through the recently identified GPR120 unsaturated fatty acid receptor. Conclusions/Significance Unsaturated fatty acids can act either as nutrients or directly in the hypothalamus, reverting diet-induced inflammation and reducing body adiposity. These data show that, in addition to pharmacological and genetic approaches, nutrients can also be attractive candidates for controlling hypothalamic inflammation in obesity. PMID:22279596

  19. Peripheral inflammation induces up-regulation of TRPV2 expression in rat DRG.

    Science.gov (United States)

    Shimosato, Goshun; Amaya, Fumimasa; Ueda, Masashi; Tanaka, Yoshifumi; Decosterd, Isabelle; Tanaka, Masaki

    2005-12-15

    The transient receptor potential vanilloid subfamily member 2 (TRPV2) is a cation channel activated by temperatures above 52 degrees C. To analyze the contribution of TRPV2 to the development of inflammation-induced hyperalgesia, the expression of TRPV2 in primary sensory neurons was analyzed after intraplantar injection of complete Freund's adjuvant (CFA). Using specific antibodies, an increase in TRPV2-expressing neurons was identified after inflammation. TRPV2 expression is concentrated in a subset of medium-sized dorsal root ganglion neurons, independent of transient receptor potential vanilloid subfamily member 1 (TRPV1) expression. A similar distribution of TRPV2 was observed after inflammation. Intraplantar injection of nerve growth factor increased TRPV1 expression but not TRPV2, suggesting that induction of TRPV2 expression is driven by a mechanism distinct from that for TRPV1. Heat hyperalgesia assessment after chemical desensitization of TRPV1 by resiniferatoxin demonstrates a possible role for TRPV2 in inflammation at high temperatures (>56 degrees C). These results suggest that TRPV2 upregulation contributes to peripheral sensitization during inflammation and is responsible for pain hypersensitivity to noxious high temperature stimuli.

  20. Effects of lipopolysaccharide-induced inflammation on expression of growth-associated genes by corticospinal neurons

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    Lieberman AR

    2006-01-01

    Full Text Available Abstract Background Inflammation around cell bodies of primary sensory neurons and retinal ganglion cells enhances expression of neuronal growth-associated genes and stimulates axonal regeneration. We have asked if inflammation would have similar effects on corticospinal neurons, which normally show little response to spinal cord injury. Lipopolysaccharide (LPS was applied onto the pial surface of the motor cortex of adult rats with or without concomitant injury of the corticospinal tract at C4. Inflammation around corticospinal tract cell bodies in the motor cortex was assessed by immunohistochemistry for OX42 (a microglia and macrophage marker. Expression of growth-associated genes c-jun, ATF3, SCG10 and GAP-43 was investigated by immunohistochemistry or in situ hybridisation. Results Application of LPS induced a gradient of inflammation through the full depth of the motor cortex and promoted c-Jun and SCG10 expression for up to 2 weeks, and GAP-43 upregulation for 3 days by many corticospinal neurons, but had very limited effects on neuronal ATF3 expression. However, many glial cells in the subcortical white matter upregulated ATF3. LPS did not promote sprouting of anterogradely labelled corticospinal axons, which did not grow into or beyond a cervical lesion site. Conclusion Inflammation produced by topical application of LPS promoted increased expression of some growth-associated genes in the cell bodies of corticospinal neurons, but was insufficient to promote regeneration of the corticospinal tract.

  1. Cholesterol crystals piercing the arterial plaque and intima trigger local and systemic inflammation.

    Science.gov (United States)

    Abela, George S

    2010-01-01

    The response to arterial wall injury is an inflammatory process, which over time becomes integral to the development of atherosclerosis and subsequent plaque instability. However, the underlying injurious agent, critical to this process, has not received much attention. In this review, a model of plaque rupture is hypothesized with two stages of inflammatory activity. In stage I (cholesterol crystal-induced cell injury and apoptosis), intracellular cholesterol crystals induce foam cell apoptosis, setting up a vicious cycle by signaling more macrophages, resulting in accumulation of extra cellular lipids. This local inflammation eventually leads to the formation of a semi-liquid, lipid-rich necrotic core of a vulnerable plaque. In stage II (cholesterol crystal-induced arterial wall injury), the saturated lipid core is now primed for crystallization, which can manifest as a clinical syndrome with a systemic inflammation response. Cholesterol crystallization is the trigger that causes core expansion, leading to intimal injury. We recently demonstrated that when cholesterol crystallizes from a liquid to a solid state, it undergoes volume expansion, which can tear the plaque cap. This observation of cholesterol crystals perforating the cap and intimal surface was made in the plaques of patients who died with acute coronary syndrome. We have also demonstrated that several agents (ie, statins, aspirin, and ethanol) can dissolve cholesterol crystals and may be exerting their immediate benefits by this direct mechanism. Also, because recent studies have demonstrated that high-sensitivity C-reactive protein may be a reliable marker in selecting patients for statin therapy, it could reflect the presence of intimal injury by cholesterol crystals. This was demonstrated in an atherosclerotic rabbit model. Therefore, we propose that cholesterol crystallization could help explain in part both local and systemic inflammation associated with atherosclerosis. Copyright © 2010

  2. The Alternaria alternata Mycotoxin Alternariol Suppresses Lipopolysaccharide-Induced Inflammation.

    Science.gov (United States)

    Grover, Shivani; Lawrence, Christopher B

    2017-07-20

    The Alternaria mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) have been shown to possess genotoxic and cytotoxic properties. In this study, the ability of AOH and AME to modulate innate immunity in the human bronchial epithelial cell line (BEAS-2B) and mouse macrophage cell line (RAW264.7) were investigated. During these studies, it was discovered that AOH and to a lesser extent AME potently suppressed lipopolysaccharide (LPS)-induced innate immune responses in a dose-dependent manner. Treatment of BEAS-2B cells with AOH resulted in morphological changes including a detached pattern of growth as well as elongated arms. AOH/AME-related immune suppression and morphological changes were linked to the ability of these mycotoxins to cause cell cycle arrest at the G2/M phase. This model was also used to investigate the AOH/AME mechanism of immune suppression in relation to aryl hydrocarbon receptor (AhR). AhR was not found to be important for the immunosuppressive properties of AOH/AME, but appeared important for the low levels of cell death observed in BEAS-2B cells.

  3. Inflammation and its resolution and the musculoskeletal system

    Directory of Open Access Journals (Sweden)

    Jiri Gallo

    2017-07-01

    The translational potential of this article: Understanding the mechanisms of inflammation and its resolution is therefore critical for the development of effective regenerative, and therapeutic strategies in orthopaedics.

  4. Biomarkers of systemic inflammation and depression and fatigue in moderate clinically stable COPD

    DEFF Research Database (Denmark)

    Al-shair, Khaled; Kolsum, Umme; Dockry, Rachel

    2011-01-01

    COPD is an inflammatory disease with major co-morbidities. It has recently been suggested that depression may be the result of systemic inflammation. We aimed to explore the association between systemic inflammation and symptoms of depression and fatigue in patients with mainly moderate and clini......COPD is an inflammatory disease with major co-morbidities. It has recently been suggested that depression may be the result of systemic inflammation. We aimed to explore the association between systemic inflammation and symptoms of depression and fatigue in patients with mainly moderate...

  5. Effects of vagus nerve stimulation and vagotomy on systemic and pulmonary inflammation in a two-hit model in rats.

    Directory of Open Access Journals (Sweden)

    Matthijs Kox

    Full Text Available Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis-induced pulmonary inflammation (first hit may be potentiated by mechanical ventilation (MV, second hit. Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX and vagus nerve stimulation (VNS on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg or moderate (15 mL/kg tidal volumes was initiated, or animals were left breathing spontaneously (SP. After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-α, IL-6, KC: p<0.05 compared to LPS-SP, but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-α, IL-6, KC: p<0.05 compared to SHAM, and resulted in decreased pO(2 (p<0.05 compared to sham-operated animals. VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated.

  6. Role of Inflammation in MPTP-Induced Dopaminergic Degeneration

    Science.gov (United States)

    2005-12-01

    Stern, G , Wilkin, GP, et al. Inflammatory regulators in Parkinson’s disease: iNOS, lipocortin-1 and cyclooxygenase 1 and 2. Mol Cell Neurosci, 16:724...INTRODUCTION profound deficit in brain dopamine (15). Another pathologi- cal hallmark of PD is the eosinophilic intraneuronal proteina -p ARKINSON’S...killing of SNpc dopamninergic ates HI202, as illustrated above. In biological systems, the pro-the a efimtion el t i ~p pain g duction of H 0 results

  7. Saccharin induced liver inflammation in mice by altering the gut microbiota and its metabolic functions.

    Science.gov (United States)

    Bian, Xiaoming; Tu, Pengcheng; Chi, Liang; Gao, Bei; Ru, Hongyu; Lu, Kun

    2017-09-01

    Maintaining the balance of the gut microbiota and its metabolic functions is vital for human health, however, this balance can be disrupted by various external factors including food additives. A range of food and beverages are sweetened by saccharin, which is generally considered to be safe despite controversial debates. However, recent studies indicated that saccharin perturbed the gut microbiota. Inflammation is frequently associated with disruptions of the gut microbiota. The aim of this study is to investigate the relationship between host inflammation and perturbed gut microbiome by saccharin. C57BL/6J male mice were treated with saccharin in drinking water for six months. Q-PCR was used to detect inflammatory markers in mouse liver, while 16S rRNA gene sequencing and metabolomics were used to reveal changes of the gut microbiota and its metabolomic profiles. Elevated expression of pro-inflammatory iNOS and TNF-α in liver indicated that saccharin induced inflammation in mice. The altered gut bacterial genera, enriched orthologs of pathogen-associated molecular patterns, such as LPS and bacterial toxins, in concert with increased pro-inflammatory metabolites suggested that the saccharin-induced liver inflammation could be associated with the perturbation of the gut microbiota and its metabolic functions. Copyright © 2017. Published by Elsevier Ltd.

  8. An Uncaria tomentosa (cat's claw) extract protects mice against ozone-induced lung inflammation.

    Science.gov (United States)

    Cisneros, Francisco J; Jayo, Manuel; Niedziela, Linda

    2005-01-15

    Ozone (O(3)) inhalation has been associated with respiratory tract inflammation and lung functional alterations. To characterize the O(3)-induced lung inflammation in mice, the effective dose and exposure time were determined. Total protein levels of bronchoalveolar lavage fluid (BALF), cytological smears, and lung histopathology and morphometry were used to assess and measure the degree of pulmonary inflammation in the mouse model. Ozone inhalation caused acute pneumonitis that was characterized by a high number of infiltrating neutrophils (PMNs) immediately after exposure and increased levels of protein in BALF in mice killed 8h after O(3) exposure. The anti-inflammatory properties of Uncaria tomentosa (UT) have been documented previously. To evaluate the anti-inflammatory effects of UT, male mice were given an UT extract for 8 days, exposed to O(3), and killed 0 or 8 h after O(3) exposure. When compared to untreated controls, UT-treated mice had significantly (p < 0.05) lower levels of protein in BALF, lower degree of epithelial necrosis, higher number of intact epithelial cell nuclei in bronchial wall, and decreased number of PMNs in the bronchiolar lumen. Therefore, UT extract appeared to prevent O(3)-induced respiratory inflammation in male mice.

  9. Antioxidant Effect of Spirulina (Arthrospira) maxima on Chronic Inflammation Induced by Freund's Complete Adjuvant in Rats.

    Science.gov (United States)

    Gutiérrez-Rebolledo, Gabriel Alfonso; Galar-Martínez, Marcela; García-Rodríguez, Rosa Virginia; Chamorro-Cevallos, Germán A; Hernández-Reyes, Ana Gabriela; Martínez-Galero, Elizdath

    2015-08-01

    One of the major mechanisms in the pathogenesis of chronic inflammation is the excessive production of reactive oxygen and reactive nitrogen species, and therefore, oxidative stress. Spirulina (Arthrospira) maxima has marked antioxidant activity in vivo and in vitro, as well as anti-inflammatory activity in certain experimental models, the latter activity being mediated probably by the antioxidant activity of this cyanobacterium. In the present study, chronic inflammation was induced through injection of Freund's complete adjuvant (CFA) in rats treated daily with Spirulina (Arthrospira) maxima for 2 weeks beginning on day 14. Joint diameter, body temperature, and motor capacity were assessed each week. On days 0 and 28, total and differential leukocyte counts and serum oxidative damage were determined, the latter by assessing lipid peroxidation and protein carbonyl content. At the end of the study, oxidative damage to joints was likewise evaluated. Results show that S. maxima favors increased mobility, as well as body temperature regulation, and a number of circulating leukocytes, lymphocytes, and monocytes in specimens with CFA-induced chronic inflammation and also protects against oxidative damage in joint tissue as well as serum. In conclusion, the protection afforded by S. maxima against development of chronic inflammation is due to its antioxidant activity.

  10. Uric Acid Induces Renal Inflammation via Activating Tubular NF-κB Signaling Pathway

    Science.gov (United States)

    Zhou, Yang; Fang, Li; Jiang, Lei; Wen, Ping; Cao, Hongdi; He, Weichun; Dai, Chunsun; Yang, Junwei

    2012-01-01

    Inflammation is a pathologic feature of hyperuricemia in clinical settings. However, the underlying mechanism remains unknown. Here, infiltration of T cells and macrophages were significantly increased in hyperuricemia mice kidneys. This infiltration of inflammatory cells was accompanied by an up-regulation of TNF-α, MCP-1 and RANTES expression. Further, infiltration was largely located in tubular interstitial spaces, suggesting a role for tubular cells in hyperuricemia-induced inflammation. In cultured tubular epithelial cells (NRK-52E), uric acid, probably transported via urate transporter, induced TNF-α, MCP-1 and RANTES mRNA as well as RANTES protein expression. Culture media of NRK-52E cells incubated with uric acid showed a chemo-attractive ability to recruit macrophage. Moreover uric acid activated NF-κB signaling. The uric acid-induced up-regulation of RANTES was blocked by SN 50, a specific NF-κB inhibitor. Activation of NF-κB signaling was also observed in tubule of hyperuricemia mice. These results suggest that uric acid induces renal inflammation via activation of NF-κB signaling. PMID:22761883

  11. The NALP3/Cryopyrin-Inflammasome Complex is Expressed in LPS-Induced Ocular Inflammation

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    José F. González-Benítez

    2008-01-01

    Full Text Available In the inflammosome complex, NALP3 or NALP1 binds to ASC and activates caspase-1 which induces IL-1β. In murine LPS-induced ocular inflammation, the production of IL-1β is increased. We suggest that NALP3- or NALP1-inflammasome complex can be participating in the LPS-induced ocular inflammation. In this work, eye, brain, testis, heart, spleen, and lung were obtained from C3H/HeN mice treated with LPS for 3 to 48 hours, and the expression of NALP1b, NALP3, ASC, caspase-1, IL-1β, and IL-18 was determined. Infiltrated leukocytes producing IL-1β in the anterior chamber were found at 12-hour posttreatment. A high upregulated expression of NALP3, ASC, caspase-1, IL-1β, and IL-18 was found at the same time when infiltrated leukocytes were observed. NALP1b was not detected in the eye of treated mice. NALP3 was also overexpressed in heart and lung. These results suggest that NALP3-, but not NALP1-inflammosome complex, is participating in the murine LPS-induced ocular inflammation.

  12. Glyphosate–rich air samples induce IL–33, TSLP and generate IL–13 dependent airway inflammation

    Science.gov (United States)

    Kumar, Sudhir; Khodoun, Marat; Kettleson, Eric M.; McKnight, Christopher; Reponen, Tiina; Grinshpun, Sergey A.; Adhikari, Atin

    2014-01-01

    Several low weight molecules have often been implicated in the induction of occupational asthma. Glyphosate, a small molecule herbicide, is widely used in the world. There is a controversy regarding a role of glyphosate in developing asthma and rhinitis among farmers, the mechanism of which is unexplored. The aim of this study was to explore the mechanisms of glyphosate induced pulmonary pathology by utilizing murine models and real environmental samples. C57BL/6, TLR4−/−, and IL-13−/− mice inhaled extracts of glyphosate-rich air samples collected on farms during spraying of herbicides or inhaled different doses of glyphosate and ovalbumin. The cellular response, humoral response, and lung function of exposed mice were evaluated. Exposure to glyphosate-rich air samples as well as glyphosate alone to the lungs increased: eosinophil and neutrophil counts, mast cell degranulation, and production of IL-33, TSLP, IL-13, and IL-5. In contrast, in vivo systemic IL-4 production was not increased. Co-administration of ovalbumin with glyphosate did not substantially change the inflammatory immune response. However, IL-13-deficiency resulted in diminished inflammatory response but did not have a significant effect on airway resistance upon methacholine challenge after 7 or 21 days of glyphosate exposure. Glyphosate-rich farm air samples as well as glyphosate alone were found to induce pulmonary IL-13-dependent inflammation and promote Th2 type cytokines, but not IL-4 for glyphosate alone. This study, for the first time, provides evidence for the mechanism of glyphosate-induced occupational lung disease. PMID:25172162

  13. Erythropoietin augments the cytokine response to acute endotoxin-induced inflammation in humans

    DEFF Research Database (Denmark)

    Hojman, Pernille; Taudorf, Sarah; Lundby, Carsten

    2009-01-01

    Recent studies have shown that erythropoietin (EPO) offers protection against ischemia, hemorrhagic shock and systemic inflammation in many tissues and it has been suggested that EPO has anti-inflammatory effects. With the aim of investigating the potential acute anti-inflammatory effects of EPO...... in a human in vivo model of acute systemic low-grade inflammation, we measured circulating inflammatory mediators after intravenous administration of Escherichia coli endotoxin (LPS) bolus injection (0.1 ng/kg of body weight) in young healthy male subjects. The subjects were divided into three groups...

  14. Titanium dioxide induced inflammation in the small intestine.

    Science.gov (United States)

    Nogueira, Carolina Maciel; de Azevedo, Walter Mendes; Dagli, Maria Lucia Zaidan; Toma, Sérgio Hiroshi; Leite, André Zonetti de Arruda; Lordello, Maria Laura; Nishitokukado, Iêda; Ortiz-Agostinho, Carmen Lúcia; Duarte, Maria Irma Seixas; Ferreira, Marcelo Alves; Sipahi, Aytan Miranda

    2012-09-14

    To investigate the effects of titanium dioxide (TiO₂) nanoparticles (NPTiO₂) and microparticles (MPTiO₂) on the inflammatory response in the small intestine of mice. Bl 57/6 male mice received distilled water suspensions containing TiO₂ (100 mg/kg body weight) as NPTiO₂ (66 nm), or MPTiO₂ (260 nm) by gavage for 10 d, once a day; the control group received only distilled water. At the end of the treatment the duodenum, jejunum and ileum were extracted for assessment of cytokines, inflammatory cells and titanium content. The cytokines interleukin (IL)-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-23, tumor necrosis factor-α (TNF-α), intracellular interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) were evaluated by enzyme-linked immunosorbent assay in segments of jejunum and ileum (mucosa and underlying muscular tissue). CD4+ and CD8+ T cells, natural killer cells, and dendritic cells were evaluated in duodenum, jejunum and ileum samples fixed in 10% formalin by immunohistochemistry. The titanium content was determined by inductively coupled plasma atomic emission spectrometry. We found increased levels of T CD4+ cells (cells/mm²) in duodenum: NP 1240 ± 139.4, MP 1070 ± 154.7 vs 458 ± 50.39 (P NP 908.4 ± 130.3, MP 813.8 ± 103.8 vs 526.6 ± 61.43 (P NP 818.60 ± 123.0, MP 640.1 ± 32.75 vs 466.9 ± 22.4 (P NP 33.98 ± 11.76, MP 74.11 ± 25.65 vs 19.06 ± 3.92 (P NP 17.36 ± 9.96, MP 22.94 ± 7.47 vs 2.19 ± 0.65 (P NP 157.20 ± 75.80, MP 134.50 ± 38.31 vs 22.34 ± 5.81 (P NP 3.71 ± 1.33, MP 5.44 ± 1.67 vs 0.99 ± 019 (P NP 15.85 ± 9.99, MP 34.08 ± 11.44 vs 2.81 ± 0.69 (P NP 780.70 ± 318.50, MP 1409.00 ± 502.20 vs 205.50 ± 63.93 (P < 0.05). Our findings indicate that TiO₂ particles induce a Th1-mediated inflammatory response in the small bowel in mice.

  15. Titanium dioxide induced inflammation in the small intestine

    Science.gov (United States)

    Nogueira, Carolina Maciel; de Azevedo, Walter Mendes; Dagli, Maria Lucia Zaidan; Toma, Sérgio Hiroshi; Leite, André Zonetti de Arruda; Lordello, Maria Laura; Nishitokukado, Iêda; Ortiz-Agostinho, Carmen Lúcia; Duarte, Maria Irma Seixas; Ferreira, Marcelo Alves; Sipahi, Aytan Miranda

    2012-01-01

    .99, MP 34.08 ± 11.44 vs 2.81 ± 0.69 (P < 0.05); and TGF-β: NP 780.70 ± 318.50, MP 1409.00 ± 502.20 vs 205.50 ± 63.93 (P < 0.05). CONCLUSION: Our findings indicate that TiO2 particles induce a Th1-mediated inflammatory response in the small bowel in mice. PMID:23002342

  16. Macrophage-stimulating protein attenuates gentamicin-induced inflammation and apoptosis in human renal proximal tubular epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ko Eun [Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Eun Young [Department of Physiology, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Chang Seong; Choi, Joon Seok; Bae, Eun Hui; Ma, Seong Kwon [Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Kyung Keun [Department of Pharmacology, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Lee, Jong Un [Department of Physiology, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Soo Wan, E-mail: skimw@chonnam.ac.kr [Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of)

    2013-05-10

    Highlights: •MSP/RON system is activated in rat kidney damaged by gentamicin. •MSP inhibits GM-induced cellular apoptosis and inflammation in HK-2 cells. •MSP attenuates GM-induced activation of MAPKs and NF-κB pathways in HK-2 cells. -- Abstract: The present study aimed to investigate whether macrophage-stimulating protein (MSP) treatment attenuates renal apoptosis and inflammation in gentamicin (GM)-induced tubule injury and its underlying molecular mechanisms. To examine changes in MSP and its receptor, recepteur d’origine nantais (RON) in GM-induced nephropathy, rats were injected with GM for 7 days. Human renal proximal tubular epithelial (HK-2) cells were incubated with GM for 24 h in the presence of different concentrations of MSP and cell viability was measured by MTT assay. Apoptosis was determined by flow cytometry of cells stained with fluorescein isothiocyanate-conjugated annexin V protein and propidium iodide. Expression of Bcl-2, Bax, caspase-3, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB), IκB-α, and mitogen-activated protein kinases (MAPKs) was analyzed by semiquantitative immunoblotting. MSP and RON expression was significantly greater in GM-treated rats, than in untreated controls. GM-treatment reduced HK-2 cell viability, an effect that was counteracted by MSP. Flow cytometry and DAPI staining revealed GM-induced apoptosis was prevented by MSP. GM reduced expression of anti-apoptotic protein Bcl-2 and induced expression of Bax and cleaved caspase 3; these effects and GM-induced expression of COX-2 and iNOS were also attenuated by MSP. GM caused MSP-reversible induction of phospho-ERK, phospho-JNK, and phospho-p38. GM induced NF-κB activation and degradation of IκB-α; the increase in nuclear NF-κB was blocked by inhibitors of ERK, JNK, p-38, or MSP pretreatment. These findings suggest that MSP attenuates GM-induced inflammation and apoptosis by inhibition of the MAPKs

  17. The relationship between inflammation and the coagulation system

    NARCIS (Netherlands)

    Choi, Goda; Schultz, Marcus J.; Levi, Marcel; van der Poll, Tom

    2006-01-01

    Inflammation and coagulation play pivotal roles in host defence. As phylogenetically old responses, there is extensive cross-talk between inflammation and coagulation in enabling an adequate immune response against potentially injurious stimuli. Immune cells are important in the initiation of

  18. Nox1 oxidase suppresses influenza a virus-induced lung inflammation and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Stavros Selemidis

    Full Text Available Influenza A virus infection is an ongoing clinical problem and thus, there is an urgent need to understand the mechanisms that regulate the lung inflammation in order to unravel novel generic pharmacological strategies. Evidence indicates that the Nox2-containing NADPH oxidase enzyme promotes influenza A virus-induced lung oxidative stress, inflammation and dysfunction via ROS generation. In addition, lung epithelial and endothelial cells express the Nox1 isoform of NADPH oxidase, placing this enzyme at key sites to regulate influenza A virus-induced lung inflammation. The aim of this study was to investigate whether Nox1 oxidase regulates the inflammatory response and the oxidative stress to influenza infection in vivo in mice. Male WT and Nox1-deficient (Nox1(-/y mice were infected with the moderately pathogenic HkX-31 (H3N2, 1×10(4 PFU influenza A virus for analysis of bodyweight, airways inflammation, oxidative stress, viral titre, lung histopathology, and cytokine/chemokine expression at 3 and 7 days post infection. HkX-31 virus infection of Nox1(-/y mice resulted in significantly greater: loss of bodyweight (Day 3; BALF neutrophilia, peri-bronchial, peri-vascular and alveolar inflammation; Nox2-dependent inflammatory cell ROS production and peri-bronchial, epithelial and endothelial oxidative stress. The expression of pro-inflammatory cytokines including CCL2, CCL3, CXCL2, IL-1β, IL-6, GM-CSF and TNF-α was higher in Nox1(-/y lungs compared to WT mice at Day 3, however, the expression of CCL2, CCL3, CXCL2, IFN-γ and the anti-inflammatory cytokine IL-10 were lower in lungs of Nox1(-/y mice vs. WT mice at Day 7. Lung viral titre, and airways infiltration of active CD8(+ and CD4(+ T lymphocytes, and of Tregs were similar between WT and Nox1(-/y mice. In conclusion, Nox1 oxidase suppresses influenza A virus induced lung inflammation and oxidative stress in mice particularly at the early phases of the infection. Nox1 and Nox2 oxidases appear

  19. The Effects of Low Dose γ-Irradiation on MIA Induced Joint Inflammation

    International Nuclear Information System (INIS)

    Ham, Seok Chan; Lee, Ko Eun; Kim, Eun-hea; Lee, Tae Woong; Lee, Won Ho; Kim, June Sun

    2010-01-01

    Inflammation of the synovial membrane is associated with the progression of cartilage degeneration and unexpected pain in osteoarthritis (OA). Inflammation produces painful sensations which are largely divided into spontaneous (non-evoked) pain and evoked pain depending on the presence of external stimuli and are characterized by hyperalgesia and allodynia Nitric oxide (NO) is related to the pathogenesis of OA as inflammatory mediator. Inducible nitric oxide synthase (iNOS) is marker of enhanced NO production in arthritic pain. In previously, low dose irradiation can suppress pro-inflammatory cytokines. But, ray therapeutic effect is unclear. Thus, present study examined the preemptive effect of low dose irradiation on the development of inflammatory pain in MIA induced OA animal model

  20. The Effects of Low Dose {gamma}-Irradiation on MIA Induced Joint Inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Ham, Seok Chan; Lee, Ko Eun; Kim, Eun-hea; Lee, Tae Woong; Lee, Won Ho; Kim, June Sun [Korea University, College of Health Science, Seoul (Korea, Republic of)

    2010-10-15

    Inflammation of the synovial membrane is associated with the progression of cartilage degeneration and unexpected pain in osteoarthritis (OA). Inflammation produces painful sensations which are largely divided into spontaneous (non-evoked) pain and evoked pain depending on the presence of external stimuli and are characterized by hyperalgesia and allodynia Nitric oxide (NO) is related to the pathogenesis of OA as inflammatory mediator. Inducible nitric oxide synthase (iNOS) is marker of enhanced NO production in arthritic pain. In previously, low dose irradiation can suppress pro-inflammatory cytokines. But, ray therapeutic effect is unclear. Thus, present study examined the preemptive effect of low dose irradiation on the development of inflammatory pain in MIA induced OA animal model

  1. Aortic VCAM-1: an early marker of vascular inflammation in collagen-induced arthritis.

    Science.gov (United States)

    Denys, Anne; Clavel, Gaëlle; Lemeiter, Delphine; Schischmanoff, Olivier; Boissier, Marie-Christophe; Semerano, Luca

    2016-05-01

    Cardiovascular disease (CVD) is a major cause of morbidity and mortality in rheumatoid arthritis (RA). There are limited experimental data on vascular involvement in arthritis models. To study the link between CVD and inflammation in RA, we developed a model of vascular dysfunction and articular inflammation by collagen-induced arthritis (CIA) in C57Bl/6 (B6) mice. We studied the expression of vascular inflammatory markers in CIA with and without concomitant hyperlipidic diet (HD). Collagen-induced arthritis was induced with intradermal injection of chicken type-II collagen followed by a boost 21 days later. Mice with and without CIA were fed a standard diet or an HD for 12 weeks starting from the day of the boost. Arthritis severity was evaluated with a validated clinical score. Aortic mRNA levels of vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS) and interleukin-17 were analysed by quantitative RT-PCR. Vascular cell adhesion molecule-1 localization in the aortic sinus was determined by immunohistochemistry. Atherosclerotic plaque presence was assessed in aortas. Collagen-induced arthritis was associated with increased expression of VCAM-1, independent of diet. VCAM-1 overexpression was detectable as early as 4 weeks after collagen immunization and persisted after 15 weeks. The HD induced atheroma plaque formation and aortic iNOS expression regardless of CIA. Concomitant CIA and HD had no additive effect on atheroma or VCAM-1 or iNOS expression. CIA and an HD diet induced a distinct and independent expression of large-vessel inflammation markers in B6 mice. This model may be relevant for the study of CVD in RA. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  2. Docetaxel-induced Meibomian duct inflammation and blockage leading to chalazion formation.

    Science.gov (United States)

    Gupta, S; Silliman, C G; Trump, D L

    2007-01-01

    We report a 71-year male with castration-resistant metastatic prostate cancer who was treated with weekly docetaxel for 12 weeks and developed significant eye irritation and dryness during treatment. Subsequently, the patient presented with a lower eyelid mass, which on excision was demonstrated to be a chalazion. Docetaxel induced Meibomian duct inflammation and blockage is the likely cause of this presentation in a patient with no history of eyelid masses in the past.

  3. Inflammation-induced bone remodeling in periodontal disease and the influence of post-menopausal osteoporosis.

    Science.gov (United States)

    Lerner, U H

    2006-07-01

    During physiological conditions, the skeleton is remodeled in so-called bone multi-cellular units. Such units have been estimated to exist at 1-2 x 10(6) sites in the adult skeleton. The number and activities of these units are regulated by a variety of hormones and cytokines. In post-menopausal osteoporosis, lack of estrogen leads to increased numbers of bone multi-cellular units and to uncoupling of bone formation and bone resorption, resulting in too little bone laid down by osteoblasts compared with the amount of bone resorbed by osteoclasts. Inflammatory processes in the vicinity of the skeleton, e.g., marginal and apical periodontitis, will affect the remodeling of the nearby bone tissue in such a way that, in most patients, the amount of bone resorbed exceeds that being formed, resulting in net bone loss (inflammation-induced osteolysis). In some patients, however, inflammation-induced bone formation exceeds resorption, and a sclerotic lesion will develop. The cellular and molecular pathogenetic mechanisms in inflammation-induced osteolysis and sclerosis are discussed in the present review. The cytokines believed to be involved in inflammation-induced remodeling are very similar to those suggested to play crucial roles in post-menopausal osteoporosis. In patients with periodontal disease and concomitant post-menopausal osteoporosis, the possibility exists that the lack of estrogen influences the activities of bone cells and immune cells in such a way that the progression of alveolar bone loss will be enhanced. In the present paper, the evidence for and against this hypothesis is presented.

  4. Butyrate Attenuates Lipopolysaccharide-Induced Inflammation in Intestinal Cells and Crohn's Mucosa through Modulation of Antioxidant Defense Machinery

    Science.gov (United States)

    Russo, Ilaria; Luciani, Alessandro; De Cicco, Paola; Troncone, Edoardo; Ciacci, Carolina

    2012-01-01

    Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease (CrD). High levels of Reactive Oxygen Species (ROS) induce the activation of the redox-sensitive nuclear transcription factor kappa-B (NF-κB), which in turn triggers the inflammatory mediators. Butyrate decreases pro-inflammatory cytokine expression by the lamina propria mononuclear cells in CrD patients via inhibition of NF-κB activation, but how it reduces inflammation is still unclear. We suggest that butyrate controls ROS mediated NF-κB activation and thus mucosal inflammation in intestinal epithelial cells and in CrD colonic mucosa by triggering intracellular antioxidant defense systems. Intestinal epithelial Caco-2 cells and colonic mucosa from 14 patients with CrD and 12 controls were challenged with or without lipopolysaccaride from Escherichia Coli (EC-LPS) in presence or absence of butyrate for 4 and 24 h. The effects of butyrate on oxidative stress, p42/44 MAP kinase phosphorylation, p65-NF-κB activation and mucosal inflammation were investigated by real time PCR, western blot and confocal microscopy. Our results suggest that EC-LPS challenge induces a decrease in Gluthation-S-Transferase-alpha (GSTA1/A2) mRNA levels, protein expression and catalytic activity; enhanced levels of ROS induced by EC-LPS challenge mediates p65-NF-κB activation and inflammatory response in Caco-2 cells and in CrD colonic mucosa. Furthermore butyrate treatment was seen to restore GSTA1/A2 mRNA levels, protein expression and catalytic activity and to control NF-κB activation, COX-2, ICAM-1 and the release of pro-inflammatory cytokine. In conclusion, butyrate rescues the redox machinery and controls the intracellular ROS balance thus switching off EC-LPS induced inflammatory response in intestinal epithelial cells and in CrD colonic mucosa. PMID:22412931

  5. Effect of Testosterone on Carrageenone Induced Inflammation in Gonadectomized Male Rats

    Directory of Open Access Journals (Sweden)

    A Zarifkar

    2009-07-01

    Full Text Available ABSTRACT: Introduction & Objective: Different nociceptive and inflammatory responses to noxious stimuli in male and female animals imply that sex hormones may affect on inflammatory factors, induction and intensity of the inflammation. The aim of the current study was to evaluate the effect of testosterone administration on carrageenone induced inflammation in gonadectomized male rats. Materials & methods: Forty male Wistar rats were divided into four groups (n=8. 1-The control rats without receiving any drug or surgical operation. 2-The sham – operated animals with surgical stress. 3-The gonadectomized rats, receiving 0.5 ml vehicle (olive oil i.p. 4-The gonadectomized rats, receiving testosterone enantate (6 mg/100 gr body weight in 0.5 ml vehicle i.p.. At the sixth day of gonadectomy operation, inflammation was induced by injection of 1% carrageenone in the right hind paw of rats. Edematous paw volume as an index of inflammation was determined by immersing it into the mercury container. Weight of paw in the mercury was measured and then the paw volume was calculated in relation to specific gravity of mercury (13.6gm/ml. Data were statistically analyzed by SPSS software using ANOVA. Results: The results showed that edematous paw volume significantly was reduced in testosterone enantate administrated gonadectomized rats compared to the control group (P<0.01. Conclusion: It can be concluded that high dose of testosterone causes attenuation of inflammatory response. The testosterone anti-inflammatory effect is probably due to inhibition of inflammatory factors (Interleukins production or decrease in receptors of inflammatory factors. Keywords: Testosterone, Carrageenone, Inflammation, Rats

  6. Hyperglycemia Aggravates Hepatic Ischemia Reperfusion Injury by Inducing Chronic Oxidative Stress and Inflammation

    Directory of Open Access Journals (Sweden)

    Yihan Zhang

    2016-01-01

    Full Text Available Aim. To investigate whether hyperglycemia will aggravate hepatic ischemia reperfusion injury (HIRI and the underlying mechanisms. Methods. Control and streptozotocin-induced diabetic Sprague-Dawley rats were subjected to partial hepatic ischemia reperfusion. Liver histology, transferase, inflammatory cytokines, and oxidative stress were assessed accordingly. Similarly, BRL-3A hepatocytes were subjected to hypoxia/reoxygenation (H/R after high (25 mM or low (5.5 mM glucose culture. Cell viability, reactive oxygen species (ROS, and activation of nuclear factor-erythroid 2-related factor 2 (Nrf2 and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB were determined. Results. Compared with control, diabetic rats presented more severe hepatic injury and increased hepatic inflammatory cytokines and oxidative stress. HIRI in diabetic rats could be ameliorated by pretreatment of N-acetyl-L-cysteine (NAC or apocynin. Excessive ROS generation and consequent Nrf2 and NF-κB translocation were determined after high glucose exposure. NF-κB translocation and its downstream cytokines were further increased in high glucose cultured group after H/R. While proper regulation of Nrf2 to its downstream antioxidases was observed in low glucose cultured group, no further induction of Nrf2 pathway by H/R after high glucose culture was identified. Conclusion. Hyperglycemia aggravates HIRI, which might be attributed to chronic oxidative stress and inflammation and potential malfunction of antioxidative system.

  7. Superoxide anion-induced pain and inflammation depends on TNFα/TNFR1 signaling in mice.

    Science.gov (United States)

    Yamacita-Borin, Fabiane Y; Zarpelon, Ana C; Pinho-Ribeiro, Felipe A; Fattori, Victor; Alves-Filho, Jose C; Cunha, Fernando Q; Cunha, Thiago M; Casagrande, Rubia; Verri, Waldiceu A

    2015-09-25

    Inhibition of tumor necrosis factor-alpha (TNFα) and superoxide anion production reduces inflammation and pain. The present study investigated whether superoxide anion-induced pain depends on TNFα signaling and the role of superoxide anion in TNFα-induced hyperalgesia to clarify the interrelation between these two mediators in the context of pain. Intraplantar injection of a superoxide anion donor (potassium superoxide) induced mechanical hyperalgesia (0.5-5h after injection), neutrophil recruitment (myeloperoxidase activity), and overt pain-like behaviors (paw flinching, paw licking, and abdominal writhings) in wild-type mice. Tumor necrosis factor receptor 1 deficiency (TNFR1-/-) and treatment of wild-type mice with etanercept (a soluble TNFR2 receptor that inhibits TNFα actions) inhibited superoxide anion-induced pain-like behaviors. TNFR1(-/-) mice were also protected from superoxide anion donor-induced oxidative stress, suggesting the role of this pathway in the maintenance of oxidative stress. Finally, we demonstrated that Apocynin (an NADPH oxidase inhibitor) or Tempol (a superoxide dismutase mimetic) treatment inhibited TNFα-induced paw mechanical hyperalgesia and neutrophil recruitment (myeloperoxidase activity). These results demonstrate that TNFα/TNFR1 signaling is important in superoxide anion-triggered pain and that TNFα/TNFR1 signaling amplifies the oxidative stress triggered by superoxide anion, which contributes to sustaining pain and inflammation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Vanadium pentoxide induces pulmonary inflammation and tumor promotion in a strain-dependent manner

    Directory of Open Access Journals (Sweden)

    Bauer Alison K

    2010-04-01

    Full Text Available Abstract Background Elevated levels of air pollution are associated with increased risk of lung cancer. Particulate matter (PM contains transition metals that may potentiate neoplastic development through the induction of oxidative stress and inflammation, a lung cancer risk factor. Vanadium pentoxide (V2O5 is a component of PM derived from fuel combustion as well as a source of occupational exposure in humans. In the current investigation we examined the influence of genetic background on susceptibility to V2O5-induced inflammation and evaluated whether V2O5 functions as a tumor promoter using a 2-stage (initiation-promotion model of pulmonary neoplasia in mice. Results A/J, BALB/cJ (BALB, and C57BL/6J (B6 mice were treated either with the initiator 3-methylcholanthrene (MCA; 10 μg/g; i.p. or corn oil followed by 5 weekly aspirations of V2O5 or PBS and pulmonary tumors were enumerated 20 weeks following MCA treatment. Susceptibility to V2O5-induced pulmonary inflammation was assessed in bronchoalveolar lavage fluid (BALF, and chemokines, transcription factor activity, and MAPK signaling were quantified in lung homogenates. We found that treatment of animals with MCA followed by V2O5 promoted lung tumors in both A/J (10.3 ± 0.9 tumors/mouse and BALB (2.2 ± 0.36 mice significantly above that observed with MCA/PBS or V2O5 alone (P 2O5 were also found to be more susceptible to V2O5-induced pulmonary inflammation and hyperpermeability (A/J>BALB>B6. Differential strain responses in inflammation were positively associated with elevated levels of the chemokines KC and MCP-1, higher NFκB and c-Fos binding activity, as well as sustained ERK1/2 activation in lung tissue. Conclusions In this study we demonstrate that V2O5, an occupational and environmentally relevant metal oxide, functions as an in vivo lung tumor promoter among different inbred strains of mice. Further, we identified a positive relationship between tumor promotion and susceptibility

  9. A recombinant cystatin from Ascaris lumbricoides attenuates inflammation of DSS-induced colitis.

    Science.gov (United States)

    Coronado, S; Barrios, L; Zakzuk, J; Regino, R; Ahumada, V; Franco, L; Ocampo, Y; Caraballo, L

    2017-04-01

    Helminthiasis may ameliorate inflammatory diseases, such as inflammatory bowel disease and asthma. Information about immunomodulators from Ascaris lumbricoides is scarce, but could be important considering the co-evolutionary relationships between helminths and humans. We evaluated the immunomodulatory effects of a recombinant cystatin from A. lumbricoides on an acute model of dextran sodium sulphate (DSS)-induced colitis in mice. From an A. lumbricoides cDNA library, we obtained a recombinant cystatin (rAl-CPI). Protease activity inhibition was demonstrated on cathepsin B and papain. Immunomodulatory effects were evaluated at two intraperitoneal doses (0.5 and 0.25 μg/G) on mice with DSS-induced colitis. Body weight, colon length, Disease Activity Index (DAI), histological inflammation score, myeloperoxidase (MPO) activity, gene expression of cytokines and cytokines levels in colon tissue were analysed. Treatment with rAl-CPI significantly reduced DAI, MPO activity and inflammation score without toxic effects. Also, IL-10 and TGF-B gene overexpression was observed in rAl-CPI-treated group compared to DSS-exposed control and healthy mice. Furthermore, a reduction in IL-6 and TNF-A expression was found, and this was confirmed by the levels of these cytokines in colonic tissue. In conclusion, rAl-CPI reduces inflammation in a mouse model of DSS-induced colitis, probably by increasing the expression of anti-inflammatory cytokines and reducing pro-inflammatory ones. © 2017 John Wiley & Sons Ltd.

  10. The "Big Bang" in obese fat: Events initiating obesity-induced adipose tissue inflammation.

    Science.gov (United States)

    Wensveen, Felix M; Valentić, Sonja; Šestan, Marko; Turk Wensveen, Tamara; Polić, Bojan

    2015-09-01

    Obesity is associated with the accumulation of pro-inflammatory cells in visceral adipose tissue (VAT), which is an important underlying cause of insulin resistance and progression to diabetes mellitus type 2 (DM2). Although the role of pro-inflammatory cytokines in disease development is established, the initiating events leading to immune cell activation remain elusive. Lean adipose tissue is predominantly populated with regulatory cells, such as eosinophils and type 2 innate lymphocytes. These cells maintain tissue homeostasis through the excretion of type 2 cytokines, such as IL-4, IL-5, and IL-13, which keep adipose tissue macrophages (ATMs) in an anti-inflammatory, M2-like state. Diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in VAT, characterized by IFN-γ. A key event is a shift of ATMs toward an M1 phenotype. Recent studies show that obesity-induced adipocyte hypertrophy results in upregulated surface expression of stress markers. Adipose stress is detected by local sentinels, such as NK cells and CD8(+) T cells, which produce IFN-γ, driving M1 ATM polarization. A rapid accumulation of pro-inflammatory cells in VAT follows, leading to inflammation. In this review, we provide an overview of events leading to adipose tissue inflammation, with a special focus on adipose homeostasis and the obesity-induced loss of homeostasis which marks the initiation of VAT inflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Necrostatin-1 enhances the resolution of inflammation by specifically inducing neutrophil apoptosis

    Science.gov (United States)

    Jie, Hongyu; He, Yi; Huang, Xuechan; Zhou, Qingyou; Han, Yanping; Li, Xing; Bai, Yongkun; Sun, Erwei

    2016-01-01

    Neutrophils play a central role in innate immunity and are rapidly recruited to sites of infection and injury. Neutrophil apoptosis is essential for the successful resolution of inflammation. Necrostatin-1 (Nec-1,methyl-thiohydantoin-tryptophan (MTH-Trp)), is a potent and specific inhibitor of necroptosis[1] (a newly identified type of cell death representing a form of programmed necrosis or regulated non apoptotic cell death) by inhibiting the receptor interacting protein 1(RIP1) kinase. Here we report that Nec-1 specifically induces caspase-dependent neutrophils apoptosis and overrides powerful anti-apoptosis signaling from survival factors such as GM-CSF and LPS. We showed that Nec-1 markedly enhanced the resolution of established neutrophil-dependent inflammation in LPS-induced acute lung injury in mice. We also provided evidence that Nec-1 promoted apoptosis by reducing the expression of the anti-apoptotic protein Mcl-1 and increasing the expression of pro-apoptotic protein Bax. Thus, Nec-1 is not only an inhibitor of necroptosis, but also a promoter of apoptosis, of neutrophils, enhancing the resolution of established inflammation by inducing apoptosis of inflammatory cells. Our results suggest that Nec-1 may have potential roles for the treatment of diseases with increased or persistent inflammatory responses. PMID:27027357

  12. Bufei Huoxue Capsule Attenuates PM2.5-Induced Pulmonary Inflammation in Mice

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    Yue Jing

    2017-01-01

    Full Text Available Atmospheric fine particulate matter 2.5 (PM 2.5 may carry many toxic substances on its surface and this may pose a public health threat. Epidemiological research indicates that cumulative ambient PM2.5 is correlated to morbidity and mortality due to pulmonary and cardiovascular diseases and cancer. Mitigating the toxic effects of PM2.5 is therefore highly desired. Bufei Huoxue (BFHX capsules have been used in China to treat pulmonary heart disease (cor pulmonale. Thus, we assessed the effects of BFHX capsules on PM2.5-induced pulmonary inflammation and the underlying mechanisms of action. Using Polysearch and Cytoscape 3.2.1 software, pharmacological targets of BFHX capsules in atmospheric PM2.5-related respiratory disorders were predicted and found to be related to biological pathways of inflammation and immune function. In a mouse model of PM2.5-induced inflammation established with intranasal instillation of PM2.5 suspension, BFHX significantly reduced pathological response and inflammatory mediators including IL-4, IL-6, IL-10, IL-8, TNF-α, and IL-1β. BFHX also reduced keratinocyte growth factor (KGF, secretory immunoglobulin A (sIgA, and collagen fibers deposition in lung and improved lung function. Thus, BFHX reduced pathological responses induced by PM2.5, possibly via regulation of inflammatory mediators in mouse lungs.

  13. Distinct inflammatory mediator patterns characterize infectious and sterile systemic inflammation in febrile neutropenic hematology patients.

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    Christine Wennerås

    Full Text Available BACKGROUND: Invasive infections and sterile tissue damage can both give rise to systemic inflammation with fever and production of inflammatory mediators. This makes it difficult to diagnose infections in patients who are already inflamed, e.g. due to cell and tissue damage. For example, fever in patients with hematological malignancies may depend on infection, lysis of malignant cells, and/or chemotherapy-induced mucosal damage. We hypothesized that it would be possible to distinguish patterns of inflammatory mediators characterizing infectious and non-infectious causes of inflammation, respectively. Analysis of a broad range of parameters using a multivariate method of pattern recognition was done for this purpose. METHODS: In this prospective study, febrile (>38°C neutropenic patients (n = 42 with hematologic malignancies were classified as having or not having a microbiologically defined infection by an infectious disease specialist. In parallel, blood was analyzed for 116 biomarkers, and 23 clinical variables were recorded for each patient. Using O-PLS (orthogonal projection to latent structures, a model was constructed based on these 139 variables that could separate the infected from the non-infected patients. Non-discriminatory variables were discarded until a final model was reached. Finally, the capacity of this model to accurately classify a validation set of febrile neutropenic patients (n = 10 as infected or non-infected was tested. RESULTS: A model that could segregate infected from non-infected patients was achieved based on discrete differences in the levels of 40 variables. These variables included acute phase proteins, cytokines, measures of coagulation, metabolism, organ stress and iron turn-over. The model correctly identified the infectious status of nine out of ten subsequently recruited febrile neutropenic hematology patients. CONCLUSIONS: It is possible to separate patients with infectious inflammation from those

  14. Klebsiella pneumoniae Siderophores Induce Inflammation, Bacterial Dissemination, and HIF-1α Stabilization during Pneumonia.

    Science.gov (United States)

    Holden, Victoria I; Breen, Paul; Houle, Sébastien; Dozois, Charles M; Bachman, Michael A

    2016-09-13

    Klebsiella pneumoniae is a Gram-negative pathogen responsible for a wide range of infections, including pneumonia and bacteremia, and is rapidly acquiring antibiotic resistance. K. pneumoniae requires secretion of siderophores, low-molecular-weight, high-affinity iron chelators, for bacterial replication and full virulence. The specific combination of siderophores secreted by K. pneumoniae during infection can impact tissue localization, systemic dissemination, and host survival. However, the effect of these potent iron chelators on the host during infection is unknown. In vitro, siderophores deplete epithelial cell iron, induce cytokine secretion, and activate the master transcription factor hypoxia inducible factor-1α (HIF-1α) protein that controls vascular permeability and inflammatory gene expression. Therefore, we hypothesized that siderophore secretion by K. pneumoniae directly contributes to inflammation and bacterial dissemination during pneumonia. To examine the effects of siderophore secretion independently of bacterial growth, we performed infections with tonB mutants that persist in vivo but are deficient in siderophore import. Using a murine model of pneumonia, we found that siderophore secretion by K. pneumoniae induces the secretion of interleukin-6 (IL-6), CXCL1, and CXCL2, as well as bacterial dissemination to the spleen, compared to siderophore-negative mutants at an equivalent bacterial number. Furthermore, we determined that siderophore-secreting K. pneumoniae stabilized HIF-1α in vivo and that bacterial dissemination to the spleen required alveolar epithelial HIF-1α. Our results indicate that siderophores act directly on the host to induce inflammatory cytokines and bacterial dissemination and that HIF-1α is a susceptibility factor for bacterial invasion during pneumonia. Klebsiella pneumoniae causes a wide range of bacterial diseases, including pneumonia, urinary tract infections, and sepsis. To cause infection, K. pneumoniae steals

  15. Effects of Bariatric Surgery on Adipokine-Induced Inflammation and Insulin Resistance

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    Zeynep eGoktas

    2013-06-01

    Full Text Available Over a third of the US population is obese and at high risk for developing type 2 diabetes, insulin resistance and other metabolic disorders. Obesity is considered a chronic low grade inflammatory condition that is primarily attributed to expansion and inflammation of adipose tissues. Indeed, adipocytes produce and secrete numerous proinflammatory and anti-inflammatory cytokines known as adipokines. When the balance of these adipokines is shifted towards higher production of proinflammatory factors, local inflammation within adipose tissues and subsequently systemic inflammation occur. These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes. These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase (JNK and serine kinases inhibitor κB kinase (IKK and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt, and nuclear factor kappa B (NF-kB. Bariatric surgery can decrease body weight and improve insulin resistance in morbidly obese subjects. However, despite reports suggesting reduced inflammation and weight-independent effects of bariatric surgery on glucose metabolism, mechanisms behind such improvements are not yet well understood. This review article focuses on some of these novel adipokines and discusses their changes after bariatric surgery and their relationship to insulin resistance, fat mass, inflammation, and glucose homeostasis.

  16. Systemic Inflammation and Evidence of a Cardio-splenic Axis in Patients with Psoriasis

    DEFF Research Database (Denmark)

    Hjuler, Kasper F; Gormsen, Lars C; Vendelbo, Mikkel H

    2017-01-01

    The spleen is thought to play a role in atherosclerosis-associated immunity and cardiovascular research has indicated the existence of a cardio-splenic axis. The aim of this study was to assess splenic 18F-fluorodeoxyglucose uptake as a measure of systemic inflammation in patients with untreated...... inflammation. These results support the existence of systemic inflammation in patients with psoriasis, and provide the rationale for a mechanistic link between psoriasis-driven inflammation and cardiovascular comorbidity through a spleen-atherosclerotic axis....

  17. Feline Immunodeficiency Virus Neuropathogenesis: A Model for HIV-Induced CNS Inflammation and Neurodegeneration.

    Science.gov (United States)

    Meeker, Rick B; Hudson, Lola

    2017-03-06

    Feline Immunodeficiency virus (FIV), similar to its human analog human immunodeficiency virus (HIV), enters the central nervous system (CNS) soon after infection and establishes a protected viral reservoir. The ensuing inflammation and damage give rise to varying degrees of cognitive decline collectively known as HIV-associated neurocognitive disorders (HAND). Because of the similarities to HIV infection and disease, FIV has provided a useful model for both in vitro and in vivo studies of CNS infection, inflammation and pathology. This mini review summarizes insights gained from studies of early infection, immune cell trafficking, inflammation and the mechanisms of neuropathogenesis. Advances in our understanding of these processes have contributed to the development of therapeutic interventions designed to protect neurons and regulate inflammatory activity.

  18. Feline Immunodeficiency Virus Neuropathogenesis: A Model for HIV-Induced CNS Inflammation and Neurodegeneration

    Science.gov (United States)

    Meeker, Rick B.; Hudson, Lola

    2017-01-01

    Feline Immunodeficiency virus (FIV), similar to its human analog human immunodeficiency virus (HIV), enters the central nervous system (CNS) soon after infection and establishes a protected viral reservoir. The ensuing inflammation and damage give rise to varying degrees of cognitive decline collectively known as HIV-associated neurocognitive disorders (HAND). Because of the similarities to HIV infection and disease, FIV has provided a useful model for both in vitro and in vivo studies of CNS infection, inflammation and pathology. This mini review summarizes insights gained from studies of early infection, immune cell trafficking, inflammation and the mechanisms of neuropathogenesis. Advances in our understanding of these processes have contributed to the development of therapeutic interventions designed to protect neurons and regulate inflammatory activity. PMID:29056673

  19. Feline Immunodeficiency Virus Neuropathogenesis: A Model for HIV-Induced CNS Inflammation and Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Rick B. Meeker

    2017-03-01

    Full Text Available Feline Immunodeficiency virus (FIV, similar to its human analog human immunodeficiency virus (HIV, enters the central nervous system (CNS soon after infection and establishes a protected viral reservoir. The ensuing inflammation and damage give rise to varying degrees of cognitive decline collectively known as HIV-associated neurocognitive disorders (HAND. Because of the similarities to HIV infection and disease, FIV has provided a useful model for both in vitro and in vivo studies of CNS infection, inflammation and pathology. This mini review summarizes insights gained from studies of early infection, immune cell trafficking, inflammation and the mechanisms of neuropathogenesis. Advances in our understanding of these processes have contributed to the development of therapeutic interventions designed to protect neurons and regulate inflammatory activity.

  20. Curcumin Inhibits Gastric Inflammation Induced by Helicobacter Pylori Infection in a Mouse Model

    Science.gov (United States)

    Santos, António M.; Lopes, Teresa; Oleastro, Mónica; Gato, Inês Vale; Floch, Pauline; Benejat, Lucie; Chaves, Paula; Pereira, Teresa; Seixas, Elsa; Machado, Jorge; Guerreiro, António S.

    2015-01-01

    Helicobacter pylori (H. pylori) infection triggers a sequence of gastric alterations starting with an inflammation of the gastric mucosa that, in some cases, evolves to gastric cancer. Efficient vaccination has not been achieved, thus it is essential to find alternative therapies, particularly in the nutritional field. The current study evaluated whether curcumin could attenuate inflammation of the gastric mucosa due to H. pylori infection. Twenty-eight C57BL/6 mice, were inoculated with the H. pylori SS1 strain; ten non-infected mice were used as controls. H. pylori infection in live mice was followed-up using a modified 13C-Urea Breath Test (13C-UBT) and quantitative real-time polymerase chain reaction (PCR). Histologically confirmed, gastritis was observed in 42% of infected non-treated mice at both 6 and 18 weeks post-infection. These mice showed an up-regulation of the expression of inflammatory cytokines and chemokines, as well as of toll-like receptors (TLRs) and MyD88, at both time points. Treatment with curcumin decreased the expression of all these mediators. No inflammation was observed by histology in this group. Curcumin treatment exerted a significant anti-inflammatory effect in H. pylori-infected mucosa, pointing to the promising role of a nutritional approach in the prevention of H. pylori induced deleterious inflammation while the eradication or prevention of colonization by effective vaccine is not available. PMID:25569625

  1. Inhibition of matrix metalloproteins 9 attenuated Candida albicans induced inflammation in mouse cornea.

    Science.gov (United States)

    Dong, C; Yang, M G

    2016-10-31

    Since the severe corneal ulceration of mouse cornea is known to occur with inflammation. As one of imperative matrix metalloproteinase, the potential roles of matrix metalloproteins 9 (MMP9) in corneal ulceration and keratitis are still unveiled caused by fungal invasion. In this study, Candida albicans (CA) inoculated wild-type KM mice cornea was used as a model pathogen in corneal inflammation.  CA invasion significantly stimulated the expression of collagen IV and MMP9 detected by RT-PCR, Real-time PCR and Immunofluorescent staining in mouse cornea as soon as 6 hours post infection, and relatively decreased at 1 day post infection. For examining the role of MMP9 in fungal keratitis, the mice corneas were subconjunctivally injected MMP9 antibody or recombinant MMP9 protein 6 hours prior to CA inoculation, using rabbit IgG as control. Subconjunctival injection of recombinant MMP9 protein prior to CA inoculation enhanced, whereas MMP9 antibody attenuated corneal ulceration and inflammation, examining basement membrane, fungal load, myeloperoxidase (MPO) and proinflammatory cytokines including Macrophage inflammatory protein 2 (MIP2), Interleukin-1β (IL-1β) and Tumor necrosis factor-α (TNF-α). Inhibition of MMP9 could potentially attenuate Candida albicans induced inflammation in mouse cornea.

  2. Curcumin Inhibits Gastric Inflammation Induced by Helicobacter Pylori Infection in a Mouse Model

    Directory of Open Access Journals (Sweden)

    António M. Santos

    2015-01-01

    Full Text Available Helicobacter pylori (H. pylori infection triggers a sequence of gastric alterations starting with an inflammation of the gastric mucosa that, in some cases, evolves to gastric cancer. Efficient vaccination has not been achieved, thus it is essential to find alternative therapies, particularly in the nutritional field. The current study evaluated whether curcumin could attenuate inflammation of the gastric mucosa due to H. pylori infection. Twenty-eight C57BL/6 mice, were inoculated with the H. pylori SS1 strain; ten non-infected mice were used as controls. H. pylori infection in live mice was followed-up using a modified 13C-Urea Breath Test (13C-UBT and quantitative real-time polymerase chain reaction (PCR. Histologically confirmed, gastritis was observed in 42% of infected non-treated mice at both 6 and 18 weeks post-infection. These mice showed an up-regulation of the expression of inflammatory cytokines and chemokines, as well as of toll-like receptors (TLRs and MyD88, at both time points. Treatment with curcumin decreased the expression of all these mediators. No inflammation was observed by histology in this group. Curcumin treatment exerted a significant anti-inflammatory effect in H. pylori-infected mucosa, pointing to the promising role of a nutritional approach in the prevention of H. pylori induced deleterious inflammation while the eradication or prevention of colonization by effective vaccine is not available.

  3. Curcumin inhibits gastric inflammation induced by Helicobacter pylori infection in a mouse model.

    Science.gov (United States)

    Santos, António M; Lopes, Teresa; Oleastro, Mónica; Gato, Inês Vale; Floch, Pauline; Benejat, Lucie; Chaves, Paula; Pereira, Teresa; Seixas, Elsa; Machado, Jorge; Guerreiro, António S

    2015-01-06

    Helicobacter pylori (H. pylori) infection triggers a sequence of gastric alterations starting with an inflammation of the gastric mucosa that, in some cases, evolves to gastric cancer. Efficient vaccination has not been achieved, thus it is essential to find alternative therapies, particularly in the nutritional field. The current study evaluated whether curcumin could attenuate inflammation of the gastric mucosa due to H. pylori infection. Twenty-eight C57BL/6 mice, were inoculated with the H. pylori SS1 strain; ten non-infected mice were used as controls. H. pylori infection in live mice was followed-up using a modified 13C-Urea Breath Test (13C-UBT) and quantitative real-time polymerase chain reaction (PCR). Histologically confirmed, gastritis was observed in 42% of infected non-treated mice at both 6 and 18 weeks post-infection. These mice showed an up-regulation of the expression of inflammatory cytokines and chemokines, as well as of toll-like receptors (TLRs) and MyD88, at both time points. Treatment with curcumin decreased the expression of all these mediators. No inflammation was observed by histology in this group. Curcumin treatment exerted a significant anti-inflammatory effect in H. pylori-infected mucosa, pointing to the promising role of a nutritional approach in the prevention of H. pylori induced deleterious inflammation while the eradication or prevention of colonization by effective vaccine is not available.

  4. Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration.

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    Spees, Alanna M; Wangdi, Tamding; Lopez, Christopher A; Kingsbury, Dawn D; Xavier, Mariana N; Winter, Sebastian E; Tsolis, Renée M; Bäumler, Andreas J

    2013-07-02

    Treatment with streptomycin enhances the growth of human commensal Escherichia coli isolates in the mouse intestine, suggesting that the resident microbial community (microbiota) can inhibit the growth of invading microbes, a phenomenon known as "colonization resistance." However, the precise mechanisms by which streptomycin treatment lowers colonization resistance remain obscure. Here we show that streptomycin treatment rendered mice more susceptible to the development of chemically induced colitis, raising the possibility that the antibiotic might lower colonization resistance by changing mucosal immune responses rather than by preventing microbe-microbe interactions. Investigation of the underlying mechanism revealed a mild inflammatory infiltrate in the cecal mucosa of streptomycin-treated mice, which was accompanied by elevated expression of Nos2, the gene that encodes inducible nitric oxide synthase. In turn, this inflammatory response enhanced the luminal growth of E. coli by nitrate respiration in a Nos2-dependent fashion. These data identify low-level intestinal inflammation as one of the factors responsible for the loss of resistance to E. coli colonization after streptomycin treatment. Our intestine is host to a complex microbial community that confers benefits by educating the immune system and providing niche protection. Perturbation of intestinal communities by streptomycin treatment lowers "colonization resistance" through unknown mechanisms. Here we show that streptomycin increases the inflammatory tone of the intestinal mucosa, thereby making the bowel more susceptible to dextran sulfate sodium treatment and boosting the Nos2-dependent growth of commensal Escherichia coli by nitrate respiration. These data point to the generation of alternative electron acceptors as a by-product of the inflammatory host response as an important factor responsible for lowering resistance to colonization by facultative anaerobic bacteria such as E. coli.

  5. Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury.

    Science.gov (United States)

    Drommelschmidt, Karla; Serdar, Meray; Bendix, Ivo; Herz, Josephine; Bertling, Frederik; Prager, Sebastian; Keller, Matthias; Ludwig, Anna-Kristin; Duhan, Vikas; Radtke, Stefan; de Miroschedji, Kyra; Horn, Peter A; van de Looij, Yohan; Giebel, Bernd; Felderhoff-Müser, Ursula

    2017-02-01

    Preterm brain injury is a major cause of disability in later life, and may result in motor, cognitive and behavioural impairment for which no treatment is currently available. The aetiology is considered as multifactorial, and one underlying key player is inflammation leading to white and grey matter injury. Extracellular vesicles secreted by mesenchymal stem/stromal cells (MSC-EVs) have shown therapeutic potential in regenerative medicine. Here, we investigated the effects of MSC-EV treatment on brain microstructure and maturation, inflammatory processes and long-time outcome in a rodent model of inflammation-induced brain injury. 3-Day-old Wistar rats (P3) were intraperitoneally injected with 0.25mg/kg lipopolysaccharide or saline and treated with two repetitive doses of 1×10 8 cell equivalents of MSC-EVs per kg bodyweight. Cellular degeneration and reactive gliosis at P5 and myelination at P11 were evaluated by immunohistochemistry and western blot. Long-term cognitive and motor function was assessed by behavioural testing. Diffusion tensor imaging at P125 evaluated long-term microstructural white matter alterations. MSC-EV treatment significantly ameliorated inflammation-induced neuronal cellular degeneration reduced microgliosis and prevented reactive astrogliosis. Short-term myelination deficits and long-term microstructural abnormalities of the white matter were restored by MSC-EV administration. Morphological effects of MSC-EV treatment resulted in improved long-lasting cognitive functions INTERPRETATION: MSC-EVs ameliorate inflammation-induced cellular damage in a rat model of preterm brain injury. MSC-EVs may serve as a novel therapeutic option by prevention of neuronal cell death, restoration of white matter microstructure, reduction of gliosis and long-term functional improvement. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Invariant Natural Killer T Cells Ameliorate Monosodium Urate Crystal-Induced Gouty Inflammation in Mice

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    Jie Wang

    2017-12-01

    Full Text Available Gout is an inflammatory arthritis caused by deposition of intra-articular monosodium urate (MSU crystal. Previous studies have focused on resident macrophage, infiltrating monocyte, and neutrophil responses to MSU crystal; yet the mechanisms of cellular changes and the potential involvement of other regulatory immune cells remain largely unknown. Invariant natural killer T (iNKT cells, an innate type of T cell, are involved in the development of various inflammatory diseases. Here, we investigate the role of iNKT cells in MSU crystal-induced gouty inflammation. MSU crystal-induced inflammatory profiles in an air-pouch model were examined in iNKT-deficient CD1d knockout (KO and wild-type (WT control mice. To explore potential mechanisms of iNKT cell regulation of gouty inflammation, we cocultured CD4+ or CD4−iNKT cells with bone marrow-derived macrophages (BMDMs. We found that iNKT cells quickly migrated to the site of inflammation upon MSU crystal stimulation in WT mice. The total number of infiltrating cells in CD1d KO mice, especially neutrophils, was dramatically increased at 6 and 12 h (P < 0.01 post-MSU crystal challenge, compared with WT controls. BMDMs cocultured with CD4+iNKT cells produced less tumor necrosis factor-α and expressed higher levels of M2 macrophage markers, including Clec7a, Pdcd1Ig2, and interleukin-4 (P < 0.01, compared with BMDMs cocultured with CD4−iNKT cells or conventional CD4+ T cells. CD4+iNKT cells are one of the key regulators of MSU crystal-induced gouty inflammation through the control of macrophage polarization. iNKT cells may serve as a new therapeutic target for gout.

  7. Enhanced lithium-induced brain recovery following cranial irradiation is not impeded by inflammation.

    Science.gov (United States)

    Malaterre, Jordane; McPherson, Cameron S; Denoyer, Delphine; Lai, Emily; Hagekyriakou, Jim; Lightowler, Sally; Shudo, Koishi; Ernst, Matthias; Ashley, David M; Short, Jennifer L; Wheeler, Greg; Ramsay, Robert G

    2012-06-01

    Radiation-induced brain injury occurs in many patients receiving cranial radiation therapy, and these deleterious effects are most profound in younger patients. Impaired neurocognitive functions in both humans and rodents are associated with inflammation, demyelination, and neural stem cell dysfunction. Here we evaluated the utility of lithium and a synthetic retinoid receptor agonist in reducing damage in a model of brain-focused irradiation in juvenile mice. We found that lithium stimulated brain progenitor cell proliferation and differentiation following cranial irradiation while also preventing oligodendrocyte loss in the dentate gyrus of juvenile mice. In response to inflammation induced by radiation, which may have encumbered the optimal reparative action of lithium, we used the anti-inflammatory synthetic retinoid Am80 that is in clinical use in the treatment of acute promyelocytic leukemia. Although Am80 reduced the number of cyclooxygenase-2-positive microglial cells following radiation treatment, it did not enhance lithium-induced neurogenesis recovery, and this alone was not significantly different from the effect of lithium on this proinflammatory response. Similarly, lithium was superior to Am80 in supporting the restoration of new doublecortin-positive neurons following irradiation. These data suggest that lithium is superior in its restorative effects to blocking inflammation alone, at least in the case of Am80. Because lithium has been in routine clinical practice for 60 years, these preclinical studies indicate that this drug might be beneficial in reducing post-therapy late effects in patients receiving cranial radiotherapy and that blocking inflammation in this context may not be as advantageous as previously suggested.

  8. Cannabinoid Receptor CB2 Is Involved in Tetrahydrocannabinol-Induced Anti-Inflammation against Lipopolysaccharide in MG-63 Cells

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    Lei Yang

    2015-01-01

    Full Text Available Cannabinoid Δ9-tetrahydrocannabinol (THC is effective in treating osteoarthritis (OA, and the mechanism, however, is still elusive. Activation of cannabinoid receptor CB2 reduces inflammation; whether the activation CB2 is involved in THC-induced therapeutic action for OA is still unknown. Cofilin-1 is a cytoskeleton protein, participating in the inflammation of OA. In this study, MG-63 cells, an osteosarcoma cell-line, were exposed to lipopolysaccharide (LPS to mimic the inflammation of OA. We hypothesized that the activation of CB2 is involved in THC-induced anti-inflammation in the MG-63 cells exposed to LPS, and the anti-inflammation is mediated by cofilin-1. We found that THC suppressed the release of proinflammatory factors, including tumor necrosis factor α (TNF-α, interleukin- (IL- 1β, IL-6, and IL-8, decreased nuclear factor-κB (NF-κB expression, and inhibited the upregulation of cofilin-1 protein in the LPS-stimulated MG-63 cells. However, administration of CB2 receptor antagonist or the CB2-siRNA, not CB1 antagonist AM251, partially abolished the THC-induced anti-inflammatory effects above. In addition, overexpression of cofilin-1 significantly reversed the THC-induced anti-inflammatory effects in MG-63 cells. These results suggested that CB2 is involved in the THC-induced anti-inflammation in LPS-stimulated MG-63 cells, and the anti-inflammation may be mediated by cofilin-1.

  9. Systemic inflammation as a predictor of clinical outcomes after lower extremity angioplasty/stenting.

    Science.gov (United States)

    DeSart, Kenneth; O'Malley, Kerri; Schmit, Bradley; Lopez, Maria-Cecilia; Moldawer, Lyle; Baker, Henry; Berceli, Scott; Nelson, Peter

    2016-09-01

    The activation state of the systemic inflammatory milieu has been proposed as a critical regulator of vascular repair after injury. We evaluated the early inflammatory response after endovascular intervention for symptomatic peripheral arterial disease to determine its association with clinical success or failure. Blood samples were obtained from 14 patients undergoing lower extremity angioplasty/stenting and analyzed using high-throughput gene arrays, multiplex serum protein analyses, and flow cytometry. Time-dependent plasma protein and monocyte phenotype analyses demonstrated endovascular revascularization had a modest influence on the overall activation state of the systemic inflammatory system, with baseline variability exceeding the perturbations induced by the intervention. In contrast, specific time-dependent changes in the monocyte genome are evident in the initial 28 days, predominately in those genes associated with leukocyte extravasation. Investigating the relationship between inflammation and the 1-year success or failure of the intervention showed no single plasma protein was correlated with outcome, but a more comprehensive cluster analysis revealed a clear pattern of protein expression that was closely related to the clinical phenotype. Corresponding examination of the monocyte genome identified a gene subset at 1 day postprocedure that was predictive of clinical outcome, with most of these genes active in cell-cycle signaling. Although the global influence of angioplasty/stenting on systemic inflammation was modest, circulating cytokine and monocyte genome analyses support a pattern of early inflammation that is associated with ultimate intervention success vs failure. Molecular profiles incorporating genes involved in monocyte cell-cycle progression and homing, or proinflammatory cytokines, or both, offer the most promise for the development of class prediction tools for clinical application. Published by Elsevier Inc.

  10. Inflammation-induced endothelial cell-derived extracellular vesicles modulate the cellular status of pericytes.

    Science.gov (United States)

    Yamamoto, Seiji; Niida, Shumpei; Azuma, Erika; Yanagibashi, Tsutomu; Muramatsu, Masashi; Huang, Ting Ting; Sagara, Hiroshi; Higaki, Sayuri; Ikutani, Masashi; Nagai, Yoshinori; Takatsu, Kiyoshi; Miyazaki, Kenji; Hamashima, Takeru; Mori, Hisashi; Matsuda, Naoyuki; Ishii, Yoko; Sasahara, Masakiyo

    2015-02-17

    Emerging lines of evidence have shown that extracellular vesicles (EVs) mediate cell-to-cell communication by exporting encapsulated materials, such as microRNAs (miRNAs), to target cells. Endothelial cell-derived EVs (E-EVs) are upregulated in circulating blood in different pathological conditions; however, the characteristics and the role of these E-EVs are not yet well understood. In vitro studies were conducted to determine the role of inflammation-induced E-EVs in the cell-to-cell communication between vascular endothelial cells and pericytes/vSMCs. Stimulation with inflammatory cytokines and endotoxin immediately induced release of shedding type E-EVs from the vascular endothelial cells, and flow cytometry showed that the induction was dose dependent. MiRNA array analyses revealed that group of miRNAs were specifically increased in the inflammation-induced E-EVs. E-EVs added to the culture media of cerebrovascular pericytes were incorporated into the cells. The E-EV-supplemented cells showed highly induced mRNA and protein expression of VEGF-B, which was assumed to be a downstream target of the miRNA that was increased within the E-EVs after inflammatory stimulation. The results suggest that E-EVs mediate inflammation-induced endothelial cell-pericyte/vSMC communication, and the miRNAs encapsulated within the E-EVs may play a role in regulating target cell function. E-EVs may be new therapeutic targets for the treatment of inflammatory diseases.

  11. Methylprednisolone stiffens aortas in lipopolysaccharide-induced chronic inflammation in rats.

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    Ya-Hui Ko

    Full Text Available INTRODUCTION: Glucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and auto-immune diseases. The current study investigated the effects of methylprednisolone (a synthetic glucocorticoid on aortic distensibility and vascular resistance in lipopolysaccharide-induced chronic inflammation in male Wistar rats. METHODS: Chronic inflammation was induced by implanting a subcutaneous slow-release ALZET osmotic pump (1 mg kg(-1 day(-1 lipopolysaccharide for either 2 or 4 weeks. Arterial wave transit time (τ was derived to describe the elastic properties of aortas using the impulse response function of the filtered aortic input impedance spectra. RESULTS: Long-term lipopolysaccharide challenge enhanced the expression of advanced glycation end products (AGEs in the aortas. Lipopolysaccharide also upregulated the inducible form of nitric oxide synthase to produce high levels of nitric oxide (NO, which resulted in vasodilation, as evidenced by the fall in total peripheral resistance (Rp . However, lipopolysaccharide challenge did not influence the elastic properties of aortas, as shown by the unaltered τ. The NO-mediated vascular relaxation may counterbalance the AGEs-induced arterial stiffening so that the aortic distensibility remained unaltered. Treating lipopolysaccharide-challenged rats with methylprednisolone prevented peripheral vasodilation because of its ability to increase Rp . However, methylprednisolone produced an increase in aorta stiffness, as manifested by the significant decline in τ. The diminished aortic distensibility by methylprednisolone paralleled a significant reduction in NO plasma levels, in the absence of any significant changes in AGEs content. CONCLUSION: Methylprednisolone stiffens aortas and elastic arteries in lipopolysaccharide-induced chronic inflammation in rats, for NO activity may be dominant as a counteraction of AGEs.

  12. Tityus serrulatus scorpion venom improves survival and lung inflammation in lethal sepsis induced by CLP in mice.

    Science.gov (United States)

    Maciel, Márcia C G; Fialho, Eder M S; Guerra, Rosane N M; Borges, Valéria M; Kwasniewski, Fábio H; Nascimento, Flávia R F

    2014-10-01

    Tityus serrulatus venom (Tsv) modifies the behavior of immune cells and induces the production of inflammatory and anti-inflammatory cytokines; such action may interfere with physiological or pathological states. Because sepsis is characterized as an inflammatory disorder, the aim of present study was to investigate the effect of a non-lethal dose of Tsv in mice submitted to a polymicrobial infection by cecal ligation and puncture (CLP) model. The parameters evaluated were survival index, cellularity on lymphoid organs, peritoneal cavity and brochoalveolar space, production of IL-10, IL-12, IL-6, TNF-α, IFN-γ and MCP-1, pulmonary inflammation and oxidative burst. The results demonstrated that in sharp contrast to CLP group in which sepsis was lethal in a 24 h period all mice pretreated with Tsv survived even 60 h after CLP. Lung inflammation, another hallmark of CLP group, was also dramatically down regulated in Tsv/CLP group. Despite pretreatment with Tsv did not reduce the inflammatory serum cytokines when compared to CLP group; there was an increase in IL-10. In conclusion, subcutaneous Tsv administration 6 h before CLP was able to control the harmful effects of sepsis (lethality and lung inflammation). We suggest that both systemic IL-10 and oxidative burst are involved in this effect. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. The association between subgingival periodontal pathogens and systemic inflammation.

    Science.gov (United States)

    Winning, Lewis; Patterson, Christopher C; Cullen, Kathy M; Stevenson, Kathryn A; Lundy, Fionnuala T; Kee, Frank; Linden, Gerard J

    2015-09-01

    To investigate associations between periodontal disease pathogens and levels of systemic inflammation measured by C-reactive protein (CRP). A representative sample of dentate 60-70-year-old men in Northern Ireland had a comprehensive periodontal examination. Men taking statins were excluded. Subgingival plaque samples were analysed by quantitative real time PCR to identify the presence of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia. High-sensitivity CRP (mg/l) was measured from fasting blood samples. Multiple linear regression analysis was performed using log-transformed CRP concentration as the dependent variable, with the presence of each periodontal pathogen as predictor variables, with adjustment for various potential confounders. A total of 518 men (mean age 63.6 SD 3.0 years) were included in the analysis. Multiple regression analysis showed that body mass index (p < 0.001), current smoking (p < 0.01), the detectable presence of P. gingivalis (p < 0.01) and hypertension (p = 0.01), were independently associated with an increased CRP. The detectable presence of P. gingivalis was associated with a 20% (95% confidence interval 4-35%) increase in CRP (mg/l) after adjustment for all other predictor variables. In these 60-70-year-old dentate men, the presence of P. gingivalis in subgingival plaque was significantly associated with a raised level of C-reactive protein. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Divergent effects of endogenous and exogenous glucocorticoid-induced leucine zipper in animal models of inflammation and arthritis.

    Science.gov (United States)

    Ngo, Devi; Beaulieu, Elaine; Gu, Ran; Leaney, Alexandra; Santos, Leilani; Fan, Huapeng; Yang, Yuanhang; Kao, Wenping; Xu, Jiake; Escriou, Virginie; Loiler, Scott; Vervoordeldonk, Margriet J; Morand, Eric F

    2013-05-01

    Glucocorticoid-induced leucine zipper (GILZ) has effects on inflammatory pathways that suggest it to be a key inhibitory regulator of the immune system, and its expression is exquisitely sensitive to induction by glucocorticoids. We undertook this study to test our hypothesis that GILZ deficiency would exacerbate experimental immune-mediated inflammation and impair the effects of glucocorticoids on inflammation and, correspondingly, that exogenous GILZ would inhibit these events. GILZ(-/-) mice were generated using the Cre/loxP system, and responses were studied in delayed-type hypersensitivity (DTH), antigen-induced arthritis (AIA), K/BxN serum-transfer arthritis, and lipopolysaccharide (LPS)-induced cytokinemia. Therapeutic expression of GILZ via administration of recombinant adeno-associated virus expressing the GILZ gene (GILZ-rAAV) was compared to the effects of glucocorticoid in collagen-induced arthritis (CIA). Increased T cell proliferation and DTH were observed in GILZ(-/-) mice, but neither AIA nor K/BxN serum-transfer arthritis was affected, and GILZ deficiency did not affect LPS-induced cytokinemia. Deletion of GILZ did not impair the effects of exogenous glucocorticoids on CIA or cytokinemia. In contrast, overexpression of GILZ in joints significantly inhibited CIA, with an effect similar to that of dexamethasone. Despite effects on T cell activation, GILZ deficiency had no effect on effector pathways of arthritis and was unexpectedly redundant with effects of glucocorticoids. These findings do not support the hypothesis that GILZ is central to the actions of glucocorticoids, but the efficacy of exogenous GILZ in CIA suggests that further evaluation of GILZ in inflammatory disease is required. Copyright © 2013 by the American College of Rheumatology.

  15. Carrageenan-Induced Colonic Inflammation Is Reduced in Bcl10 Null Mice and Increased in IL-10-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Sumit Bhattacharyya

    2013-01-01

    Full Text Available The common food additive carrageenan is a known activator of inflammation in mammalian tissues and stimulates both the canonical and noncanonical pathways of NF-κB activation. Exposure to low concentrations of carrageenan (10 μg/mL in the water supply has produced glucose intolerance, insulin resistance, and impaired insulin signaling in C57BL/6 mice. B-cell leukemia/lymphoma 10 (Bcl10 is a mediator of inflammatory signals from Toll-like receptor (TLR 4 in myeloid and epithelial cells. Since the TLR4 signaling pathway is activated in diabetes and by carrageenan, we addressed systemic and intestinal inflammatory responses following carrageenan exposure in Bcl10 wild type, heterozygous, and null mice. Fecal calprotectin and circulating keratinocyte chemokine (KC, nuclear RelA and RelB, phospho(Thr559-NF-κB-inducing kinase (NIK, and phospho(Ser36-IκBα in the colonic epithelial cells were significantly less (P<0.001 in the carrageenan-treated Bcl10 null mice than in controls. IL-10-deficient mice exposed to carrageenan in a germ-free environment showed an increase in activation of the canonical pathway of NF-κB (RelA activation, but without increase in RelB or phospho-Bcl10, and exogenous IL-10 inhibited only the canonical pathway of NF-κB activation in cultured colonic cells. These findings demonstrate a Bcl10 requirement for maximum development of carrageenan-induced inflammation and lack of complete suppression by IL-10 of carrageenan-induced inflammation.

  16. Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice.

    Science.gov (United States)

    Wood, Tyler T; Winden, Duane R; Marlor, Derek R; Wright, Alex J; Jones, Cameron M; Chavarria, Michael; Rogers, Geraldine D; Reynolds, Paul R

    2014-11-15

    The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time. Copyright © 2014 the American Physiological Society.

  17. BMP-7 ameliorates cobalt alloy particle-induced inflammation by suppressing Th17 responses.

    Science.gov (United States)

    Chen, Fengrong; Chen, Ruisong; Liu, Haoyuan; Sun, Rupeng; Huang, Jianming; Huang, Zheyuan; Jian, Guojian

    2017-10-01

    Metal wear debris has been shown to activate an aseptic osteolytic process that causes failure in total joint arthroplasty (TJA). This osteolysis is characterized by a proinflammatory, self-propagating immune response involving primarily macrophages, dendritic cells, and activated osteoclasts, as well as T cells and B cells. The human bone morphogenic protein (BMP)-7, on the other hand, was shown to promote osteoblast survival, and reversed the downregulation of anabolic Smad proteins and Runx2 following cobalt injury. Therefore, we investigated the effect and mechanism of BMP-7 on the proinflammatory immune responses in osteoarthritis patients with previous TJA. Cobalt-treated monocytes/macrophages presented significantly elevated levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF), both of which were suppressed by the addition of exogenous BMP-7. In patients with TJA, the serum BMP-7 level was inversely associated with the level of IL-6 and TNF secreted by monocytes/macrophages. Cobalt-treated monocytes/macrophages effectively supported Th17 inflammation, by an IL-6-dependent but not TNF-dependent mechanism. BMP-7, however, significantly suppressed cobalt-induced Th17 inflammation. In patients with TJA, the risk of osteolysis development was positively associated with the frequency of Th17 cells and negatively associated with the level of BMP-7. Together, these results demonstrated that BMP-7 could serve as a therapeutic agent in treating patients with metal wear debris-induced inflammation. © 2017 APMIS. Published by John Wiley & Sons Ltd.

  18. Bardoxolone Methyl Prevents High-Fat Diet-Induced Colon Inflammation in Mice.

    Science.gov (United States)

    Dinh, Chi H L; Yu, Yinghua; Szabo, Alexander; Zhang, Qingsheng; Zhang, Peng; Huang, Xu-Feng

    2016-04-01

    Obesity induces chronic, low-grade inflammation, which increases the risk of colon cancer. We investigated the preventive effects of Bardoxolone methyl (BARD) on high-fat diet (HFD)-induced inflammation in a mouse colon. Male C57BL/6J mice (n=7) were fed a HFD (HFD group), HFD plus BARD (10 mg/kg) in drinking water (HFD/BARD group), or normal laboratory chow diet (LFD group) for 21 weeks. In HFD mice, BARD reduced colon thickness and decreased colon weight per length. This was associated with an increase in colon crypt depth and the number of goblet cells per crypt. BARD reduced the expression of F4/80 and CD11c but increased CD206 and IL-10, indicating an anti-inflammatory effect. BARD prevented an increase of the intracellular pro-inflammatory biomarkers (NF-қB, p NF-қB, IL-6, TNF-α) and cell proliferation markers (Cox2 and Ki67). BARD prevented fat deposition in the colon wall and prevented microbial population changes. Overall, we report the preventive effects of BARD on colon inflammation in HFD-fed mice through its regulation of macrophages, NF-қB, cytokines, Cox2 and Ki67, fat deposition and microflora. © 2016 The Histochemical Society.

  19. 1,8-cineol attenuates LPS-induced acute pulmonary inflammation in mice.

    Science.gov (United States)

    Zhao, Chunzhen; Sun, Jianbo; Fang, Chunyan; Tang, Fadi

    2014-04-01

    Eucalyptol, also known as 1,8-cineol, is a monoterpene and has been shown to exert anti-inflammatory and antioxidant effect. It is traditionally used to treat respiratory disorders due to its secretolytic properties. In the present study, we evaluated the effect of 1,8-cineol on pulmonary inflammation in a mouse model of acute lung injury. We found that 1,8-cineol significantly decreased the level of TNF-α and IL-1β, and increased the level of IL-10 in lung tissues after acute lung injury induced by lipopolysaccharide (LPS). It also reduced the expression of nuclear factor kappa B (NF-κB) p65 and toll-like receptor 4 (TLR4), and myeloperoxidase activity in lung tissues. In addition, 1,8-cineol reduced the amounts of inflammatory cells in bronchoalveolar lavage fluid (BALF), including neutrophils and macrophages, and significantly decreased the protein content in BALF and the lung wet/dry weight (W/D) ratio. Its effect on LPS-induced pulmonary inflammation was associated with suppression of TLR4 and NF-κB expressions. Our results provide evidence that 1,8-cineol inhibits acute pulmonary inflammation, indicating its potential for the treatment of acute lung injury.

  20. Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO pathway.

    Science.gov (United States)

    Phillips, Matthew C; Dheer, Rishu; Santaolalla, Rebeca; Davies, Julie M; Burgueño, Juan; Lang, Jessica K; Toborek, Michal; Abreu, Maria T

    2018-01-15

    Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs. We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred. Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR. Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation. These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice.

    Science.gov (United States)

    Pouwels, Simon D; Zijlstra, G Jan; van der Toorn, Marco; Hesse, Laura; Gras, Renee; Ten Hacken, Nick H T; Krysko, Dmitri V; Vandenabeele, Peter; de Vries, Maaike; van Oosterhout, Antoon J M; Heijink, Irene H; Nawijn, Martijn C

    2016-02-15

    Recent data indicate a role for airway epithelial necroptosis, a regulated form of necrosis, and the associated release of damage-associated molecular patterns (DAMPs) in the development of chronic obstructive pulmonary disease (COPD). DAMPs can activate pattern recognition receptors (PRRs), triggering innate immune responses. We hypothesized that cigarette smoke (CS)-induced epithelial necroptosis and DAMP release initiate airway inflammation in COPD. Human bronchial epithelial BEAS-2B cells were exposed to cigarette smoke extract (CSE), and necrotic cell death (membrane integrity by propidium iodide staining) and DAMP release (i.e., double-stranded DNA, high-mobility group box 1, heat shock protein 70, mitochondrial DNA, ATP) were analyzed. Subsequently, BEAS-2B cells were exposed to DAMP-containing supernatant of CS-induced necrotic cells, and the release of proinflammatory mediators [C-X-C motif ligand 8 (CXCL-8), IL-6] was evaluated. Furthermore, mice were exposed to CS in the presence and absence of the necroptosis inhibitor necrostatin-1, and levels of DAMPs and inflammatory cell numbers were determined in bronchoalveolar lavage fluid. CSE induced a significant increase in the percentage of necrotic cells and DAMP release in BEAS-2B cells. Stimulation of BEAS-2B cells with supernatant of CS-induced necrotic cells induced a significant increase in the release of CXCL8 and IL-6, in a myeloid differentiation primary response gene 88-dependent fashion. In mice, exposure of CS increased the levels of DAMPs and numbers of neutrophils in bronchoalveolar lavage fluid, which was statistically reduced upon treatment with necrostatin-1. Together, we showed that CS exposure induces necrosis of bronchial epithelial cells and subsequent DAMP release in vitro, inducing the production of proinflammatory cytokines. In vivo, CS exposure induces neutrophilic airway inflammation that is sensitive to necroptosis inhibition. Copyright © 2016 the American Physiological Society.

  2. Attenuation of Oxidative Stress and Inflammation by Portulaca oleracea in Streptozotocin-Induced Diabetic Rats.

    Science.gov (United States)

    Samarghandian, Saeed; Borji, Abasalt; Farkhondeh, Tahereh

    2017-10-01

    The present study was designed to investigate the protective effect of the aqueous extract of Portulaca oleracea against hyperglycemic, oxidative damage and inflammation in the serum of streptozotocin (STZ)-induced diabetic rats. In the present study, the rats were divided into the following groups of 8 animals each: control, untreated diabetic, 3 Portulaca oleracea (100, 200, 400 mg/kg/d)-treated diabetic groups. At the end of the 4-week period, glucose, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), glutathione (GSH), and total antioxidant status (TAS) levels were measured. STZ caused an elevation in the serum levels of glucose, MDA, IL-6, and TNF-α with reduction in the levels of GSH and TAS ( P Portulaca oleracea ameliorated glucose, MDA, IL-6, TNF-α, GSH, and TAS levels in diabetic groups versus to the untreated groups ( P Portulaca oleracea prevented hyperglycemia by preventing the oxidative stress and inflammation.

  3. HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure.

    Science.gov (United States)

    Yang, Runkuan; Zou, Xiaoping; Tenhunen, Jyrki; Tønnessen, Tor Inge

    2017-01-01

    Acute liver failure (ALF) is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF) and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT). BT triggers/induces systemic inflammatory responses syndrome (SIRS), which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

  4. HMGB1 and Extracellular Histones Significantly Contribute to Systemic Inflammation and Multiple Organ Failure in Acute Liver Failure

    Directory of Open Access Journals (Sweden)

    Runkuan Yang

    2017-01-01

    Full Text Available Acute liver failure (ALF is the culmination of severe liver cell injury from a variety of causes. ALF occurs when the extent of hepatocyte death exceeds the hepatic regenerative capacity. ALF has a high mortality that is associated with multiple organ failure (MOF and sepsis; however, the underlying mechanisms are still not clear. Emerging evidence shows that ALF patients/animals have high concentrations of circulating HMGB1, which can contribute to multiple organ injuries and mediate gut bacterial translocation (BT. BT triggers/induces systemic inflammatory responses syndrome (SIRS, which can lead to MOF in ALF. Blockade of HMGB1 significantly decreases BT and improves hepatocyte regeneration in experimental acute fatal liver injury. Therefore, HMGB1 seems to be an important factor that links BT and systemic inflammation in ALF. ALF patients/animals also have high levels of circulating histones, which might be the major mediators of systemic inflammation in patients with ALF. Extracellular histones kill endothelial cells and elicit immunostimulatory effect to induce multiple organ injuries. Neutralization of histones can attenuate acute liver, lung, and brain injuries. In conclusion, HMGB1 and histones play a significant role in inducing systemic inflammation and MOF in ALF.

  5. Role of spleen-derived IL-10 in prevention of systemic low-grade inflammation by obesity [Review].

    Science.gov (United States)

    Gotoh, Koro; Fujiwara, Kansuke; Anai, Manabu; Okamoto, Mitsuhiro; Masaki, Takayuki; Kakuma, Tetsuya; Shibata, Hirotaka

    2017-04-29

    Obesity can be associated with systemic low-grade inflammation that leads to obesity-related metabolic disorders. Recent studies raise the possibility that the inflammation in hypothalamus, liver and white adipose tissue (WAT) contributes to the pathogenesis of diet-induced obesity. We focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine produced from spleen in obesity because it is indicated that obesity decreases the expression of pro-inflammatory cytokines in spleen. Obesity results in decrease of IL-10 synthesis from spleen, probably due to reduction of B-cells expression by promoting oxidative stress and apoptosis in spleen. Splenectomy (SPX) aggravates the inflammatory response in hypothalamus, liver and WAT. These SPX-induced alterations are inhibited by systemic administration of IL-10. Moreover, in IL-10 deficiency, SPX had little effect on the inflammatory responses in these multiple organs. We show the role of spleen-derived IL-10 on inflammatory responses in obesity.

  6. Exposure-Dependent Control of Malaria-Induced Inflammation in Children

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    Portugal, Silvia; Moebius, Jacqueline; Skinner, Jeff; Doumbo, Safiatou; Doumtabe, Didier; Kone, Younoussou; Dia, Seydou; Kanakabandi, Kishore; Sturdevant, Daniel E.; Virtaneva, Kimmo; Porcella, Stephen F.; Li, Shanping; Doumbo, Ogobara K.; Kayentao, Kassoum; Ongoiba, Aissata

    2014-01-01

    In malaria-naïve individuals, Plasmodium falciparum infection results in high levels of parasite-infected red blood cells (iRBCs) that trigger systemic inflammation and fever. Conversely, individuals in endemic areas who are repeatedly infected are often asymptomatic and have low levels of iRBCs, even young children. We hypothesized that febrile malaria alters the immune system such that P. falciparum re-exposure results in reduced production of pro-inflammatory cytokines/chemokines and enhan...

  7. Cordycepin inhibits LPS-induced acute lung injury by inhibiting inflammation and oxidative stress.

    Science.gov (United States)

    Lei, Jiaji; Wei, Youlei; Song, Pengcheng; Li, Yongchao; Zhang, Tianze; Feng, Qingjiang; Xu, Guangquan

    2018-01-05

    Acute lung injury (ALI) is a common severe clinical syndrome in intensive care unit. Inflammation has been reported to play a critical role in the development of ALI. Cordycepin, an active component isolated from Cordyceps militaris, has been reported to have anti-inflammatory effects. However, the anti-inflammatory effects of cordycepin on LPS-induced ALI remain unclear. Therefore, in the present study, we assessed whether cordycepin could attenuate ALI induced by LPS. The mice were conditioned with cordycepin 1h before intranasal instillation of LPS. Lung wet/dry (W/D) ratio, MPO activity, MDA content, and inflammatory cytokines production were detected. The expression of NF-κB p65, I-κB, Nrf2, and HO-1 were detected by western blot analysis. We found that LPS significantly increased lung wet/dry (W/D) ratio, MPO activity, MDA content, and inflammatory cytokines production. However, the increases were significantly inhibited by treatment of cordycepin. LPS-induced NF-κB activation was also suppressed by cordycepin. In addition, cordycepin was found to up-regulate the expression of Nrf2 and HO-1 in a dose-dependent manner. In conclusion, our results demonstrated that cordycepin could attenuate LPS-induced ALI effectively, probably due to inhibition of inflammation and oxidative stress. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Immune modulatory effects of IL-22 on allergen-induced pulmonary inflammation.

    Directory of Open Access Journals (Sweden)

    Ping Fang

    Full Text Available IL-22 is a Th17/Th22 cytokine that is increased in asthma. However, recent animal studies showed controversial findings in the effects of IL-22 in allergic asthma. To determine the role of IL-22 in ovalbumin-induced allergic inflammation we generated inducible lung-specific IL-22 transgenic mice. Transgenic IL-22 expression and signaling activity in the lung were determined. Ovalbumin (OVA-induced pulmonary inflammation, immune responses, and airway hyperresponsiveness (AHR were examined and compared between IL-22 transgenic mice and wild type controls. Following doxycycline (Dox induction, IL-22 protein was readily detected in the large (CC10 promoter and small (SPC promoter airway epithelial cells. IL-22 signaling was evidenced by phosphorylated STAT3. After OVA sensitization and challenge, compared to wild type littermates, IL-22 transgenic mice showed decreased eosinophils in the bronchoalveolar lavage (BAL, and in lung tissue, decreased mucus metaplasia in the airways, and reduced AHR. Among the cytokines and chemokines examined, IL-13 levels were reduced in the BAL fluid as well as in lymphocytes from local draining lymph nodes of IL-22 transgenic mice. No effect was seen on the levels of serum total or OVA-specific IgE or IgG. These findings indicate that IL-22 has immune modulatory effects on pulmonary inflammatory responses in allergen-induced asthma.

  9. Epidermal fatty acid binding protein promotes high-fat diet-induced skin inflammation

    Science.gov (United States)

    Rao, Enyu; Sun, Yanwen; Grossmann, Michael E.; Morris, Rebecca J.; Cleary, Margot P.; Li, Bing

    2015-01-01

    SUMMARY Defining specific cellular and molecular mechanisms in most obesity-related diseases remains an important challenge. Here we report a serendipitous finding that consumption of a high-fat diet (HFD) greatly increased the occurrence of skin lesions in C57BL/6 mice. We demonstrated that HFD induced the accumulation of a specific type of CD11c+ macrophages in skin preceding detectable lesions. These cells primed skin to induce IL-1β and IL-18 signaling, which further promoted the cytokines IFNγ- and IL-17-mediated skin inflammation. Mechanistically, epidermal fatty acid binding protein (E-FABP) was significantly upregulated in skin of obese mice, which coupled lipid droplet formation and NLRP3 inflammasome activation. Deficiency of E-FABP in obese mice decreased recruitment of CD11c+ macrophages in skin tissues, reduced production of IL-1β and IL-18, and consequently dampened activation of effector T cells. Furthermore, E-FABP deficient mice are completely resistant to HFD-induced skin lesions. Collectively, E-FABP represents a molecular sensor triggering HFD-induced skin inflammation. PMID:25992864

  10. Epidermal Fatty Acid binding protein promotes skin inflammation induced by high-fat diet.

    Science.gov (United States)

    Zhang, Yuwen; Li, Qiang; Rao, Enyu; Sun, Yanwen; Grossmann, Michael E; Morris, Rebecca J; Cleary, Margot P; Li, Bing

    2015-05-19

    Defining specific cellular and molecular mechanisms in most obesity-related diseases remains an important challenge. Here we report a serendipitous finding that consumption of a high-fat diet (HFD) greatly increased the occurrence of skin lesions in C57BL/6 mice. We demonstrated that HFD induced the accumulation of a specific type of CD11c(+) macrophages in skin preceding detectable lesions. These cells primed skin to induce IL-1β and IL-18 signaling, which further promoted the cytokines IFN-γ- and IL-17-mediated skin inflammation. Mechanistically, epidermal fatty acid binding protein (E-FABP) was significantly upregulated in skin of obese mice, which coupled lipid droplet formation and NLRP3 inflammasome activation. Deficiency of E-FABP in obese mice decreased recruitment of CD11c(+) macrophages in skin tissues, reduced production of IL-1β and IL-18, and consequently dampened activation of effector T cells. Furthermore, E-FABP-deficient mice are completely resistant to HFD-induced skin lesions. Collectively, E-FABP represents a molecular sensor triggering HFD-induced skin inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Ultraviolet radiation-induced inflammation activates β-catenin signaling in mouse skin and skin tumors.

    Science.gov (United States)

    Prasad, Ram; Katiyar, Santosh K

    2014-04-01

    UVB-induced inflammation, in particular the overexpression of cyclooxygenase-2 (COX-2) and prostaglandin (PG) E2, has been implicated in photocarcinogenesis. UVB-induced COX-2 has been associated with β-catenin signaling in keratinocytes. However, a definitive role for COX-2 in the activation of β-catenin signaling as well as its role in UVB-induced skin tumors has not been established. We report that exposure of the skin to UVB resulted in a time- and dose-dependent activation of β-catenin in C3H/HeN mice. This response was COX-2-dependent as UVB-exposed COX-2-deficient mice exhibited significantly lower levels of UVB-induced activation of β-catenin. Moreover, treatment of mice with indomethacin, a COX-2 inhibitor, and an EP2 antagonist inhibited UVB-induced β-catenin signaling. Exposure of SKH-1 hairless mice to UVB radiation (180 mJ/cm2) 3 times a week for 24 weeks resulted in activation of β-catenin signaling in UVB-irradiated skin as well as UVB-induced skin tumors. Concomitantly, the levels of CK1α and GSK-3β, which are responsible for β-catenin signaling, were reduced while the levels of c-Myc and cyclin D1, which are downstream targets of β-catenin, were increased. To further verify the role of UVB-induced inflammation in activation of β-catenin signaling, a high-fat-diet model was used. Administration of high-fat diet exacerbated UVB-induced inflammation. Administration of the high-fat diet enhanced β-catenin signaling and the levels of its downstream targets (c-Myc, cyclin D1, cyclin D2, MMP-2 and MMP-9) in UVB-exposed skin and skin tumors in SKH-1 mice. These data suggest that UV-induced COX-2/PGE2 stimulates β-catenin signaling, and that β-catenin activation may contribute to skin carcinogenesis.

  12. Inflammation in lung after acute myocardial infarction is induced by dendritic cell-mediated immune response.

    Science.gov (United States)

    Hu, L J; Ren, W Y; Shen, Q J; Ji, H Y; Zhu, L

    2017-01-01

    The present study was performed to describe the changes of lung tissues in mice with acute myocardial infarction (AMI) and also explain the cell mechanism involved in inflammation in lung. AMI was established by left coronary ligation in mice. Then mice were divided into three groups: control group, MW1 group (sampling after surgery for one week) and MW2 group (sampling after surgery for two weeks). Afterwards, measurement of lung weight and lung histology, cell sorting in bronchoalveolar lavage (BAL) fluid and detection of several adhesive molecules, inflammatory molecules as well as enzyme associated with inflammation were performed. Moreover, dendritic cells (DCs) were isolated from bone marrow of C57B/L6 mice. After incubating with necrotic myocardium, the expression of antigen presenting molecules, co-stimulatory molecules and inflammatory molecules were detected by flow cytometry or immunohistochemistry in DCs. We also detected T-cell proliferation after incubating with necrotic myocardium-treated DCs. AMI induced pathological changes of lung tissue and increased inflammatory cell amount in BAL fluid. AMI also increased the expression of several inflammatory factors, adhesive molecules and enzymes associated with inflammation. CD11c and TLR9, which are DC surface markers, showed a significantly increased expression in mice with AMI. Additionally, necrotic myocardium significantly increased the expression of co-stimulatory factors including CD83 and CD80, inflammatory cytokines including TNF-α, IFN-γ and NF-κB in DCs. Furthermore, DCs treated with necrotic myocardium also significantly promoted T-cell proliferation. AMI induced inflammation in lung and these pathological changes were mediated by DC-associated immune response.

  13. Haemophilus influenzae from Patients with Chronic Obstructive Pulmonary Disease Exacerbation Induce More Inflammation than Colonizers

    Science.gov (United States)

    Chin, Cecilia L.; Manzel, Lori J.; Lehman, Erin E.; Humlicek, Alicia L.; Shi, Lei; Starner, Timothy D.; Denning, Gerene M.; Murphy, Timothy F.; Sethi, Sanjay; Look, Dwight C.

    2005-01-01

    Rationale: Airway infection with Haemophilus influenzae causes airway inflammation, and isolation of new strains of this bacteria is associated with increased risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine whether strains of H. influenzae associated with exacerbations cause more inflammation than strains that colonize the airways of patients with COPD. Methods: Exacerbation strains of H. influenzae were isolated from patients during exacerbation of clinical symptoms with subsequent development of a homologous serum antibody response and were compared with colonization strains that were not associated with symptom worsening or an antibody response. Bacterial strains were compared using an in vivo mouse model of airway infection and in vitro cell culture model of bacterial adherence and defense gene and signaling pathway activation in primary human airway epithelial cells. Results: H. influenzae associated with exacerbations caused more airway neutrophil recruitment compared with colonization strains in the mouse model of airway bacterial infection. Furthermore, exacerbation strains adhered to epithelial cells in significantly higher numbers and induced more interleukin-8 release after interaction with airway epithelial cells. This effect was likely mediated by increased activation of the nuclear factor-κB and p38 mitogen-activated protein kinase signaling pathways. Conclusions: The results indicate that H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation and likely have differences in virulence compared with colonizing strains. These findings support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function. PMID:15805181

  14. Different regulation of cigarette smoke induced inflammation in upper versus lower airways

    Directory of Open Access Journals (Sweden)

    Bracke Ken R

    2010-07-01

    Full Text Available Abstract Background Cigarette smoke (CS is known to initiate a cascade of mediator release and accumulation of immune and inflammatory cells in the lower airways. We investigated and compared the effects of CS on upper and lower airways, in a mouse model of subacute and chronic CS exposure. Methods C57BL/6 mice were whole-body exposed to mainstream CS or air, for 2, 4 and 24 weeks. Bronchoalveolar lavage fluid (BAL was obtained and tissue cryosections from nasal turbinates were stained for neutrophils and T cells. Furthermore, we evaluated GCP-2, KC, MCP-1, MIP-3α, RORc, IL-17, FoxP3, and TGF-β1 in nasal turbinates and lungs by RT-PCR. Results In both upper and lower airways, subacute CS-exposure induced the expression of GCP-2, MCP-1, MIP-3α and resulted in a neutrophilic influx. However, after chronic CS-exposure, there was a significant downregulation of inflammation in the upper airways, while on the contrary, lower airway inflammation remained present. Whereas nasal FoxP3 mRNA levels already increased after 2 weeks, lung FoxP3 mRNA increased only after 4 weeks, suggesting that mechanisms to suppress inflammation occur earlier and are more efficient in nose than in lungs. Conclusions Altogether, these data demonstrate that CS induced inflammation may be differently regulated in the upper versus lower airways in mice. Furthermore, these data may help to identify new therapeutic targets in this disease model.

  15. Induction of Heme Oxygenase-1 with Hemin Reduces Obesity-Induced Adipose Tissue Inflammation via Adipose Macrophage Phenotype Switching

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    Thai Hien Tu

    2014-01-01

    Full Text Available Adipose macrophages with the anti-inflammatory M2 phenotype protect against obesity-induced inflammation and insulin resistance. Heme oxygenase-1 (HO-1, which elicits antioxidant and anti-inflammatory activity, modulates macrophage phenotypes and thus is implicated in various inflammatory diseases. Here, we demonstrate that the HO-1 inducer, hemin, protects against obesity-induced adipose inflammation by inducing macrophages to switch to the M2 phenotype. HO-1 induction by hemin reduced the production of proinflammatory cytokines (TNF-α and IL-6 from cocultured adipocytes and macrophages by inhibiting the activation of inflammatory signaling molecules (JNK and NF-κB in both cell types. Hemin enhanced transcript levels of M2 macrophage marker genes (IL-4, Mrc1, and Clec10a in the cocultures, while reducing transcripts of M1 macrophage markers (CD274 and TNF-α. The protective effects of hemin on adipose inflammation and macrophage phenotype switching were confirmed in mice fed a high-fat diet, and these were associated with PPARγ upregulation and STAT6 activation. These findings suggest that induction of HO-1 with hemin protects against obesity-induced adipose inflammation through M2 macrophage phenotype switching, which is induced by the PPARγ and STAT6 pathway. HO-1 inducers such as hemin may be useful for preventing obesity-induced adipose inflammation.

  16. Blocking neurogenic inflammation for the treatment of acute disorders of the central nervous system.

    Science.gov (United States)

    Lewis, Kate Marie; Turner, Renée Jade; Vink, Robert

    2013-01-01

    Classical inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of neurogenic inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of neurogenic inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and neurogenic inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis.

  17. Blocking Neurogenic Inflammation for the Treatment of Acute Disorders of the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Kate Marie Lewis

    2013-01-01

    Full Text Available Classical inflammation is a well-characterized secondary response to many acute disorders of the central nervous system. However, in recent years, the role of neurogenic inflammation in the pathogenesis of neurological diseases has gained increasing attention, with a particular focus on its effects on modulation of the blood-brain barrier BBB. The neuropeptide substance P has been shown to increase blood-brain barrier permeability following acute injury to the brain and is associated with marked cerebral edema. Its release has also been shown to modulate classical inflammation. Accordingly, blocking substance P NK1 receptors may provide a novel alternative treatment to ameliorate the deleterious effects of neurogenic inflammation in the central nervous system. The purpose of this paper is to provide an overview of the role of substance P and neurogenic inflammation in acute injury to the central nervous system following traumatic brain injury, spinal cord injury, stroke, and meningitis.

  18. Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events.

    Science.gov (United States)

    Pussinen, Pirkko J; Tuomisto, Karolina; Jousilahti, Pekka; Havulinna, Aki S; Sundvall, Jouko; Salomaa, Veikko

    2007-06-01

    In periodontitis, overgrowth of gram-negative bacteria may cause endotoxemia and systemic inflammation leading to cardiovascular diseases (CVD). We investigated in a prospective study the associations of serum endotoxin, antibodies to periodontal pathogens, and inflammation markers with the risk of incident CVD. The FINRISK 1992 cohort of 6051 individuals was followed up for 10 years. We examined 185 incident CVD events and a control cohort of 320 individuals using a prospective case-cohort design. High antibody response to periodontal pathogens independently predicted incident CVD events with hazard ratios (HR, quartile 4 versus quartiles 1 to 3, 95% CI) of 1.87 (1.13 to 3.08). The subjects with a high antibody response and high CRP or interleukin (IL)-6 had multivariate-adjusted HRs of 3.01 (1.27 to 7.09) and 3.11 (1.42 to 6.83) compared with low-responders, respectively. The corresponding HRs for high endotoxin concentration were 1.82 (1.22 to 2.73, alone), 3.92 (1.99 to 7.74, with CRP), 3.54 (1.78 to 7.03, with IL-6), and 2.26 (1.13 to 4.52, with tumor necrosis factor (TNF)-alpha) after adjusting for age and gender. These associations were abolished after adjusting for serum lipids. High endotoxin/HDL ratio, however, had a multivariate-adjusted HR of 1.92 (1.19 to 3.08) for CVD events. Our results suggest that the exposure to periodontal pathogens or endotoxin induces systemic inflammation leading to increased risk for CVD.

  19. Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation.

    Science.gov (United States)

    Cheng, Tao; Liu, Qingbo; Zhang, Rui; Zhang, Ying; Chen, Jianfeng; Yu, Ronghuan; Ge, Gaoxiang

    2014-12-01

    Enzymes involved in collagen biosynthesis, including lysyl oxidase (LOX), have been proposed as potential therapeutic targets for idiopathic pulmonary fibrosis. LOX expression is significantly upregulated in bleomycin (BLM)-induced lung fibrosis, and knockdown of LOX expression or inhibition of LOX activity alleviates the lung fibrosis. Unexpectedly, treatment of the mice with LOX inhibitor at the inflammatory stage, but not the fibrogenic stage, efficiently reduces collagen deposition and normalizes lung architecture. Inhibition of LOX impairs inflammatory cell infiltration, TGF-β signaling, and myofibroblast accumulation. Furthermore, ectopic expression of LOX sensitizes the fibrosis-resistant Balb/c mice to BLM-induced inflammation and lung fibrosis. These results suggest that LOX is indispensable for the progression of BLM-induced experimental lung fibrosis by aggravating the inflammatory response and subsequent fibrosis process after lung injury. © The Author (2014). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  20. The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity.

    Science.gov (United States)

    Weidmann, Henri; Heikaus, Laura; Long, Andy T; Naudin, Clément; Schlüter, Hartmut; Renné, Thomas

    2017-11-01

    The contact system is a potent procoagulant and proinflammatory plasma protease cascade that is initiated by binding ("contact")-induced, auto-activation of factor XII zymogen. Formed active serine protease FXIIa then cleaves plasma prekallikrein to kallikrein that in turn liberates the mediator bradykinin from its precursor high molecular weight kininogen. Bradykinin induces inflammation with implications for host defense and innate immunity. FXIIa also triggers the intrinsic pathway of coagulation that has been shown to critically contribute to thrombosis. Vice versa, FXII deficiency impairs thrombosis in animal models without inducing abnormal excessive bleeding. Recent work has established the FXIIa-driven contact system as promising target for anticoagulant and anti-inflammatory drugs. This review focuses on the biochemistry of the contact system, its regulation by endogenous and exogenous inhibitors, and roles in disease states. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Intestinal Dysbiosis, Barrier Dysfunction, and Bacterial Translocation Account for CKD-Related Systemic Inflammation.

    Science.gov (United States)

    Andersen, Kirstin; Kesper, Marie Sophie; Marschner, Julian A; Konrad, Lukas; Ryu, Mi; Kumar Vr, Santhosh; Kulkarni, Onkar P; Mulay, Shrikant R; Romoli, Simone; Demleitner, Jana; Schiller, Patrick; Dietrich, Alexander; Müller, Susanna; Gross, Oliver; Ruscheweyh, Hans-Joachim; Huson, Daniel H; Stecher, Bärbel; Anders, Hans-Joachim

    2017-01-01

    CKD associates with systemic inflammation, but the underlying cause is unknown. Here, we investigated the involvement of intestinal microbiota. We report that collagen type 4 α3-deficient mice with Alport syndrome-related progressive CKD displayed systemic inflammation, including increased plasma levels of pentraxin-2 and activated antigen-presenting cells, CD4 and CD8 T cells, and Th17- or IFNγ-producing T cells in the spleen as well as regulatory T cell suppression. CKD-related systemic inflammation in these mice associated with intestinal dysbiosis of proteobacterial blooms, translocation of living bacteria across the intestinal barrier into the liver, and increased serum levels of bacterial endotoxin. Uremia did not affect secretory IgA release into the ileum lumen or mucosal leukocyte subsets. To test for causation between dysbiosis and systemic inflammation in CKD, we eradicated facultative anaerobic microbiota with antibiotics. This eradication prevented bacterial translocation, significantly reduced serum endotoxin levels, and fully reversed all markers of systemic inflammation to the level of nonuremic controls. Therefore, we conclude that uremia associates with intestinal dysbiosis, intestinal barrier dysfunction, and bacterial translocation, which trigger the state of persistent systemic inflammation in CKD. Uremic dysbiosis and intestinal barrier dysfunction may be novel therapeutic targets for intervention to suppress CKD-related systemic inflammation and its consequences. Copyright © 2016 by the American Society of Nephrology.

  2. Brain morphology links systemic inflammation to cognitive function in midlife adults.

    Science.gov (United States)

    Marsland, Anna L; Gianaros, Peter J; Kuan, Dora C-H; Sheu, Lei K; Krajina, Katarina; Manuck, Stephen B

    2015-08-01

    Inflammation is linked to cognitive decline in midlife, but the neural basis for this link is unclear. One possibility is that inflammation associates with adverse changes in brain morphology, which accelerates cognitive aging and later dementia risk. Clear evidence is lacking, however, regarding whether inflammation relates to cognition in midlife via changes in brain morphology. Accordingly, the current study examines whether associations of inflammation with cognitive function are mediated by variation in cortical gray matter volume among midlife adults. Plasma levels of interleukin (IL)-6 and C-reactive protein (CRP), relatively stable markers of peripheral systemic inflammation, were assessed in 408 community volunteers aged 30-54 years. All participants underwent structural neuroimaging to assess global and regional brain morphology and completed neuropsychological tests sensitive to early changes in cognitive function. Measurements of brain morphology (regional tissue volumes and cortical thickness and surface area) were derived using Freesurfer. Higher peripheral inflammation was associated with poorer spatial reasoning, short term memory, verbal proficiency, learning and memory, and executive function, as well as lower cortical gray and white matter volumes, hippocampal volume and cortical surface area. Mediation models with age, sex and intracranial volume as covariates showed cortical gray matter volume to partially mediate the association of inflammation with cognitive performance. Exploratory analyses of body mass suggested that adiposity may be a source of the inflammation linking brain morphology to cognition. Inflammation and adiposity might relate to cognitive decline via influences on brain morphology. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Molecular toxicology of sulfur mustard-induced cutaneous inflammation and blistering

    International Nuclear Information System (INIS)

    Kehe, K.; Balszuweit, F.; Steinritz, D.; Thiermann, H.

    2009-01-01

    Sulfur mustard (SM) is a strong alkylating agent, which produces subepidermal blisters, erythema and inflammation after skin contact. Despite the well-described SM-induced gross and histopathological changes, the exact underlying molecular mechanisms of these events are still a matter of research. As part of an international effort to elucidate the components of cellular signal transduction pathways, a large body of data has been accumulated in the last decade of SM research, revealing deeper insight into SM-induced inflammation, DNA damage response, cell death signaling, and wound healing. SM potentially alkylates nearly every constituent of the cell, leading to impaired cellular functions. However, SM-induced DNA alkylation has been identified as a major trigger of apoptosis. This includes monofunctional SM-DNA adducts as well as DNA crosslinks. As a consequence, DNA replication is blocked, which leads to cell cycle arrest and DNA single and double strand breaks. The SM-induced DNA damage results in poly(ADP-ribose) polymerase (PARP) activation. High SM concentrations induce PARP overactivation, thus depleting cellular NAD + and ATP levels, which in consequence results in necrotic cell death. Mild PARP activation does not disturb cellular energy levels and allows apoptotic cell death or recovery to occur. SM-induced apoptosis has been linked both to the extrinsic (death receptor, Fas) and intrinsic (mitochondrial) pathway. Additionally, SM upregulates many inflammatory mediators including interleukin (IL)-1α, IL-1β, IL-6, IL-8, tumor necrosis factor-α (TNF-α) and others. Recently, several investigators linked NF-κB activation to this inflammatory response. This review briefly summarizes the skin toxicity of SM, its proposed toxicodynamic actions and strategies for the development of improved medical therapy.

  4. Ganoderma applanatum terpenes protect mouse liver against benzo(α)pyren-induced oxidative stress and inflammation.

    Science.gov (United States)

    Ma, Jie-Qiong; Liu, Chan-Min; Qin, Zhi-Hong; Jiang, Ji-Hong; Sun, Yun-Zhi

    2011-05-01

    Ganoderma applanatum terpenes (GAT) have been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of GAT against benzo(a)pyrene (BaP) induced oxidative stress and inflammation in mouse liver, and explored the potential mechanism of its action. Our data showed that GAT significantly decreased levels of ALT and AST in serum and the liver histological injury in BaP-treated mice. GAT markedly decreased the levels of ROS, MDA and lowered the GSH/GSSG ratio in the liver of BaP-treated mice. Furthermore, GAT markedly inhibited the BaP-induced increase of Cu/Zn-SOD, CAT, GPx and GST activities in the mouse liver. Western blot analysis showed that GAT significantly inhibited inflammation by pressing the expression of IL-1β and COX-2 and inhibiting NF-κB translocation in the liver of BaP-treated mice. In conclusion, these results suggested that GAT could protect the mouse liver against BaP-induced injury by improving hepatic function, attenuating histopathologic changes, decreasing levels of ROS and MDA, renewing the activities of antioxidant enzymes and suppressing inflammatory response. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Dexmedetomidine Ameliorate CLP-Induced Rat Intestinal Injury via Inhibition of Inflammation.

    Science.gov (United States)

    Chen, Yanqing; Miao, Liyan; Yao, Yusheng; Wu, Weilan; Wu, Xiaodan; Gong, Cansheng; Qiu, Liangcheng; Chen, Jianping

    2015-01-01

    The aim was to verify that dexmedetomidine (DEX) can attenuate CLP-induced intestinal injury via inhibition of inflammation. Male Sprague-Dawley (SD) rats were randomly allocated into Sham group and the other three CLP model groups, in terms of different treatments: placebo, DEX, and yohimbine plus DEX (DEX + YOH) groups. Pathology examination was conducted with HE stain. To identify differences among groups, the levels of DAO, and D-lactate in serum were measured by spectrophotometry, and the levels of TNF-α, IL-1β, and IL-6 in serum and organ were measured by ELISA. The expressions of occludin and TLR4 in tissue were detected by Western blot. The survival rate of an additional group of animals within 7 d was recorded. In DEX group, mortality was lower, histology change was minor, DAO, and D-lactate levels were reduced, and occludin expression was increased; the expressions of TNF-α, IL-1β, IL-6, and TLR4 were also decreased in DEX group. These results indicated that acute intestinal injury induced by CLP was mitigated by DEX treatment. However, these effects of DEX were significantly attenuated by yohimbine in DEX + YOH group. Our study indicated the protective effects of DEX on CLP-induced injury, which may be associated with the inhibition of inflammation via modulating TLR4 pathway and can be blocked by yohimbine.

  6. Vaccination with IL-6 analogues induces autoantibodies to IL-6 and influences experimentally induced inflammation

    DEFF Research Database (Denmark)

    Galle, Pia; Jensen, Lene; Andersson, Christina

    2007-01-01

    IL-6 is involved in inflammation and a therapeutic target. 0.1% of Danish blood donors have nanomolar plasma concentrations of polyclonal, picomolar affinity and in vitro as well as in vivo neutralizing IgG autoantibodies to IL-6 (aAb-IL-6). Such donors are assumed to be severely IL-6 deficient; ...... principle might be a viable alternative in immune competent humans suffering from disorders driven by IL-6....

  7. Ferulic Acid on Glucose Dysregulation, Dyslipidemia, and Inflammation in Diet-Induced Obese Rats: An Integrated Study

    Science.gov (United States)

    González-Aguilar, Gustavo A.; Loarca-Piña, Guadalupe; Ezquerra-Brauer, Josafat-Marina; Domínguez Avila, J. Abraham; Robles-Sánchez, Maribel

    2017-01-01

    Obesity is considered to be a low-grade chronic inflammatory process, which is associated with cardiovascular and metabolic diseases. An integral evaluation of the effects of ferulic acid on biomarkers of glucose dysregulation, dyslipidemia, inflammation, and antioxidant potential induced by a high-fat diet (HFD) in rats was carried out. Three groups of male Wistar rats (six per group) consumed a basal diet (BD), which was supplemented with either lard at 310 g/kg (HFD) or lard and ferulic acid at 2 g/kg (HFD + FA), ad libitum for eight weeks. Body weight gain, hyperplasia, and hypertrophy in abdominal fat tissues were higher in the HFD group than in the HFD+FA group. The rats fed a HFD + FA significantly inhibited the increase in plasma lipids and glucose, compared with the HFD group. Biomarkers associated with inflammation were found at higher concentrations in the serum of rats fed a HFD than the HFD + FA group. Plasma antioxidant levels were lower in HFD rats compared to rats fed the HFD + FA. These results suggest that ferulic acid improves the obesogenic status induced by HFD, and we elucidated the integral effects of ferulic acid on a biological system. PMID:28661434

  8. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

    Directory of Open Access Journals (Sweden)

    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  9. Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue.

    Science.gov (United States)

    Neyrinck, Audrey M; Alligier, Maud; Memvanga, Patrick B; Névraumont, Elodie; Larondelle, Yvan; Préat, Véronique; Cani, Patrice D; Delzenne, Nathalie M

    2013-01-01

    Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.

  10. Experimental blunt chest trauma-induced myocardial inflammation and alteration of gap-junction protein connexin 43.

    Directory of Open Access Journals (Sweden)

    Miriam Kalbitz

    Full Text Available Severe blunt chest trauma in humans is associated with high mortality rates. Whereas lung tissue damage and lung inflammation after blunt chest trauma have extensively been investigated, the traumatic and posttraumatic effects on the heart remain poorly understood. Therefore, the purpose of this study was to define cardiac injury patterns in an experimental blunt chest trauma model in rats.Experimental blunt chest trauma was induced by a blast wave in rats, with subsequent analysis of its effects on the heart. The animals were subjected either to a sham or trauma procedure. Systemic markers for cardiac injury were determined after 24 h and 5 days. Postmortem analysis of heart tissue addressed structural injury and inflammation 24 h and 5 days after trauma.Plasma levels of extracellular histones were elevated 24 h and 5 days after blunt chest trauma compared to sham-treated animals. In the heart, up-regulation of interleukin-1β 24 h after trauma and increased myeloperoxidase activity 24 h and 5 days after trauma were accompanied by reduced complement C5a receptor-1 expression 24 h after trauma. Histological analysis revealed extravasation of erythrocytes and immunohistochemical analysis alteration of the pattern of the gap-junction protein connexin 43. Furthermore, a slight reduction of α-actinin and desmin expression in cardiac tissue was found after trauma together with a minor increase in sarcoplasmatic/endoplasmatic reticlulum calcium-ATPase (SERCA expression.The clinically highly relevant rat model of blast wave-induced blunt chest trauma is associated with cardiac inflammation and structural alterations in cardiac tissue.

  11. Experimental blunt chest trauma-induced myocardial inflammation and alteration of gap-junction protein connexin 43.

    Science.gov (United States)

    Kalbitz, Miriam; Amann, Elisa Maria; Bosch, Belinda; Palmer, Annette; Schultze, Anke; Pressmar, Jochen; Weber, Birte; Wepler, Martin; Gebhard, Florian; Schrezenmeier, Hubert; Brenner, Rolf; Huber-Lang, Markus

    2017-01-01

    Severe blunt chest trauma in humans is associated with high mortality rates. Whereas lung tissue damage and lung inflammation after blunt chest trauma have extensively been investigated, the traumatic and posttraumatic effects on the heart remain poorly understood. Therefore, the purpose of this study was to define cardiac injury patterns in an experimental blunt chest trauma model in rats. Experimental blunt chest trauma was induced by a blast wave in rats, with subsequent analysis of its effects on the heart. The animals were subjected either to a sham or trauma procedure. Systemic markers for cardiac injury were determined after 24 h and 5 days. Postmortem analysis of heart tissue addressed structural injury and inflammation 24 h and 5 days after trauma. Plasma levels of extracellular histones were elevated 24 h and 5 days after blunt chest trauma compared to sham-treated animals. In the heart, up-regulation of interleukin-1β 24 h after trauma and increased myeloperoxidase activity 24 h and 5 days after trauma were accompanied by reduced complement C5a receptor-1 expression 24 h after trauma. Histological analysis revealed extravasation of erythrocytes and immunohistochemical analysis alteration of the pattern of the gap-junction protein connexin 43. Furthermore, a slight reduction of α-actinin and desmin expression in cardiac tissue was found after trauma together with a minor increase in sarcoplasmatic/endoplasmatic reticlulum calcium-ATPase (SERCA) expression. The clinically highly relevant rat model of blast wave-induced blunt chest trauma is associated with cardiac inflammation and structural alterations in cardiac tissue.

  12. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    Energy Technology Data Exchange (ETDEWEB)

    Gandhi, Adarsh, E-mail: adarsh.gandhi@nih.gov [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Guo, Tao, E-mail: tguo4@jhu.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Shah, Pranav [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States); Moorthy, Bhagavatula [Baylor College of Medicine, Department of Pediatrics, 1102 Bates Avenue, Suite 530, Houston, TX 77030 (United States); Ghose, Romi, E-mail: rghose@uh.edu [University of Houston, Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, 1441 Moursund Street, Room 517, Houston, TX 77030 (United States)

    2013-02-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP{sup +/+} and TIRAP{sup −/−} mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP{sup +/+} mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP{sup −/−} mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies

  13. Correlation of TLR4 and KLF7 in Inflammation Induced by Obesity.

    Science.gov (United States)

    Wang, Cuizhe; Ha, Xiaodan; Li, Wei; Xu, Peng; Gu, Yajuan; Wang, Tingting; Wang, Yan; Xie, Jianxin; Zhang, Jun

    2017-02-01

    Objective Recent studies have revealed a link between toll-like receptors (TLRs), Kruppel-like factors (KLFs), and the adipose tissue inflammation associated with obesity. TLR4 is associated with chronic inflammation in obesity. KLF7 is known to play an important role in the differentiation of adipocytes, but its role in visceral adipose tissue inflammation has not yet been investigated. Thus, the objective of this study was to determine the correlation of TLR4 and KLF7 in inflammation induced by obesity. Methods A total of 32 Wistar male rat subjects were fed in the center for experimental animals of Shihezi University. The rats were divided into normal control (NC) and high-fat diet (HFD) group. Surgical instruments were used to collect rats' visceral adipose tissue samples in the 10th week after HFD feeding. Ninety-five Uygur subjects between 20 and 90 years old were enrolled in the present study. The subjects were divided into two groups: the normal control group (NC, 18.0 kg/m 2  ≤ BMI ≤ 23.9 kg/m 2 , n = 50) and the obesity group (OB, BMI ≥ 28 kg/m 2 , n = 45), and visceral adipose tissue was collected from the subjects. Anthropometric and clinical parameters were measured using standard procedures; biochemical indices were detected using the glucose oxidase-peroxidase method and a standardized automatic biochemistry analyzer; the plasma levels of inflammatory factors and adipocytokines were measured by enzyme-linked immunosorbent assay (ELISA); the mRNA and protein expression levels of key genes involved in the inflammatory signaling pathway were measured by real-time PCR and Western blot. Results In rats, compared with the NC group, the weight, Lee's index, waist circumference, visceral fat mass, and the plasma level of Glu, TG, FFA, and TNF-α were higher in the HFD group, while the plasma levels of LPT and APN were significantly lower in the HFD group in the 10th week. Furthermore, compared with the NC group, visceral adipose

  14. Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

    International Nuclear Information System (INIS)

    Gandhi, Adarsh; Guo, Tao; Shah, Pranav; Moorthy, Bhagavatula; Ghose, Romi

    2013-01-01

    Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP +/+ and TIRAP −/− mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ∼ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP +/+ mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP −/− mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs. -- Highlights: ► Inflammation augments the toxicity of an idiosyncratic hepatotoxin chlorpromazine. ► Activation of Toll-like receptors by LPS or LTA induces chlorpromazine toxicity. ► Sustained stress kinase (JNK) activation is associated with chlorpromazine toxicity. ► These studies provide novel mechanistic

  15. Telomere-mediated chromosomal instability triggers TLR4 induced inflammation and death in mice.

    Directory of Open Access Journals (Sweden)

    Rabindra N Bhattacharjee

    Full Text Available BACKGROUND: Telomeres are essential to maintain chromosomal stability. Cells derived from mice lacking telomerase RNA component (mTERC-/- mice display elevated telomere-mediated chromosome instability. Age-dependent telomere shortening and associated chromosome instability reduce the capacity to respond to cellular stress occurring during inflammation and cancer. Inflammation is one of the important risk factors in cancer progression. Controlled innate immune responses mediated by Toll-like receptors (TLR are required for host defense against infection. Our aim was to understand the role of chromosome/genome instability in the initiation and maintenance of inflammation. METHODOLOGY/PRINCIPAL FINDINGS: We examined the function of TLR4 in telomerase deficient mTERC-/- mice harbouring chromosome instability which did not develop any overt immunological disorder in pathogen-free condition or any form of cancers at this stage. Chromosome instability was measured in metaphase spreads prepared from wildtype (mTERC+/+, mTERC+/- and mTERC-/- mouse splenocytes. Peritoneal and/or bone marrow-derived macrophages were used to examine the responses of TLR4 by their ability to produce inflammatory mediators TNFalpha and IL6. Our results demonstrate that TLR4 is highly up-regulated in the immune cells derived from telomerase-null (mTERC-/- mice and lipopolysaccharide, a natural ligand for TLR4 stabilises NF-kappaB binding to its promoter by down-regulating ATF-3 in mTERC-/- macrophages. CONCLUSIONS/SIGNIFICANCE: Our findings implied that background chromosome instability in the cellular level stabilises the action of TLR4-induced NF-kappaB action and sensitises cells to produce excess pro-inflammatory mediators. Chromosome/genomic instability data raises optimism for controlling inflammation by non-toxic TLR antagonists among high-risk groups.

  16. Synergistic effect of κ-carrageenan on oxazolone-induced inflammation in BALB/c mice.

    Science.gov (United States)

    Wu, Wei; Wang, Feng; Gao, Xin; Niu, Tingting; Zhu, Xiaojuan; Yan, Xiaojun; Chen, Haimin

    2016-03-25

    Carrageenan is a traditional ingredient that has been widely used in the food industry. In the present study, we propose a hypothesis that carrageenan is a conditional inflammatory agent. When the intestinal tract is in an "unhealthy" state such as that during bacterial infection or acute inflammation, carrageenan can synergistically enhance the inflammatory response. BALB/C mice received κ-carrageenan via intragastric administration prior to the induction of oxazolone colitis. Weight changes, survival rate, histologic change, secretion of inflammatory cytokines, ratio of regulatory T cells (Tregs) in peripheral blood, and expression of genes and proteins involved in inflammation and cell proliferation in the colonic mucosa were examined. Intragastric administration of κ-carrageenan to BALB/c mice prior to the induction of oxazolone colitis resulted in an aggravation of body weight loss, a decrease in the survival ratio, aggravation of colonic inflammation, and decrease in the ratio of CD4 + CD25+/CD4+. The secretion of interleukin-4 (IL-4), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) also significantly increased after κ-carrageenan administration. κ-Carrageenan, together with oxazolone, suppressed the expression of forkhead box p3 (FOXp3) and increased the expression of Toll-like receptor 4 (TLR4), Nuclear factor-κB (NF-κB), and proliferating cell nuclear antigen in the colonic mucosa. These results were confirmed by qRT-PCR and western blot analyses at the molecular and protein levels, respectively. κ-Carrageenan aggravated oxazolone-induced intestinal inflammation in BALB/c mice. This effect is associated with an activation of the TLR4-NF-κB pathway, a decreased ratio of Tregs, and the induction of Th2-dependent immune responses.

  17. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism.

    Science.gov (United States)

    Wigerblad, Gustaf; Bas, Duygu B; Fernades-Cerqueira, Cátia; Krishnamurthy, Akilan; Nandakumar, Kutty Selva; Rogoz, Katarzyna; Kato, Jungo; Sandor, Katalin; Su, Jie; Jimenez-Andrade, Juan Miguel; Finn, Anja; Bersellini Farinotti, Alex; Amara, Khaled; Lundberg, Karin; Holmdahl, Rikard; Jakobsson, Per-Johan; Malmström, Vivianne; Catrina, Anca I; Klareskog, Lars; Svensson, Camilla I

    2016-04-01

    An interesting and so far unexplained feature of chronic pain in autoimmune disease is the frequent disconnect between pain and inflammation. This is illustrated well in rheumatoid arthritis (RA) where pain in joints (arthralgia) may precede joint inflammation and persist even after successful anti-inflammatory treatment. In the present study, we have addressed the possibility that autoantibodies against citrullinated proteins (ACPA), present in RA, may be directly responsible for the induction of pain, independent of inflammation. Antibodies purified from human patients with RA, healthy donors and murinised monoclonal ACPA were injected into mice. Pain-like behaviour was monitored for up to 28 days, and tissues were analysed for signs of pathology. Mouse osteoclasts were cultured and stimulated with antibodies, and supernatants analysed for release of factors. Mice were treated with CXCR1/2 (interleukin (IL) 8 receptor) antagonist reparixin. Mice injected with either human or murinised ACPA developed long-lasting pronounced pain-like behaviour in the absence of inflammation, while non-ACPA IgG from patients with RA or control monoclonal IgG were without pronociceptive effect. This effect was coupled to ACPA-mediated activation of osteoclasts and release of the nociceptive chemokine CXCL1 (analogue to human IL-8). ACPA-induced pain-like behaviour was reversed with reparixin. The data suggest that CXCL1/IL-8, released from osteoclasts in an autoantibody-dependent manner, produces pain by activating sensory neurons. The identification of this new pain pathway may open new avenues for pain treatment in RA and also in other painful diseases associated with autoantibody production and/or osteoclast activation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  18. Different Mechanisms of Inflammation Induced in Virus and Autoimmune-Mediated Models of Multiple Sclerosis in C57BL6 Mice

    Directory of Open Access Journals (Sweden)

    Abhinoy Kishore

    2013-01-01

    Full Text Available Multiple sclerosis (MS is an inflammatory demyelinating disease of the human central nervous system (CNS. Neurotropic demyelinating strain of MHV (MHV-A59 or its isogenic recombinant strain RSA59 induces MS-like disease in mice mediated by microglia, along with a small population of T cells. The mechanism of demyelination is at least in part due to microglia-mediated myelin stripping, with some direct axonal injury. Immunization with myelin oligodendrocyte glycoprotein (MOG induces experimental autoimmune encephalomyelitis (EAE, a mainly CD4+ T-cell-mediated disease, although CD8+ T cells may play a significant role in demyelination. It is possible that both autoimmune and nonimmune mechanisms such as direct viral toxicity may induce MS. Our study directly compares CNS pathology in autoimmune and viral-induced MS models. Mice with viral-induced and EAE demyelinating diseases demonstrated similar patterns and distributions of demyelination that accumulated over the course of the disease. However, significant differences in acute inflammation were noted. Inflammation was restricted mainly to white matter at all times in EAE, whereas inflammation initially largely involved gray matter in acute MHV-induced disease and then is subsequently localized only in white matter in the chronic disease phase. The presence of dual mechanisms of demyelination may be responsible for the failure of immunosuppression to promote long-term remission in many MS patients.

  19. Areca nut chewing and systemic inflammation: evidence of a common pathway for systemic diseases

    Directory of Open Access Journals (Sweden)

    Shafique Kashif

    2012-06-01

    Full Text Available Abstract Background Areca nut, the seed of fruit of an oriental palm, known as Areca catechu, is commonly chewed in many countries. Diabetes, hypertension, cardiovascular diseases, oropharyngeal and oesophageal cancers have been associated with areca nut chewing and the mechanism by which areca nut chewing increases the risk of systemic diseases remains elusive. We hypothesize that systemic inflammation may be elevated among areca nut users, which is linked with many systemic diseases. Therefore, this present study was conducted to examine the systemic inflammation among areca nut chewers and healthy controls. Methods This was an observational cross sectional study carried out on areca nut chewers and healthy individuals in Karachi, Pakistan. Participants were selected from a region of the city by invitation request sent from door to door. Information was collected regarding the socio-demographic profile and the pattern of use, and a blood sample was obtained to measure the level of C-reactive protein (CRP. We carried out multiple logistic regressions to investigate the association between socio-demographic profile, areca nut chewing and CRP levels. Results We carried out final analysis on 1112 individuals of which 556 were areca nut chewers and 556 were the age, gender and area matched controls. Areca nut chewers had a significantly higher proportion of men (15.1%, n = 84 who had an elevated CRP (>10 mg/dl as compared to controls (5.2%, n = 29. Multivariate analyses showed that areca nut chewers had significantly higher odds of an elevated CRP (OR = 3.23, 95% CI 2.08-5.02, p value Conclusions Areca nut chewing has a significant association with systemic inflammation. Further work is required to confirm that systemic inflammation is the main pathway by which areca nut use increases the risk of systemic diseases.

  20. Tofacitinib ameliorates inflammation in a rat model of airway neutrophilia induced by inhaled LPS.

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    Calama, Elena; Ramis, Isabel; Domènech, Anna; Carreño, Cristina; De Alba, Jorge; Prats, Neus; Miralpeix, Montserrat

    2017-04-01

    The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model. Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o. Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue. In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs

  1. SOCS3 Expression Correlates with Severity of Inflammation, Expression of Proinflammatory Cytokines, and Activation of STAT3 and p38 MAPK in LPS-Induced Inflammation In Vivo

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    João Antônio Chaves de Souza

    2013-01-01

    Full Text Available SOCS3 is an inducible endogenous negative regulator of JAK/STAT pathway, which is relevant in inflammatory conditions. We used a model of LPS-induced periodontal disease in rats to correlate SOCS3 expression with the inflammatory status. In vitro we used a murine macrophage cell line to assess the physical interaction between SOCS3 and STAT3 by coimmunoprecipitation. 30 ug of LPS from Escherichia coli were injected in the gingival tissues on the palatal aspect of first molars of the animals 3x/week for up to 4 weeks. Control animals were injected with the vehicle (PBS. The rats were sacrificed at 7, 15, and 30 days. Inflammation and gene expression were assessed by stereometric analysis, immunohistochemistry, RT-qPCR, and western blot. LPS injections increased inflammation, paralleled by an upregulation of SOCS3, of the proinflammatory cytokines IL-1β, IL-6, and TNF-α and increased phosphorylation of STAT3 and p38 MAPK. SOCS3 expression accompanied the severity of inflammation and the expression of proinflammatory cytokines, as well as the activation status of STAT3 and p38 MAPK. LPS stimulation in a macrophage cell line in vitro induced transient STAT3 activation, which was inversely correlated with a dynamic physical interaction with SOCS3, suggesting that this may be a mechanism for SOCS3 regulatory function.

  2. Melatonin Attenuates Intermittent Hypoxia-Induced Lipid Peroxidation and Local Inflammation in Rat Adrenal Medulla

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    Yu Liu

    2014-10-01

    Full Text Available Chronic intermittent hypoxia (CIH induces lipid peroxidation and leads to cardiovascular dysfunction, in which impaired activities of the adrenal medulla are involved. This may be caused by CIH-induced injury in the adrenal medulla, for which the mechanism is currently undefined. We tested the hypothesis that melatonin ameliorates the CIH-induced lipid peroxidation, local inflammation and cellular injury in rat adrenal medulla. Adult Sprague–Dawley rats were exposed to air (normoxic control or hypoxia mimicking a severe recurrent sleep apnoeic condition for 14 days. The injection of melatonin (10 mg/kg or vehicle was given before the daily hypoxic treatment. We found that levels of malondialdehyde and nitrotyrosine were significantly increased in the vehicle-treated hypoxic group, when compared with the normoxic control or hypoxic group treated with melatonin. Also, the protein levels of antioxidant enzymes (superoxide dismutase (SOD-1 and SOD-2 were significantly lowered in the hypoxic group treated with vehicle but not in the melatonin group. In addition, the level of macrophage infiltration and the expression of inflammatory cytokines (tumor necrosis factor (TNF-α, interleukin (IL-1β and IL-6 and mediators (inducible nitric oxide synthase (iNOS, cyclooxygenase-2 (COX-2 were elevated in the vehicle-treated hypoxic group, but were significantly ameliorated by the melatonin treatment. Moreover, the amount of apoptotic cells in the hypoxic groups was significantly less in the melatonin-treated group. In conclusion, CIH-induced lipid peroxidation causes local inflammation and cellular injury in the adrenal medulla. The antioxidant and anti-inflammatory actions of melatonin are indicative of a protective agent against adrenal damage in patients with severe obstructive sleep apnea syndrome.

  3. Auraptene in the Peels of Citrus kawachiensis (Kawachi Bankan Ameliorates Lipopolysaccharide-Induced Inflammation in the Mouse Brain

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    Satoshi Okuyama

    2014-01-01

    Full Text Available Examination of the dried peel powder of Citrus kawachiensis, one of the citrus products of Ehime, Japan, showed that it contained naringin (NGIN; 44.02 ± 0.491 mg/g, narirutin (NRTN; 4.46 ± 0.0563 mg/g, auraptene (AUR; 4.07 ± 0.033 mg/g, and 3,5,6,7,8,3′,4′-heptamethoxyflavone (HMF; 0.27 ± 0.0039 mg/g. When this dried peel powder was orally preadministered at the dose of 1.2 or 2.4 g/kg/day for 7 days into lipopolysaccharide- (LPS- injected mice, an animal model of systemic inflammation, it suppressed (1 LPS-induced loss of body weight and abnormal behavior in the open field, (2 LPS-induced activation of microglia and astrocytes in the hippocampus, and (3 LPS-induced expression of cyclooxygenase (COX-2, which were coexpressed in astrocytes of these mice. When NGIN or AUR was preadministered to LPS-injected mice at an amount similar to that in the peel powder, AUR, but not NGIN, had the ability to suppress the LPS-induced inflammation in the brain of these model mice. The dried powder of flavedo tissue (the outer colored layer of the mesocarp of a citrus fruit and juice, which contained sufficient amounts of AUR, also had anti-inflammatory effect. These results suggest that AUR was the main ingredient responsible for the anti-inflammatory property of the dried peels of C. kawachiensis.

  4. Ganoderma Triterpenoids Exert Antiatherogenic Effects in Mice by Alleviating Disturbed Flow-Induced Oxidative Stress and Inflammation

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    Pei-Ling Hsu

    2018-01-01

    Full Text Available Ganoderma mushrooms, used in traditional Chinese medicine to promote health and longevity, have become widely accepted as herbal supplements. Ganoderma lucidum (GL, a commonly seen ganoderma species, is commercially cultivated under controlled conditions for more consistent chemical composition. The medicinal properties of GL are attributable to its antioxidant and anti-inflammatory activities. We intended to assess the effect of GL in atherosclerosis, an arterial condition associated with chronic oxidative stress and inflammation, using a carotid-artery-ligation mouse model. Flow turbulence created in the ligated artery induces oxidative stress and neointimal hyperplasia, a feature of early atherogenesis. Daily oral GL prevented neointimal thickening 2 weeks after ligation. Moreover, the ganoderma triterpenoid (GT crude extract isolated from GL abolished ligation-induced neointima formation. Mechanistically, endothelial dysfunction was observed 3 days after ligation before any structural changes could be detected. GTs alleviated the oxidative stress and restored the atheroresistent status of endothelium by inhibiting the induction of a series of atherogenic factors, including endothelin-1, von Willebrand factor, and monocyte chemoattractant protein-1 after 3-day ligation. The anti-inflammatory activity of GTs was tested in cultured human umbilical vein endothelial cells (HUVECs exposed to disturbed flow in an in vitro perfusion system. GTs abolished the induction of proinflammatory VCAM-1, TNF-α, and IL-6 by oscillatory shear stress. Moreover, the antioxidant activity of GTs was tested in HUVECs against the insult of H2O2. GTs dissipated the cellular superoxide accumulation imposed by H2O2, thereby mitigating H2O2-induced cell damage and proatherogenic response. Our results revealed the atheroprotective properties of ganoderma mushrooms and identified triterpenoids as the critical constituents for those effects. GTs prevent atherogenesis by

  5. Increased blood-brain barrier vulnerability to systemic inflammation in an Alzheimer disease mouse model.

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    Takeda, Shuko; Sato, Naoyuki; Ikimura, Kazuko; Nishino, Hirohito; Rakugi, Hiromi; Morishita, Ryuichi

    2013-08-01

    Behavioral and psychological problems are often observed in patients with dementia such as that associated with Alzheimer disease, and these noncognitive symptoms place an extremely heavy burden on the family and caregivers. Although it is well know that these symptoms often are triggered by infection of peripheral organs, the underlying mechanisms for these pathological conditions are still unclear. In this study, using an Alzheimer amyloid precursor protein (APP)-transgenic mouse, we analyzed behavioral changes and brain inflammatory response induced by peripheral administration of lipopolysaccharide. Application of a unique in vivo microdialysis system revealed that the increase in brain inflammatory cytokine (interleukin-6) level was significantly higher in APP-Tg than in wild-type mice after peripheral lipopolysaccharide injection, which was associated with more severe sickness behaviors. The blood-brain barrier became more permeable in APP-Tg mice during peripherally evoked inflammation, suggesting the increased vulnerability of the blood-brain barrier to inflammation in this animal model of Alzheimer's disease. These findings might provide insight into the pathogenesis of noncognitive symptoms in dementia and a basis to develop new therapeutic treatments for them. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Myocyte TLR4 enhances enteric and systemic inflammation driving late murine endotoxic ileus

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    Buchholz, Bettina M.; Shapiro, Richard A.; Vodovotz, Yoram; Billiar, Timothy R.; Sodhi, Chhinder P.; Hackam, David J.

    2015-01-01

    Myocytes are nonhemopoietic in origin and functionally essential in generating gastrointestinal motility. In endotoxemia, a rapid-onset nonhemopoietic mechanism potently triggers early ileus in a Toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88)-dependent manner. Moreover, synergistically with hemopoietic cells, nonhemopoietic cells escalate late ileus via an IL-6 receptor-dependent inflammation-driven pathway. We therefore specifically investigated the role of myocytes in TLR4-triggered inflammation and ileus. TLR4+/+, TLR4−/−, bmTLR4+/+/TLR4−/− chimera, SM22-Cre−/−TLR4flox/flox, and selective myocyte TLR4-deficient (SM22-Cre+/−TLR4flox/flox) mice were injected intraperitoneally with purified lipopolysaccharide. SM22-driven Cre recombinase activity was selectively detected in cardiac, gastrointestinal, skeletal, and vascular myocytes, of small-sized vessels in a two-color fluorescent Cre reporter mouse. In contrast to nonhemopoietic TLR4 deficiency, deletion of myocyte TLR4 signaling prevented neither endotoxin-induced suppression of spontaneous jejunal contractility in vitro nor early ileus in vivo at 6 h. Circulating plasma colony-stimulating factor 3 was greatly elevated during endotoxemia, independent of myocyte TLR4 signaling or time. TLR4 activation of myocytes contributed significantly to an early enteric IL-6 mRNA induction and systemic IL-6 release, as well as to a late increase in circulating chemokine (C-X-C motif) ligand 1 (CXCL1) and IL-17. Consequently, inhibition of myocyte TLR4 signaling allowed functional recovery of motility by preventing inflammation-driven late ileus at 24 h. Direct TLR4 activation of myocytes is not responsible for nonhemopoietic-mediated early ileus. However, myocytes are proinflammatory cells that potently drive enteric and systemic inflammation, subsequently fueling late mediator-triggered ileus. Specifically, the myocyte TLR4-dependent inflammatory signature of elevated

  7. The Tumor Suppressor Gene, RASSF1A, Is Essential for Protection against Inflammation -Induced Injury

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    Fiteih, Yahya; Law, Jennifer; Volodko, Natalia; Mohamed, Anwar; El-Kadi, Ayman O. S.; Liu, Lei; Odenbach, Jeff; Thiesen, Aducio; Onyskiw, Christina; Ghazaleh, Haya Abu; Park, Jikyoung; Lee, Sean Bong; Yu, Victor C.; Fernandez-Patron, Carlos; Alexander, R. Todd; Wine, Eytan; Baksh, Shairaz

    2013-01-01

    Ras association domain family protein 1A (RASSF1A) is a tumor suppressor gene silenced in cancer. Here we report that RASSF1A is a novel regulator of intestinal inflammation as Rassf1a+/−, Rassf1a−/− and an intestinal epithelial cell specific knockout mouse (Rassf1a IEC-KO) rapidly became sick following dextran sulphate sodium (DSS) administration, a chemical inducer of colitis. Rassf1a knockout mice displayed clinical symptoms of inflammatory bowel disease including: increased intestinal permeability, enhanced cytokine/chemokine production, elevated nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) activity, elevated colonic cell death and epithelial cell injury. Furthermore, epithelial restitution/repair was inhibited in DSS-treated Rassf1a−/− mice with reduction of several makers of proliferation including Yes associated protein (YAP)-driven proliferation. Surprisingly, tyrosine phosphorylation of YAP was detected which coincided with increased nuclear p73 association, Bax-driven epithelial cell death and p53 accumulation resulting in enhanced apoptosis and poor survival of DSS-treated Rassf1a knockout mice. We can inhibit these events and promote the survival of DSS-treated Rassf1a knockout mice with intraperitoneal injection of the c-Abl and c-Abl related protein tyrosine kinase inhibitor, imatinib/gleevec. However, p53 accumulation was not inhibited by imatinib/gleevec in the Rassf1a−/− background which revealed the importance of p53-dependent cell death during intestinal inflammation. These observations suggest that tyrosine phosphorylation of YAP (to drive p73 association and up-regulation of pro-apoptotic genes such as Bax) and accumulation of p53 are consequences of inflammation-induced injury in DSS-treated Rassf1a−/− mice. Mechanistically, we can detect robust associations of RASSF1A with membrane proximal Toll-like receptor (TLR) components to suggest that RASSF1A may function to interfere and restrict TLR

  8. Interaction of the endocrine system with inflammation: a function of energy and volume regulation.

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    Straub, Rainer H

    2014-02-13

    During acute systemic infectious disease, precisely regulated release of energy-rich substrates (glucose, free fatty acids, and amino acids) and auxiliary elements such as calcium/phosphorus from storage sites (fat tissue, muscle, liver, and bone) are highly important because these factors are needed by an energy-consuming immune system in a situation with little or no food/water intake (sickness behavior). This positively selected program for short-lived infectious diseases is similarly applied during chronic inflammatory diseases. This review presents the interaction of hormones and inflammation by focusing on energy storage/expenditure and volume regulation. Energy storage hormones are represented by insulin (glucose/lipid storage and growth-related processes), insulin-like growth factor-1 (IGF-1) (muscle and bone growth), androgens (muscle and bone growth), vitamin D (bone growth), and osteocalcin (bone growth, support of insulin, and testosterone). Energy expenditure hormones are represented by cortisol (breakdown of liver glycogen/adipose tissue triglycerides/muscle protein, and gluconeogenesis; water retention), noradrenaline/adrenaline (breakdown of liver glycogen/adipose tissue triglycerides, and gluconeogenesis; water retention), growth hormone (glucogenic, lipolytic; has also growth-related aspects; water retention), thyroid gland hormones (increase metabolic effects of adrenaline/noradrenaline), and angiotensin II (induce insulin resistance and retain water). In chronic inflammatory diseases, a preponderance of energy expenditure pathways is switched on, leading to typical hormonal changes such as insulin/IGF-1 resistance, hypoandrogenemia, hypovitaminosis D, mild hypercortisolemia, and increased activity of the sympathetic nervous system and the renin-angiotensin-aldosterone system. Though necessary during acute inflammation in the context of systemic infection or trauma, these long-standing changes contribute to increased mortality in chronic

  9. Mast cells modulate acute ozone-induced inflammation of the murine lung

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    Kleeberger, S.R.; Seiden, J.E.; Levitt, R.C.; Zhang, L.Y. (Johns Hopkins School of Public Health, Baltimore, MD (United States))

    1993-11-01

    We hypothesized that mast cells modulate lung inflammation that develops after acute ozone (O3) exposure. Two tests were done: (1) genetically mast-cell-deficient (WBB6F1-W/Wv, WCB6F1-SI/SId) and bone-marrow-transplanted W/Wv mice were exposed to O3 or filtered air, and the inflammatory responses were compared with those of mast-cell-sufficient congenic mice (WBB6F1-(+)/+, WCB6F1-(+)/+); (2) genetically O3-susceptible C57BL/6J mice were treated pharmacologically with putative mast-cell modulators or vehicle, and the O3-induced inflammatory responses were compared. Mice were exposed to 1.75 ppm O3 or air for 3 h, and lung inflammation was assessed by bronchoalveolar lavage (BAL) 6 and 24 h after exposure. Relative to O3-exposed W/Wv and SI/SId mice, the mean numbers of lavageable polymorphonuclear leukocytes (PMNs) and total BAL protein concentration (a marker of permeability) were significantly greater in the respective O3-exposed normal congenic +/+ mice (p < 0.05). Mast cells were reconstituted in W/Wv mice by transplantation of bone marrow cells from congenic +/+ mice, and O3-induced lung inflammation was assessed in the mast-cell-replete W/Wv mice. After O3 exposure, the changes in lavageable PMNs and total protein of mast-cell-replete W/Wv mice were not different from age-matched normal +/+ control mice, and they were significantly greater than those of sham-transplanted W/Wv mice (p < 0.05). Genetically susceptible C57BL/6J mice were pretreated with a mast-cell stabilizer (nedocromil sodium), secretagogue (compound 48/80), or vehicle, and the mice were exposed to O3.

  10. Geraniol alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis

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    Jiang, Kangfeng; Zhang, Tao; Yin, Nannan; Ma, Xiaofei; Zhao, Gan; Wu, Haichong; Qiu, Changwei; Deng, Ganzhen

    2017-01-01

    Geraniol (GOH), a special type of acyclic monoterpene alcohol, has been widely used to treat many diseases associated with inflammation and apoptosis. Acute lung injury (ALI) is a common clinical disease in humans characterized by pulmonary inflammation and apoptosis. In the present study, we investigated the protective effects of GOH in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.7 cells. In vivo, GOH treatment markedly ameliorated pathological injury and pulmonary cell apoptosis and reduced the wet/dry (W/D) weight ratio of lungs, myeloperoxidase (MPO) activity and the production of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). In vitro, the levels of pro-inflammatory cytokines, iNOS and COX-2 were significantly increased in LPS-stimulated RAW 264.7 cells, an effect that was decreased by GOH treatment. Moreover, GOH treatment dramatically reduced the expression of Toll-like receptor 4 (TLR4) and then prevented the nuclear factor-κB (NF-κB) activation. GOH treatment also promoted anti-apoptotic Bcl-2 expression and inhibited pro-apoptotic Bax and Caspase-3 expression. Furthermore, knockdown of TLR4 expression exerted a similar effect and inhibited the phosphorylation of p65, as well as the Bax and Caspase-3 expression. Taken together, these results suggest that GOH treatment alleviates LPS-induced ALI via inhibiting pulmonary inflammation and apoptosis, a finding that might be associated with the inhibition of TLR4-mediated NF-κB and Bcl-2/Bax signalling pathways. PMID:29050341

  11. Anti-inflammatory effects of royal jelly on ethylene glycol induced renal inflammation in rats

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    Zeyneb Aslan

    2015-10-01

    Full Text Available ABSTRACT Objective: In this study, anti-inflammatory effects of Royal Jelly were investigated by inducing renal inflammation in rats with the use of ethylene glycol. For this purpose, the calcium oxalate urolithiasis model was obtained by feeding rats with ethylene glycol in drinking water. Materials and Methods: The rats were divided in five study groups. The 1st group was determined as the control group. The rats in the 2nd group received ethylene glycol (1% in drinking water. The rats in the 3rd group were daily fed with Royal Jelly by using oral gavage. The 4th group was determined as the preventive group and the rats were fed with ethylene glycol (1% in drinking water while receiving Royal Jelly via oral gavage. The 5th group was determined as the therapeutic group and received ethylene glycol in drinking water during the first 2 weeks of the study and Royal Jelly via oral gavage during the last 2 weeks of the study. Results: At the end of the study, proinflammatory/anti-inflammatory cytokines, TNF-α, IL-1β and IL-18 levels in blood and renal tissue samples from the rats used in the application were measured. Conclusion: The results have shown that ethylene glycol does induce inflammation and renal damage. This can cause the formation of reactive oxygen species. Royal Jelly is also considered to have anti-inflammatory effects due to its possible antiradical and antioxidative effects. It can have positive effects on both the prevention of urolithiasis and possible inflammation during the existing urolithiasis and support the medical treatment.

  12. Mucosal exposure to cockroach extract induces allergic sensitization and allergic airway inflammation

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    Arizmendi Narcy G

    2011-12-01

    Full Text Available Abstract Background Allergic sensitization to aeroallergens develops in response to mucosal exposure to these allergens. Allergic sensitization may lead to the development of asthma, which is characterized by chronic airway inflammation. The objective of this study is to describe in detail a model of mucosal exposure to cockroach allergens in the absence of an exogenous adjuvant. Methods Cockroach extract (CE was administered to mice intranasally (i.n. daily for 5 days, and 5 days later mice were challenged with CE for 4 consecutive days. A second group received CE i.n. for 3 weeks. Airway hyperresponsiveness (AHR was assessed 24 h after the last allergen exposure. Allergic airway inflammation was assessed by BAL and lung histology 48 h after the last allergen exposure. Antigen-specific antibodies were assessed in serum. Lungs were excised from mice from measurement of cytokines and chemokines in whole lung lysate. Results Mucosal exposure of Balb/c mice to cockroach extract induced airway eosinophilic inflammation, AHR and cockroach-specific IgG1; however, AHR to methacholine was absent in the long term group. Lung histology showed patchy, multicentric damage with inflammatory infiltrates at the airways in both groups. Lungs from mice from the short term group showed increased IL-4, CCL11, CXCL1 and CCL2 protein levels. IL4 and CXCL1 were also increased in the BAL of cockroach-sensitized mice in the short-term protocol. Conclusions Mucosal exposure to cockroach extract in the absence of adjuvant induces allergic airway sensitization characterized by AHR, the presence of Th2 cytokines in the lung and eosinophils in the airways.

  13. Critical Role of IRAK-M in Regulating Antigen-Induced Airway Inflammation.

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    Zhang, Mingqiang; Chen, Wei; Zhou, Weixun; Bai, Yan; Gao, Jinming

    2017-11-01

    Asthma is an airway epithelium disorder involving allergic lung inflammation. IL-1 receptor-associated kinase M (IRAK-M) is a negative regulator of Toll-like receptor (TLR) signaling on airway epithelial cells and macrophages, and it is known to limit the overproduction of cytokines during the inflammatory process. However, the direct role of IRAK-M in asthma pathogenesis is unclear. In the present study, we found a significant elevation of IRAK-M expression in mouse lungs after ovalbumin (OVA) exposure. Compared with wild-type mice, IRAK-M knockout (KO) mice responded to OVA challenge with significantly worse infiltration of airway inflammatory cells, greater airway responsiveness, higher proinflammatory cytokine levels in lung homogenates, and more prominent T-helper cell type 2 (Th2) and Th17 deviation. OVA exposure also induced higher activities of dendritic cells (DCs) and macrophages from IRAK-M KO mouse lungs. Furthermore, adoptive transfer of either IRAK-M KO bone-marrow-derived DCs or macrophages into wild-type mice aggravated OVA-induced airway inflammation. In vitro experiments showed that IRAK-M KO naive CD4 + T cells were more prone to differentiate into Th17 cells, but not regulatory T cells. Consistently, activation of IκBζ was significantly increased in the absence of IRAK-M, facilitating Th17 polarization. These findings suggest that IRAK-M plays a crucial role in the regulation of allergic airway inflammation by modifying the function of airway epithelia, DCs, and macrophages, and the differentiation of naive CD4 + T cells. Modulation of IRAK-M may provide a novel target for the control of asthma.

  14. Characterization of inflammation and immune cell modulation induced by low-dose LPS administration to healthy volunteers

    NARCIS (Netherlands)

    Dillingh, Marlous R.; van Poelgeest, Eveline P.; Malone, Karen E.; Kemper, Elles M.; Stroes, Erik S. G.; Moerland, Matthijs; Burggraaf, Jacobus

    2014-01-01

    Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies,

  15. Ebi3 PreventsTrypanosoma cruzi-Induced Myocarditis by Dampening IFN-γ-Driven Inflammation.

    Science.gov (United States)

    Medina, Tiago Silva; Oliveira, Gabriela Gonçalves; Silva, Maria Cláudia; David, Bruna Araújo; Silva, Grace Kelly; Fonseca, Denise Morais; Sesti-Costa, Renata; Frade, Amanda Farage; Baron, Monique Andrade; Ianni, Barbara; Pereira, Alexandre Costa; Chevillard, Christophe; Cunha-Neto, Edécio; Marin-Neto, José Antonio; Silva, João Santana

    2017-01-01

    The identification of anti-inflammatory mediators can reveal important targetable molecules capable of counterbalancing Trypanosoma cruzi -induced myocarditis. Composed of Ebi3 and IL-27p28 subunits, IL-27 is produced by myeloid cells and is able to suppress inflammation by inducing IL-10-producing Tr1 cells, thus emerging as a potential candidate to ameliorate cardiac inflammation induced by T. cruzi . Although IL-27 has been extensively characterized as a suppressive cytokine that prevents liver immunopathogenesis after T. cruzi infection, the mechanisms underlying its effects on T. cruzi -induced myocarditis remain largely unknown. Here, wild-type (WT) and Ebi3-deficient animals were intraperitoneally infected with trypomastigotes of T. cruzi Y strain and used to evaluate the potential anti-inflammatory properties of Ebi3 during T. cruzi infection. The survival rates of mice were daily recorded, the frequency of inflammatory cells was analyzed by flow cytometry and inflammatory mediators were measured by ELISA, real-time PCR and PCR array. We reported that T. cruzi -induced myocarditis was prevented by Ebi3. Stressors mainly recognized by TLR2 and TLR4 receptors on myeloid cells were essential to trigger IL-27p28 production. In addition, Ebi3 regulated IFN-γ-mediated myocarditis by promoting an anti-inflammatory environment through IL-10, which was most likely produced by Tr1 cells rather than classical regulatory T cells (Tregs), in the heart tissue of T. cruzi -infected animals. Furthermore, in vivo IFN-γ blockade ameliorated the host survival without compromising the parasite control in the bloodstream. In humans, IL-27p28 was correlated with cardiac protection during Chagas disease. Patients with mild clinical forms of the disease produced high levels of IL-27p28, whereas lower levels were found in those with severe forms. In addition, polymorphic sites at Ebi3 gene were associated with severe cardiomyopathy in patients with Chagas disease. Collectively

  16. The Relevance of miRNA-21 in HSV-Induced Inflammation in a Mouse Model

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    Bunsoon Choi

    2015-04-01

    Full Text Available The purpose of this study was to clarify the correlation between microRNA-21 (miR-21 expression and inflammation in a herpes simplex virus (HSV-induced Behçet’s Disease (BD mouse model. miR-21 was compared between BD patients and healthy controls in peripheral blood mononuclear cells (PBMC. For miR-21 inhibition, miR-21 antagomir was applied to BD mice. The change of symptoms was monitored. The levels of cytokines and related molecules were determined by ELISA and real time qPCR. Treatment with colchicine or pentoxifylline down-regulated the level of miR-21 with improved symptoms in mice. miR-21 inhibition was accompanied by down-regulated serum levels of IL-17 and IL-6. The expression levels of PDCD4, RhoB, PD-1, IL-12p35, and toll-like receptor-4 were also regulated by miR-21 inhibition. miR-21 was correlated with HSV-induced BD-like inflammation in mice and BD patients. The expression of miR-21 was regulated by antagomir in mice.

  17. BAFF and its receptors involved in the inflammation progress in adjuvant induced arthritis rats.

    Science.gov (United States)

    Wei, Fang; Xu, Shu; Jia, Xiaoyi; Sun, Xiaojing; Yang, Xuezhi; Wei, Wei; Chang, Yan

    2016-02-01

    This study is in order to clear the roles of BAFF and its receptors in the inflammation course of autoimmune arthritis. We used a T cell-mediated experimental autoimmune model adjuvant-induced arthritis (AA) rat to study the profiles of BAFF and its receptors in spleen during the inflammation arthritis induction and the effects of BAFF on DCs functions. In vivo, the levels of BAFF and the expression of BAFF-R, TACI were increased in spleen from very early stage of AA. The lesions of spleen were definite correlated with increased levels of BAFF in homogenization. The mature of DCs and increased number in spleen were mainly at early stage of arthritis. In addition, the levels of Interleukin (IL)-12 were found highest and IL-10 were found lowest at this time too. In vitro recombinant BAFF promoted maturation of DCs and inhibited the phagocytosis of DCs. Under stimulation of BAFF on DCs, the levels of tumor necrosis factor (TNF)-α, IL-6, IL-12 were increased, IL-10 and transforming growth factor (TGF)-β1 were decreased. Moreover, BAFF-treated DCs induced proliferation of CD4(+) T cell. These findings support the crucial pathogenic role of DCs, BAFF, and its receptors in the development of experimental arthritis. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Diethylcarbamazine Reduces Chronic Inflammation and Fibrosis in Carbon Tetrachloride- (CCl4- Induced Liver Injury in Mice

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    Sura Wanessa Santos Rocha

    2014-01-01

    Full Text Available This study investigated the anti-inflammatory effects of DEC on the CCl4-induced hepatotoxicity in C57BL/6 mice. Chronic inflammation was induced by i.p. administration of CCl4 0.5 μL/g of body weight through two injections a week for 6 weeks. DEC (50 mg/kg was administered by gavage for 12 days before finishing the CCl4 induction. Histological analyses of the DEC-treated group exhibited reduced inflammatory process and prevented liver necrosis and fibrosis. Immunohistochemical and immunofluorescence analyses of the DEC-treated group showed reduced COX-2, IL1β, MDA, TGF-β, and αSMA immunopositivity, besides exhibiting decreased IL1β, COX-2, NFκB, IFNγ, and TGFβ expressions in the western blot analysis. The DEC group enhanced significantly the IL-10 expression. The reduction of hepatic injury in the DEC-treated group was confirmed by the COX-2 and iNOS mRNA expression levels. Based on the results of the present study, DEC can be used as a potential anti-inflammatory drug for chronic hepatic inflammation.

  19. Linalool attenuates lung inflammation induced by Pasteurella multocida via activating Nrf-2 signaling pathway.

    Science.gov (United States)

    Wu, Qianchao; Yu, Lijun; Qiu, Jiaming; Shen, Bingyu; Wang, Di; Soromou, Lanan Wassy; Feng, Haihua

    2014-08-01

    Pasteurellosis caused by Pasteurella multocida manifest often as respiratory infection in farmed small ruminants. Although the incidence of pasteurellosis due to P. multocida mainly takes the form of pneumonia, there is limited information on host factors that play a role in disease pathogenesis in the milieu of host-pathogen interactions. Nuclear factor-erythroid 2 related factor 2 (Nrf-2), a critical regulator for various inflammatory and immune responses by controlling oxidative stress, may play an important role in the processes of inflammation induced by P. multocida. In this study, linalool, a natural compound of the essential oils in several aromatic plant species, elevated nuclear Nrf-2 protein translocation in the A549 lung cell line and in vivo. The P. multocida-induced pro-inflammatory cytokines expression was abrogated by Nrf-2 siRNA. Postponed treatment with linalool decreased lung neutrophil accumulation and enhanced clearance of P. multocida. Furthermore, linalool significantly increased the expression of antioxidant enzymes regulated by Nrf-2 and diminished lung tissue levels of several pro-inflammatory cytokines, including tumor necrosis factor α (TNF-α) and interleukin (IL)-6. In addition, animals treated with linalool had a marked improvement in survival. These findings have uncovered that linalool acts as a novel Nrf-2 activator for a novel therapeutic strategy in pathogen-mediated lung inflammation. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Science.gov (United States)

    Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  1. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Taiki Kida

    Full Text Available Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2 remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT mice, H-PGDS-deficient mice (H-PGDS-/- represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  2. Cannabidiol (CBD) enhances lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice.

    Science.gov (United States)

    Karmaus, Peer W F; Wagner, James G; Harkema, Jack R; Kaminski, Norbert E; Kaplan, Barbara L F

    2013-01-01

    Cannabidiol (CBD) is a plant-derived cannabinoid that has been predominantly characterized as anti-inflammatory. However, it is clear that immune effects of cannabinoids can vary with cannabinoid concentration, or type or magnitude of immune stimulus. The present studies demonstrate that oral administration of CBD enhanced lipopolysaccharide (LPS)-induced pulmonary inflammation in C57BL/6 mice. The enhanced inflammatory cell infiltrate as observed in bronchoalveolar lavage fluid (BALF) was comprised mainly of neutrophils, with some monocytes. Concomitantly, CBD enhanced pro-inflammatory cytokine mRNA production, including tumor necrosis factor-α (Tnfa), interleukins (IL)-5 and -23 (Il6, Il23), and granulocyte colony stimulating factor (Gcsf). These results demonstrate that the CBD-mediated enhancement of LPS-induced pulmonary inflammation is mediated at the level of transcription of a variety of pro-inflammatory genes. The significance of these studies is that CBD is part of a therapeutic currently in use for spasticity and pain in multiple sclerosis patients, and therefore it is important to further understand mechanisms by which CBD alters immune function.

  3. Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization

    OpenAIRE

    Krakowiak, MS; Noto, JM; Piazuelo, MB; Hardbower, DM; Romero-Gallo, J; Delgado, A; Chaturvedi, R; Correa, P; Wilson, KT; Peek, RM

    2014-01-01

    Helicobacter pylori is the strongest risk factor for the development of gastric cancer. Although the specific mechanisms by which this pathogen induces carcinogenesis have not been fully elucidated, high-expression interleukin (IL)-1β alleles are associated with increased gastric cancer risk among H. pylori-infected persons. In addition, loss of matrix metalloproteinase 7 (MMP7) increases mucosal inflammation in mouse models of epithelial injury, and we have shown that gastric inflammation is...

  4. Regulation of hippocampal neurogenesis by systemic factors including stress, glucocorticoids, sleep, and inflammation

    NARCIS (Netherlands)

    Lucassen, P.J.; Oomen, C.; van Dam, A.-M.; Czéh, B.; Gage, F.H.; Kempermann, G.; Song, H.

    2008-01-01

    This review summarizes and discusses the regulation of adult neurogenesis and hippocampal cellular plasticity by systemic factors. We focus on the role of stress, glucocorticoids, and related factors such as sleep deprivation and inflammation.

  5. Zingerone suppresses liver inflammation induced by antibiotic mediated endotoxemia through down regulating hepatic mRNA expression of inflammatory markers in Pseudomonas aeruginosa peritonitis mouse model.

    Directory of Open Access Journals (Sweden)

    Lokender Kumar

    Full Text Available Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP and inflammatory cytokines (MIP-2, IL-6 and TNF-α were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2 indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti

  6. Zingerone Suppresses Liver Inflammation Induced by Antibiotic Mediated Endotoxemia through Down Regulating Hepatic mRNA Expression of Inflammatory Markers in Pseudomonas aeruginosa Peritonitis Mouse Model

    Science.gov (United States)

    Kumar, Lokender; Chhibber, Sanjay; Harjai, Kusum

    2014-01-01

    Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale) against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP) and inflammatory cytokines (MIP-2, IL-6 and TNF-α) were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2) indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti

  7. Gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte.

    Science.gov (United States)

    Zhao, Lei; Ye, Juan; Wu, Guo-Tai; Peng, Xue-Jing; Xia, Peng-Fei; Ren, Yuan

    2015-08-22

    In traditional Chinese medicine, Gentiana macrophylla Pall have been prescribed for the treatment of pain and inflammatory conditions. In addition, it is a common Tibetan medicinal herb used for the treatment of tonsillitis, urticaria, and rheumatoid arthritis (RA), while the flowers of G. macrophylla Pall have been traditionally treated as an anti-inflammatory agent to clear heat in Mongolian medicine. The secoiridoid glycosides and their derivatives are the primary active components of G. macrophylla and have been demonstrated to be effective as anti-inflammatory agents. Solvent extraction and D101 macroporous resin columns were employed to concentratethe gentiopicroside. Gentiopicroside cytotoxicity was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; the toxicity of gentiopicroside in chondrocytes was reconfirmed using Hoechst staining. Western blotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were utilized to explore the protective effects and mechanisms of gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte. The MTT assay demonstrated that 50, 500, and 1,500 μg/mL of gentiopicroside exhibited no significant toxicity to chondrocytes (P>0.05) after 24h. Using immunohistochemistry, ELISA, RT-PCR, Western blot method to explore the protective effect and mechanism of gentiopicroside on chondrocytes induced by IL-1β. The results showed some pathways of IL-1β signal transduction were inhibited by gentiopicroside in rat chondrocytes: p38, ERK and JNK. Meanwhile, gentiopicroside showed inhibition in the IL-1β-induced release of MMPs while increasing Collagen type II expression. The current study demonstrated that gentiopicroside exhibited a potent protective effect on IL-1β induced inflammation response in rat articular chondrocyte. Thus, gentiopicroside could be a potential therapeutic strategy for treatment of OA. Copyright © 2015

  8. Akkermansia Muciniphila Protects Against Atherosclerosis by Preventing Metabolic Endotoxemia-Induced Inflammation in Apoe-/- Mice.

    Science.gov (United States)

    Li, Jin; Lin, Shaoqiang; Vanhoutte, Paul M; Woo, Connie W; Xu, Aimin

    2016-06-14

    Altered composition of the gut microbiota is involved in both the onset and progression of obesity and diabetes mellitus. However, the link between gut microbiota and obesity-related cardiovascular complications has not been explored. The present study was designed to investigate the role of Akkermansia muciniphila, a mucin-degrading bacterium with beneficial effects on metabolism, in the pathogenesis of atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice. Apoe(-/-) mice on normal chow diet or a Western diet were treated with A muciniphila by daily oral gavage for 8 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time polymerase chain reaction analysis demonstrated that the fecal abundance of A muciniphila was significantly reduced by Western diet. Replenishment with A muciniphila reversed Western diet-induced exacerbation of atherosclerotic lesion formation without affecting hypercholesterolemia. A muciniphila prevented Western diet-induced inflammation in both the circulation and local atherosclerotic lesion, as evidenced by reduced macrophage infiltration and expression of proinflammatory cytokines and chemokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia. A muciniphila-mediated reduction in circulating endotoxin level could be attributed to the induction of intestinal expression of the tight junction proteins (zona occuldens protein-1 and occludin), thereby reversing Western diet-induced increases in gut permeability. Long-term infusion of endotoxin to Apoe(-/-) mice reversed the protective effect of A muciniphila against atherosclerosis. A muciniphila attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier. © 2016 American Heart Association, Inc.

  9. Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

    International Nuclear Information System (INIS)

    Chen, Jing; Mo, Yiqun; Schlueter, Connie F.; Hoyle, Gary W.

    2013-01-01

    Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury

  10. Inhibition of chlorine-induced pulmonary inflammation and edema by mometasone and budesonide

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jing; Mo, Yiqun; Schlueter, Connie F.; Hoyle, Gary W., E-mail: Gary.Hoyle@louisville.edu

    2013-10-15

    Chlorine gas is a widely used industrial compound that is highly toxic by inhalation and is considered a chemical threat agent. Inhalation of high levels of chlorine results in acute lung injury characterized by pneumonitis, pulmonary edema, and decrements in lung function. Because inflammatory processes can promote damage in the injured lung, anti-inflammatory therapy may be of potential benefit for treating chemical-induced acute lung injury. We previously developed a chlorine inhalation model in which mice develop epithelial injury, neutrophilic inflammation, pulmonary edema, and impaired pulmonary function. This model was used to evaluate nine corticosteroids for the ability to inhibit chlorine-induced neutrophilic inflammation. Two of the most potent corticosteroids in this assay, mometasone and budesonide, were investigated further. Mometasone or budesonide administered intraperitoneally 1 h after chlorine inhalation caused a dose-dependent inhibition of neutrophil influx in lung tissue sections and in the number of neutrophils in lung lavage fluid. Budesonide, but not mometasone, reduced the levels of the neutrophil attractant CXCL1 in lavage fluid 6 h after exposure. Mometasone or budesonide also significantly inhibited pulmonary edema assessed 1 day after chlorine exposure. Chlorine inhalation resulted in airway hyperreactivity to inhaled methacholine, but neither mometasone nor budesonide significantly affected this parameter. The results suggest that mometasone and budesonide may represent potential treatments for chemical-induced lung injury. - Highlights: • Chlorine causes lung injury when inhaled and is considered a chemical threat agent. • Corticosteroids may inhibit lung injury through their anti-inflammatory actions. • Corticosteroids inhibited chlorine-induced pneumonitis and pulmonary edema. • Mometasone and budesonide are potential rescue treatments for chlorine lung injury.

  11. Andrographolide Sodium Bisulfate Prevents UV-Induced Skin Photoaging through Inhibiting Oxidative Stress and Inflammation

    Directory of Open Access Journals (Sweden)

    Janis Ya-Xian Zhan

    2016-01-01

    Full Text Available Andrographolide sodium bisulfate (ASB, a water-soluble form made from andrographolide through sulfonating reaction, is an antioxidant and anti-inflammatory drug; however, the antiphotoaging effect of ASB has still not been revealed. Oxidative stress and inflammation are known to be responsible for ultraviolet (UV irradiation induced skin damage and consequently premature aging. In this study, we aimed at examining the effect of ASB on UV-induced skin photoaging of mice by physiological and histological analysis of skin and examination of skin antioxidant enzymes and immunity analyses. Results showed that topical administration of ASB suppressed the UV-induced skin thickness, elasticity, wrinkles, and water content, while ASB, especially at dose of 3.6 mg/mouse, increased the skin collagen content by about 53.17%, decreased the epidermal thickness by about 41.38%, and prevented the UV-induced disruption of collagen fibers and elastic fibers. Furthermore, ASB decreased MDA level by about 40.21% and upregulated the activities of SOD and CAT and downregulated the production of IL-1β, IL-6, IL-10, and TNF-α in UV-irradiated mice. Our study confirmed the protective effect of ASB against UV-induced photoaging and initially indicated that this effect can be attributed to its antioxidant and anti-inflammatory activities in vivo, suggesting that ASB may be a potential antiphotoaging agent.

  12. Andrographolide Sodium Bisulfate Prevents UV-Induced Skin Photoaging through Inhibiting Oxidative Stress and Inflammation

    Science.gov (United States)

    Zhan, Janis Ya-Xian; Wang, Xiu-Fen; Liu, Yu-Hong; Zhang, Zhen-Biao; Wang, Lan; Chen, Jian-Nan; Huang, Song; Zeng, Hui-Fang; Lai, Xiao-Ping

    2016-01-01

    Andrographolide sodium bisulfate (ASB), a water-soluble form made from andrographolide through sulfonating reaction, is an antioxidant and anti-inflammatory drug; however, the antiphotoaging effect of ASB has still not been revealed. Oxidative stress and inflammation are known to be responsible for ultraviolet (UV) irradiation induced skin damage and consequently premature aging. In this study, we aimed at examining the effect of ASB on UV-induced skin photoaging of mice by physiological and histological analysis of skin and examination of skin antioxidant enzymes and immunity analyses. Results showed that topical administration of ASB suppressed the UV-induced skin thickness, elasticity, wrinkles, and water content, while ASB, especially at dose of 3.6 mg/mouse, increased the skin collagen content by about 53.17%, decreased the epidermal thickness by about 41.38%, and prevented the UV-induced disruption of collagen fibers and elastic fibers. Furthermore, ASB decreased MDA level by about 40.21% and upregulated the activities of SOD and CAT and downregulated the production of IL-1β, IL-6, IL-10, and TNF-α in UV-irradiated mice. Our study confirmed the protective effect of ASB against UV-induced photoaging and initially indicated that this effect can be attributed to its antioxidant and anti-inflammatory activities in vivo, suggesting that ASB may be a potential antiphotoaging agent. PMID:26903706

  13. Biochanin A inhibits lipopolysaccharide-induced inflammation in human umbilical vein endothelial cells.

    Science.gov (United States)

    Ming, Xiaodong; Ding, Mingfeng; Zhai, Bo; Xiao, Lei; Piao, Taikui; Liu, Ming

    2015-09-01

    Biochanin A, an isoflavone isolated from red clover, cabbage or alfalfa, has been reported to have anti-inflammatory activity. However, the effects of biochanin A on vascular inflammation have not been investigated. In this study, we investigate the anti-inflammatory effects of biochanin A on lipopolysaccharide (LPS)-induced inflammatory response in human umbilical vein endothelial cells (HUVEC cells). The HUVEC cells were treated with biochanin A for 12h before exposure to LPS. The expression of ECAMs, including VCAM-1, ICAM-1, E-selectin, NF-κB and PPAR-γ was detected by Western blotting. The expression of cytokines TNF-α and IL-8 was detected by ELISA. The results showed that biochanin A inhibited LPS-induced TNF-α and IL-8 production. Meanwhile, biochanin A also suppressed VCAM-1, ICAM-1, and E-selectin expression induced by LPS. We also found that biochanin A inhibited NF-κB activation induced by LPS. Furthermore, biochanin A could activate PPAR-γ and the anti-inflammatory effects of biochanin A can be reversed by GW9662, a specific antagonist for PPAR-γ. In conclusion, the anti-inflammatory effect of biochanin A is associated with activating PPAR-γ, thereby attenuating NF-κB activation and LPS-induced inflammatory response. These findings suggest that biochanin A may be a therapeutic agent for inflammatory cardiovascular disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Inhibitory effect of cucurbitacin B on imiquimod-induced skin inflammation

    International Nuclear Information System (INIS)

    Li, Zheng Jun; Shin, Jung-Min; Choi, Dae-Kyoung; Lim, Seul Ki; Yoon, Tae-Jin; Lee, Young Ho; Sohn, Kyung-Cheol; Im, Myung; Lee, Young; Seo, Young-Joon; Kim, Chang Deok; Lee, Jeung-Hoon

    2015-01-01

    Psoriasis is a common skin disease, of which pathogenesis involves the increase of inflammatory reaction in epidermal cells. In an attempt to find therapeutics for psoriasis, we found that cucurbitacin B has an inhibitory potential on imiquimod-induced inflammation of keratinocytes. Cucurbitacin B significantly inhibited imiquimod-induced expression of crucial psoriatic cytokines, such as IL-8 and CCL20, via down-regulation of NF-κB and STAT3 signaling pathway in human keratinocytes. In addition, keratinocyte proliferation was markedly inhibited by cucurbitacin B. The potential beneficial effect of cucurbitacin B on psoriasis was further validated in imiquimod-induced psoriasiform dermatitis of experimental animal. Topical application of cucurbitacin B resulted in significant reduction of epidermal hyperplasia and inflammatory cytokines production, and ameliorated the psoriatic symptom. Taken together, these results suggest that cucurbitacin B may be a potential candidate for the treatment of psoriasis. - Highlights: • Cucurbitacin B has a potential for inhibiting the growth of keratinocytes. • Cucurbitacin B inhibits imiquimod-induced inflammatory reaction in keratinocytes. • Cucurbitacin B inhibits imiquimod-induced psoriasiform dermatitis in experimental animal

  15. Inhibitory effect of cucurbitacin B on imiquimod-induced skin inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zheng Jun; Shin, Jung-Min; Choi, Dae-Kyoung; Lim, Seul Ki [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Yoon, Tae-Jin [Department of Dermatology, School of Medicine, Gyeongsang National University, Jinju (Korea, Republic of); Lee, Young Ho [Department of Anatomy, School of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Sohn, Kyung-Cheol; Im, Myung; Lee, Young; Seo, Young-Joon; Kim, Chang Deok [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Lee, Jeung-Hoon, E-mail: jhoon@cnu.ac.kr [Department of Dermatology, School of Medicine, Chungnam National University, Daejeon (Korea, Republic of); Skin Med Company, Daejeon (Korea, Republic of)

    2015-04-17

    Psoriasis is a common skin disease, of which pathogenesis involves the increase of inflammatory reaction in epidermal cells. In an attempt to find therapeutics for psoriasis, we found that cucurbitacin B has an inhibitory potential on imiquimod-induced inflammation of keratinocytes. Cucurbitacin B significantly inhibited imiquimod-induced expression of crucial psoriatic cytokines, such as IL-8 and CCL20, via down-regulation of NF-κB and STAT3 signaling pathway in human keratinocytes. In addition, keratinocyte proliferation was markedly inhibited by cucurbitacin B. The potential beneficial effect of cucurbitacin B on psoriasis was further validated in imiquimod-induced psoriasiform dermatitis of experimental animal. Topical application of cucurbitacin B resulted in significant reduction of epidermal hyperplasia and inflammatory cytokines production, and ameliorated the psoriatic symptom. Taken together, these results suggest that cucurbitacin B may be a potential candidate for the treatment of psoriasis. - Highlights: • Cucurbitacin B has a potential for inhibiting the growth of keratinocytes. • Cucurbitacin B inhibits imiquimod-induced inflammatory reaction in keratinocytes. • Cucurbitacin B inhibits imiquimod-induced psoriasiform dermatitis in experimental animal.

  16. Circulating histones are major mediators of systemic inflammation and cellular injury in patients with acute liver failure.

    Science.gov (United States)

    Wen, Zongmei; Lei, Zhen; Yao, Lu; Jiang, Ping; Gu, Tao; Ren, Feng; Liu, Yan; Gou, Chunyan; Li, Xiuhui; Wen, Tao

    2016-09-29

    Acute liver failure (ALF) is a life-threatening systemic disorder. Here we investigated the impact of circulating histones, recently identified inflammatory mediators, on systemic inflammation and liver injury in murine models and patients with ALF. We analyzed histone levels in blood samples from 62 patients with ALF, 60 patients with chronic liver disease, and 30 healthy volunteers. We incubated patients' sera with human L02 hepatocytes and monocytic U937 cells to assess cellular damage and cytokine production. d-galactosamine plus lipopolysaccharide (GalN/LPS), concanavalin A (ConA), and acetaminophen (APAP) were given to C57BL/6N mice to induce liver injury, respectively, and the pathogenic role of circulating histones was studied. Besides, the protective effect of nonanticoagulant heparin, which can bind histones, was evaluated with in vivo and ex vivo investigations. We observed that circulating histones were significantly increased in patients with ALF, and correlated with disease severity and mortality. Significant systemic inflammation was also pronounced in ALF patients, which were associated with histone levels. ALF patients' sera induced significant L02 cell death and stimulated U937 cells to produce cytokines, which were abrogated by nonanticoagulant heparin. Furthermore, circulating histones were all released remarkably in GalN/LPS, ConA, and APAP-treated mice, and associated with high levels of inflammatory cytokines. Heparin reduced systemic inflammation and liver damage in mice, suggesting that it could interfere with histone-associated liver injury. Collectively, these findings demonstrate that circulating histones are critical mediators of systemic inflammation and cellular damage in ALF, which may be potentially translatable for clinical use.

  17. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Duraisamy Kempuraj

    Full Text Available Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown.In duct ligation-induced acute pancreatitis in mice and rats, we found that (a IL-33 concentration was increased in the pancreas; (b mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c plasma histamine and pancreatic substance P concentrations were increased; and (d pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α. Also, IL-33 activated ERK in human pancreatic tissue.As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation

  18. The novel cytokine interleukin-33 activates acinar cell proinflammatory pathways and induces acute pancreatic inflammation in mice.

    Science.gov (United States)

    Kempuraj, Duraisamy; Twait, Erik C; Williard, Deborah E; Yuan, Zuobiao; Meyerholz, David K; Samuel, Isaac

    2013-01-01

    Acute pancreatitis is potentially fatal but treatment options are limited as disease pathogenesis is poorly understood. IL-33, a novel IL-1 cytokine family member, plays a role in various inflammatory conditions but its role in acute pancreatitis is not well understood. Specifically, whether pancreatic acinar cells produce IL-33 when stressed or respond to IL-33 stimulation, and whether IL-33 exacerbates acute pancreatic inflammation is unknown. In duct ligation-induced acute pancreatitis in mice and rats, we found that (a) IL-33 concentration was increased in the pancreas; (b) mast cells, which secrete and also respond to IL-33, showed degranulation in the pancreas and lung; (c) plasma histamine and pancreatic substance P concentrations were increased; and (d) pancreatic and pulmonary proinflammatory cytokine concentrations were increased. In isolated mouse pancreatic acinar cells, TNF-α stimulation increased IL-33 release while IL-33 stimulation increased proinflammatory cytokine release, both involving the ERK MAP kinase pathway; the flavonoid luteolin inhibited IL-33-stimulated IL-6 and CCL2/MCP-1 release. In mice without duct ligation, exogenous IL-33 administration induced pancreatic inflammation without mast cell degranulation or jejunal inflammation; pancreatic changes included multifocal edema and perivascular infiltration by neutrophils and some macrophages. ERK MAP kinase (but not p38 or JNK) and NF-kB subunit p65 were activated in the pancreas of mice receiving exogenous IL-33, and acinar cells isolated from the pancreas of these mice showed increased spontaneous cytokine release (IL-6, CXCL2/MIP-2α). Also, IL-33 activated ERK in human pancreatic tissue. As exogenous IL-33 does not induce jejunal inflammation in the same mice in which it induces pancreatic inflammation, we have discovered a potential role for an IL-33/acinar cell axis in the recruitment of neutrophils and macrophages and the exacerbation of acute pancreatic inflammation. IL-33 is

  19. Magnetic ferroferric oxide nanoparticles induce vascular endothelial cell dysfunction and inflammation by disturbing autophagy

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Lu, E-mail: chaperones@163.com [College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001 (China); Wang, XueQin; Miao, YiMing; Chen, ZhiQiang; Qiang, PengFei; Cui, LiuQing; Jing, Hongjuan [College of Bioengineering, Henan University of Technology, Lianhua Street, Zhengzhou 450001 (China); Guo, YuQi [Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052 (China)

    2016-03-05

    Highlights: • B-Fe{sub 3}O{sub 4}NPs did not induce cell apoptosis or necrosis in HUVECs within 24 h. • B-Fe{sub 3}O{sub 4}NPs induced HUVEC dysfunction and inflammation. • B-Fe{sub 3}O{sub 4}NPs induced enhanced autophagic activity and blockade of autophagy flux. • Suppression of autophagy dysfunction attenuated B-Fe{sub 3}O{sub 4}NP-induced HUVEC dysfunction. - Abstract: Despite the considerable use of magnetic ferroferric oxide nanoparticles (Fe{sub 3}O{sub 4}NPs) worldwide, their safety is still an important topic of debate. In the present study, we detected the toxicity and biological behavior of bare-Fe{sub 3}O{sub 4}NPs (B-Fe{sub 3}O{sub 4}NPs) on human umbilical vascular endothelial cells (HUVECs). Our results showed that B-Fe{sub 3}O{sub 4}NPs did not induce cell death within 24 h even at concentrations up to 400 μg/ml. The level of nitric oxide (NO) and the activity of endothelial NO synthase (eNOS) were decreased after exposure to B-Fe{sub 3}O{sub 4}NPs, whereas the levels of proinflammatory cytokines were elevated. Importantly, B-Fe{sub 3}O{sub 4}NPs increased the accumulation of autophagosomes and LC3-II in HUVECs through both autophagy induction and the blockade of autophagy flux. The levels of Beclin 1 and VPS34, but not phosphorylated mTOR, were increased in the B-Fe{sub 3}O{sub 4}NP-treated HUVECs. Suppression of autophagy induction or stimulation of autophagy flux, at least partially, attenuated the B-Fe{sub 3}O{sub 4}NP-induced HUVEC dysfunction. Additionally, enhanced autophagic activity might be linked to the B-Fe{sub 3}O{sub 4}NP-induced production of proinflammatory cytokines. Taken together, these results demonstrated that B-Fe{sub 3}O{sub 4}NPs disturb the process of autophagy in HUVECs, and eventually lead to endothelial dysfunction and inflammation.

  20. Transient inflammation-induced ongoing pain is driven by TRPV1 sensitive afferents

    Directory of Open Access Journals (Sweden)

    Mercado Ramon

    2011-01-01

    Full Text Available Abstract Background Tissue injury elicits both hypersensitivity to evoked stimuli and ongoing, stimulus-independent pain. We previously demonstrated that pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of inflammation-induced ongoing pain. Results Intraplantar Complete Freund's Adjuvant (CFA produced thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal clonidine produced robust conditioned place preference (CPP in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal clonidine blocked CFA-induced thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked pain. Peripheral nerve block by lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the lidocaine paired chamber, indicating that injury-induced ongoing pain is driven by afferent fibers innervating the site of injury. Pretreatment with resiniferatoxin (RTX, an ultrapotent capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal hypersensitivity and abolished the CPP elicited by administration of popliteal fossa lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective TRPV1 receptor antagonist, AMG9810, at a dose that reversed CFA-induced thermal hyperalgesia failed to reduce CFA-induced ongoing pain or guarding behavior. Conclusions These data demonstrate that inflammation induces both ongoing pain and evoked hypersensitivity that can be differentiated on the basis of time course. Ongoing pain (a is transient, (b driven by peripheral input resulting from the injury, (c dependent on TRPV1 positive

  1. High-fat diet feeding differentially affects the development of inflammation in the central nervous system.

    Science.gov (United States)

    Guillemot-Legris, Owein; Masquelier, Julien; Everard, Amandine; Cani, Patrice D; Alhouayek, Mireille; Muccioli, Giulio G

    2016-08-26

    Obesity and its associated disorders are becoming a major health issue in many countries. The resulting low-grade inflammation not only affects the periphery but also the central nervous system. We set out to study, in a time-dependent manner, the effects of a high-fat diet on different regions of the central nervous system with regard to the inflammatory tone. We used a diet-induced obesity model and compared at several time-points (1, 2, 4, 6, 8, and 16 weeks) a group of mice fed a high-fat diet with its respective control group fed a standard diet. We also performed a large-scale analysis of lipids in the central nervous system using HPLC-MS, and we then tested the lipids of interest on a primary co-culture of astrocytes and microglial cells. We measured an increase in the inflammatory tone in the cerebellum at the different time-points. However, at week 16, we evidenced that the inflammatory tone displayed significant differences in two different regions of the central nervous system, specifically an increase in the cerebellum and no modification in the cortex for high-fat diet mice when compared with chow-fed mice. Our results clearly suggest region-dependent as well as time-dependent adaptations of the central nervous system to the high-fat diet. The differences in inflammatory tone between the two regions considered seem to involve astrocytes but not microglial cells. Furthermore, a large-scale lipid screening coupled to ex vivo testing enabled us to identify three classes of lipids-phosphatidylinositols, phosphatidylethanolamines, and lysophosphatidylcholines-as well as palmitoylethanolamide, as potentially responsible for the difference in inflammatory tone. This study demonstrates that the inflammatory tone induced by a high-fat diet does not similarly affect distinct regions of the central nervous system. Moreover, the lipids identified and tested ex vivo showed interesting anti-inflammatory properties and could be further studied to better characterize

  2. Neonatal bladder inflammation induces long-term visceral pain and altered responses of spinal neurons in adult rats.

    Science.gov (United States)

    Kannampalli, Pradeep; Babygirija, Reji; Zhang, Jiang; Poe, Michael M; Li, Guanguan; Cook, James M; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N

    2017-03-27

    Painful events early in life have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. However, the intrinsic mechanism is not well studied. We previously reported that neonatal bladder inflammation causes chronic visceral hypersensitivity along with molecular disruption of spinal GABAergic system in rats. The present study investigates whether these molecular changes affect the integrative function and responses of bladder-sensitive primary afferent and spinal neurons. Neonatal bladder inflammation was induced by intravesicular injection of zymosan during postnatal (P) days 14-16. In adulthood (P60), the viscero-motor response (VMR) to visceral stimuli was significantly inhibited by intrathecal (i.t) HZ166 (GABA Aα-2 agonist) only in neonatally saline-treated, but not in neonatally zymosan-treated rats. HZ166 significantly inhibited the responses of bladder-responsive lumbosacral (LS) spinal neurons to urinary bladder distension (UBD) and slow infusion (SI) in neonatally saline-treated rats. Similar results were also observed in naïve adult rats where HZ166 produced significant inhibition of bladder-responsive spinal neurons. However, HZ166 did not inhibit responses of UBD-responsive spinal neurons from neonatally zymosan-treated rats. The drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD and SI in either group of rats tested. Immunohistochemical studies showed a significantly lower level of GABA Aα-2 receptor expression in the LS spinal cord of neonatally zymosan-treated rats compared to saline-treated rats. These findings indicate that neonatal bladder inflammation leads to functional and molecular alteration of spinal GABA Aα-2 receptor subtypes, which may result in chronic visceral hyperalgesia in adulthood. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Secretoglobin Superfamily Protein SCGB3A2 Alleviates House Dust Mite-Induced Allergic Airway Inflammation in Mice.

    Science.gov (United States)

    Yoneda, Mitsuhiro; Xu, Lei; Kajiyama, Hiroaki; Kawabe, Shuko; Paiz, Jorge; Ward, Jerrold M; Kimura, Shioko

    2016-01-01

    Secretoglobin (SCGB) 3A2, a novel, lung-enriched, cytokine-like, secreted protein of small molecular weight, was demonstrated to exhibit various biological functions including anti-inflammatory, antifibrotic and growth-factor activities. Anti-inflammatory activity was uncovered using the ovalbumin-induced allergic airway inflammation model. However, further validation of this activity using knockout mice in a different allergic inflammation model is necessary in order to establish the antiallergic inflammatory role for this protein. Scgb3a2-null (Scgb3a2-/-) mice were subjected to nasal inhalation of Dermatophagoides pteronyssinus extract for 5 days/week for 5 consecutive weeks; control mice received nasal inhalation of saline as a comparator. Airway inflammation was assessed by histological analysis, the number of inflammatory cells and various Th2-type cytokine levels in the lungs and bronchoalveolar lavage fluids by qRT-PCR and ELISA, respectively. Exacerbated inflammation was found in the airway of Scgb3a2-/- mice subjected to house dust mite (HDM)-induced allergic airway inflammation compared with saline-treated control groups. All the inflammation end points were increased in the Scgb3a2-/- mice. The Ccr4 and Ccl17 mRNA levels were higher in HDM-treated lungs of Scgb3a2-/- mice than wild-type mice or saline-treated Scgb3a2-/- mice, whereas no changes were observed for Ccr3 and Ccl11 mRNA levels. These results demonstrate that SCGB3A2 has an anti-inflammatory activity in the HDM-induced allergic airway inflammation model, in which SCGB3A2 may modulate the CCR4-CCL17 pathway. SCGB3A2 may provide a useful tool to treat allergic airway inflammation, and further studies on the levels and function of SCGB3A2 in asthmatic patients are warranted. © 2016 S. Karger AG, Basel.

  4. Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.

    Science.gov (United States)

    Hamid, U; Krasnodembskaya, A; Fitzgerald, M; Shyamsundar, M; Kissenpfennig, A; Scott, C; Lefrancais, E; Looney, M R; Verghis, R; Scott, J; Simpson, A J; McNamee, J; McAuley, D F; O'Kane, C M

    2017-11-01

    Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS. To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS. Healthy volunteers were randomised to receive placebo or aspirin 75  or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes. In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage. These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the

  5. Etanercept ameliorates inflammation and pain in a novel mono-arthritic multi-flare model of streptococcal cell wall induced arthritis.

    Science.gov (United States)

    Chakravarthy, Kalyan; Faltus, Robert; Robinson, Gain; Sevilla, Raquel; Shin, John; Zielstorff, Mark; Byford, Alan; Leccese, Erica; Caniga, Michael J; Hseih, SuChun; Zhang, Shuli; Chiu, Chi-Sung; Zhang-Hoover, Jie; Moy, Lily Y; McLeod, Robbie L; Stoffregen, Dana; Zhang, Weisheng; Murtaza, Anwar; Cicmil, Milenko

    2014-12-04

    The impact of anti-TNF, corticosteroid and analgesic therapy on inflammation and pain was evaluated in a novel mono-arthritic multi-flare rat Streptococcal Cell Wall (SCW) model using Etanercept, Dexamethasone and Buprenorphine. Multiple flares of arthritis were induced with an intra-articular injection of SCW in the hind ankle on day 1, followed by intravenous challenges on days 21 and 42. Inflammation and pain were monitored in the hind paws. Cytokine profiling, cell phenotyping, bioluminescence imaging and histopathological evaluation were also performed. Local injection of SCW caused a rapid onset of inflammation and pain in the injected ankle which resolved within 4 days (Flare 1). Intravenous injection 20 days after sensitization resulted in an increase in ankle diameter and pain, which partially resolved in 8 days (Flare 2). The subsequent intra-venous injection in the same animals 14 days after resulted in a more chronic disease with inflammation and pain persisting over a period of 10 days (Flare 3). In Flare 2, therapeutic administration of Dexamethasone inhibited paw swelling (95%; Ppain (55%; Ppain (80%; Ppain by ≥30%. Expression of IL-1β, IL-6, MCP-1 and CINC was reduced by >50% (Ppain by 25%. Prior treatment with Etanercept in Flare 2 followed by re-administration in Flare 3 led to a complete loss in the efficacy of Etanercept. Systemic exposure of Etanercept corroborated with lack of efficacy. Dexamethasone inhibited inflammation and pain in both Flares 2 and 3 (Pinflammation and pain simultaneously in this model. Etanercept and Dexamethasone inhibited inflammation, pain and proinflammatory cytokines in this model. Taken together, this model facilitates the assessment of anti-rheumatic agents targeting inflammation and pain in the multiple flare paradigm and offers a powerful tool for drug discovery.

  6. Lactate dehydrogenase inhibitors can reverse inflammation induced changes in colon cancer cells.

    Science.gov (United States)

    Manerba, Marcella; Di Ianni, Lorenza; Govoni, Marzia; Roberti, Marinella; Recanatini, Maurizio; Di Stefano, Giuseppina

    2017-01-01

    The inflammatory microenvironment is an essential component of neoplastic lesions and can significantly impact on tumor progression. Besides facilitating invasive growth, inflammatory cytokines were also found to reprogram cancer cell metabolism and to induce aerobic glycolysis. Previous studies did not consider the possible contribution played in these changes by lactate dehydrogenase (LDH). The A isoform of LDH (LDH-A) is the master regulator of aerobic glycolysis; it actively reduces pyruvate and causes enhanced lactate levels in tumor tissues. In cancer cells, lactate was recently found to directly increase migration ability; moreover, when released in the microenvironment, it can facilitate matrix remodeling. In this paper, we illustrate that treatment of human colon adenocarcinoma cells with TNF-α and IL-17, two pro-inflammatory cytokines, modifies LDH activity, causing a shift toward the A isoform which results in increased lactate production. At the same time, the two cytokines appeared to induce features of epithelial-mesenchymal transition in the treated cells, such as reduction of E-cadherin levels and increased secretion of metalloproteinases. Noteworthy, oxamate and galloflavin, two inhibitors of LDH activity which reduce lactate production in cells, were found to relieve the inflammation-induced effects. These results suggest LDH-A and/or lactate as common elements at the cross-road between cancer cell metabolism, tumor progression and inflammation. At present, LDH inhibitors suitable for clinical use are actively searched as possible anti-proliferative agents; our data lead to hypothesize for these compounds a wider potential in anticancer treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Effects of olanzapine on LPS-induced inflammation in rat primary glia cells.

    Science.gov (United States)

    Faour-Nmarne, Caroline; Azab, Abed N

    2016-01-01

    Olanzapine (OLZ) is an atypical antipsychotic drug that also has mood-stabilizing effects. The mechanism of action of OLZ is not fully understood. Accumulating data suggest that inflammation plays a role in the pathophysiology of mental disorders and that psychotropic drugs exhibit some anti-inflammatory properties. This study was undertaken to examine the effects of OLZ on LPS-induced inflammation in rat primary glia cells. Glia cells were extracted from newborn rat brains. OLZ (1 or 50 µM) was added to culture medium at 6 or 72 h before addition of LPS for another 18 h, and levels of IL-10, prostaglandin (PG) E2, NO and TNF-α, and expression of cyclo-oxygensase (COX)-2 and inducible NO synthase (iNOS) were determined. Treatment with 50 µM OLZ (but not 1 µM) significantly decreased LPS-induced secretion of IL-10, PGE2 and TNF-α. In contrast, 50 µM OLZ significantly increased NO levels. OLZ did not alter the expression of COX-2 or iNOS in LPS-treated cells. These results suggest that OLZ differently affects the secretion of inflammatory mediators. Most of the significant effects of OLZ were obtained when 50 µM was used, which is a high and probably therapeutically irrelevant concentration. Therefore, under the conditions used in the present study OLZ seemed to lack a potent anti-inflammatory effect. © The Author(s) 2015.

  8. T-Helper Type 2 Cells Direct Antigen-Induced Eosinophilic Skin Inflammation in Mice.

    Science.gov (United States)

    Kaminuma, Osamu; Nishimura, Tomoe; Kitamura, Noriko; Saeki, Mayumi; Hiroi, Takachika; Mori, Akio

    2018-01-01

    Eosinophilic inflammation in combination with immunoglobulin E (IgE) production is a characteristic feature of atopic dermatitis. Although activated T-helper type (Th) 2 cells play critical roles in the local accumulation and activation of eosinophils, whether they induce eosinophilic skin inflammation, independent of the IgE-mediated pathway has been unclear. To address the functional role of T cells in allergic skin diseases, we herein transferred Th1/Th2-differentiated or naive DO11.10 T cells into unprimed BALB/c mice. Ovalbumin-specific Th2 cells, as well as eosinophils, accumulated in the skin upon antigen challenge, despite the absence of antigen-specific IgE. Neither antigen-specific Th1 nor naive T cells induced eosinophil accumulation, although Th1 cells by themselves migrated into the skin. Interleukin (IL)-4, IL-5, and eotaxin were specifically produced in the skin of antigen-challenged, Th2 cell-transferred mice, whereas interferon (IFN)-γ and regulated on activation, normal T cell expressed and secreted (RANTES) were preferentially produced in Th1 cells-transferred mice. Production of monocyte chemoattractant protein (MCP)-1 and MCP-3 was enhanced by both Th1 and Th2 cells. The accumulation of eosinophils and Th2 cells in the skin was suppressed by both dexamethasone and FK506, indicating an essential role of Th2 cells in eosinophil recruitment. We conclude that Th2 cells can induce eosinophilic infiltration into the skin in the absence of antigen-specific IgE. Copyright © 2018 The Korean Academy of Asthma, Allergy and Clinical Immunology · The Korean Academy of Pediatric Allergy and Respiratory Disease.

  9. KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium.

    Science.gov (United States)

    Lappas, Martha

    2015-05-01

    The transcription factor Kruppel-like factor 5 (KLF5) has been shown to associate with nuclear factor kappa B (NFκB) to regulate genes involved in inflammation. However, there are no studies on the expression and regulation of KLF5 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour on KLF5 expression in both foetal membranes and myometrium; ii) the pro-inflammatory cytokine interleukin 1 beta (IL1β), bacterial product flagellin and the viral dsRNA analogue poly(I:C) on KLF5 expression and iii) KLF5 knockdown by siRNA in human myometrial primary cells on pro-inflammatory and pro-labour mediators. In foetal membranes, there was no effect of term or preterm labour on KLF5 expression. In myometrium, the term labour was associated with an increase in nuclear KLF5 protein expression. Moreover, KLF5 expression was also increased in myometrial cells treated with IL1β, flagellin or poly(IC), likely factors contributing to preterm birth. KLF5 silencing in myometrial cells significantly decreased IL1β-induced cytokine expression (IL6 and IL8 mRNA expression and release), COX2 mRNA expression, and subsequent release of prostaglandins PGE2 and PGF2 α. KLF5 silencing also significantly reduced flagellin- and poly(I:C)-induced IL6 and IL8 mRNA expression. Lastly, IL1β-, flagellin- and poly(I:C)-stimulated NFκB transcriptional activity was significantly suppressed in KLF5-knockout myometrial cells. In conclusion, this study describes novel data in which KLF5 is increased in labouring myometrium, and KLF5 silencing decreased inflammation- and infection-induced pro-labour mediators. © 2015 Society for Reproduction and Fertility.

  10. Activation of Epac alleviates inflammation and vascular leakage in LPS-induced acute murine lung injury.

    Science.gov (United States)

    Wang, Xuefeng; Song, Shunde; Hu, Zhengqiang; Zhang, Zhewen; Li, Yajun; Yan, Chunguang; Li, Zigang; Tang, Huifang

    2017-12-01

    Exchange protein directly activated by cAMP (Epac) is an important molecule in cAMP signal transduction, but the effect of Epac on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is unclear. In this study, we treated in vitro and in vivo models with the Epac activator 8CPT to determine the effect and related mechanisms of Epac. The in vitro results indicate that 8CPT inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) release from mouse macrophages (MH-S), whereas the protein kinase A (PKA) activator 6BnZ has no effect. Furthermore, Epac over-expression can significantly suppress TNF-α release from LPS induced MH-S cell, while Epac siRNA can slightly increase TNF-α release. Moreover, 8CPT reduces LPS-induced microvascular permeability in human pulmonary microvascular endothelial cells (HPMVECs), whereas the PKA activator 6BnZ has no effect. In mice with LPS-induced ALI, 8CPT significantly reduces LPS-induced inflammatory cytokine release, neutrophil recruitment, and albumin leakage. LPS simultaneously decreases the Epac but not the PKA levels. However, 8CPT reverses the decreased Epac levels. Furthermore, the mechanism involves the small GTPase Rac1/2 but not the mitogen-activated protein kinase (MAPK) pathway. Thus, Epac activation reduces inflammation and microvascular permeability in LPS-induced lung injury and an Epac activator represents a novel choice for the early therapy of ALI. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  11. Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation.

    Science.gov (United States)

    Li, Qingjie; Winston, John H; Sarna, Sushil K

    2016-02-01

    Gastric hypersensitivity is one of the key contributors to the postprandial symptoms of epigastric pain/discomfort, satiety, and fullness in functional dyspepsia patients. Epidemiological studies found that adverse early-life experiences are risk factors for the development of gastric hypersensitivity. Preclinical studies found that neonatal colon inflammation elevates plasma norepinephrine (NE), which upregulates expression of nerve growth factor (NGF) in the muscularis externa of the gastric fundus. Our goal was to investigate the cellular mechanisms by which NE upregulates the expression of NGF in gastric hypersensitive (GHS) rats, which were subjected previously to neonatal colon inflammation. Neonatal colon inflammation upregulated NGF protein, but not mRNA, in the gastric fundus of GHS rats. Western blotting showed upregulation of p110γ of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phosphoinositide-dependent kinase-1 (PDK1), pAKT(Ser473), and phosphorylated 4E-binding protein (p4E-BP1)(Thr70), suggesting AKT activation and enhanced NGF protein translation. AKT inhibitor MK-2206 blocked the upregulation of NGF in the fundus of GHS rats. Matrix metalloproteinase 9 (MMP-9), the major NGF-degrading protease, was suppressed, indicating that NGF degradation was impeded. Incubation of fundus muscularis externa with NE upregulated NGF by modulating the protein translation and degradation pathways. Yohimbine, an α2-adrenergic receptor antagonist, upregulated plasma NE and NGF expression by activating the protein translation and degradation pathways in naive rats. In contrast, a cocktail of adrenergic receptor antagonists suppressed the upregulation of NGF by blocking the activation of the protein translation and degradation pathways. Our findings provide evidence that the elevation of plasma NE induces NGF expression in the gastric fundus. Copyright © 2016 the American Physiological Society.

  12. ADAR1 deletion induces NFκB and interferon signaling dependent liver inflammation and fibrosis.

    Science.gov (United States)

    Ben-Shoshan, Shirley Oren; Kagan, Polina; Sultan, Maya; Barabash, Zohar; Dor, Chen; Jacob-Hirsch, Jasmine; Harmelin, Alon; Pappo, Orit; Marcu-Malina, Victoria; Ben-Ari, Ziv; Amariglio, Ninette; Rechavi, Gideon; Goldstein, Itamar; Safran, Michal

    2017-05-04

    Adenosine deaminase acting on RNA (ADAR) 1 binds and edits double-stranded (ds) RNA secondary structures found mainly within untranslated regions of many transcripts. In the current research, our aim was to study the role of ADAR1 in liver homeostasis. As previous studies show a conserved immunoregulatory function for ADAR1 in mammalians, we focused on its role in preventing chronic hepatic inflammation and the associated activation of hepatic stellate cells to produce extracellular matrix and promote fibrosis. We show that hepatocytes specific ADAR1 knock out (KO) mice display massive liver damage with multifocal inflammation and fibrogenesis. The bioinformatics analysis of the microarray gene-expression datasets of ADAR1 KO livers reveled a type-I interferons signature and an enrichment for immune response genes compared to control littermate livers. Furthermore, we found that in vitro silencing of ADAR1 expression in HepG2 cells leads to enhanced transcription of NFκB target genes, foremost of the pro-inflammatory cytokines IL6 and IL8. We also discovered immune cell-independent paracrine signaling among ADAR1-depleted HepG2 cells and hepatic stellate cells, leading to the activation of the latter cell type to adopt a profibrogenic phenotype. This paracrine communication dependent mainly on the production and secretion of the cytokine IL6 induced by ADAR1 silencing in hepatocytes. Thus, our findings shed a new light on the vital regulatory role of ADAR1 in hepatic immune homeostasis, chiefly its inhibitory function on the crosstalk between the NFκB and type-I interferons signaling cascades, restraining the development of liver inflammation and fibrosis.

  13. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

    Directory of Open Access Journals (Sweden)

    Izziki Mohamed

    2009-01-01

    Full Text Available Abstract Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH. Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6. Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/- and wild-type (IL-6+/+ mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.

  14. Effects of hydrogen sulfide on inflammation in caerulein-induced acute pancreatitis

    Directory of Open Access Journals (Sweden)

    Bhatia Madhav

    2009-12-01

    Full Text Available Abstract Background Hydrogen sulfide (H2S, a gaseous mediator plays an important role in a wide range of physiological and pathological processes. H2S has been extensively studied for its various roles in cardiovascular and neurological disorders. However, the role of H2S in inflammation is still controversial. The current study was aimed to investigate the therapeutic potential of sodium hydrosulfide (NaHS, an H2S donor in in vivo model of acute pancreatitis in mice. Methods Acute pancreatitis was induced in mice by hourly caerulein injections (50 μg/kg for 10 hours. Mice were treated with different dosages of NaHS (5 mg/kg, 10 mg/kg or 15 mg/kg or with vehicle, distilled water (DW. NaHS or DW was administered 1 h before induction of pancreatitis. Mice were sacrificed 1 h after the last caerulein injection. Blood, pancreas and lung tissues were collected and were processed to measure the plasma amylase, myeloperoxidase (MPO activities in pancreas and lung and chemokines and adhesion molecules in pancreas and lung. Results It was revealed that significant reduction of inflammation, both in pancreas and lung was associated with NaHS 10 mg/kg. Further the anti-inflammatory effects of NaHS 10 mg/kg were associated with reduction of pancreatic and pulmonary inflammatory chemokines and adhesion molecules. NaHS 5 mg/kg did not cause significant improvement on inflammation in pancreas and associated lung injury and NaHS 15 mg/kg did not further enhance the beneficial effects seen with NaHS 10 mg/kg. Conclusion In conclusion, these data provide evidence for anti-inflammatory effects of H2S based on its dosage used.

  15. Systemic inflammation in chronic obstructive pulmonary disease and lung cancer: common driver of pulmonary cachexia?

    Science.gov (United States)

    Ceelen, Judith J M; Langen, Ramon C J; Schols, Annemie M W J

    2014-12-01

    In this article, a putative role of systemic inflammation as a driver of pulmonary cachexia induced by either chronic obstructive pulmonary disease or nonsmall cell lung cancer is reviewed. Gaps in current translational research approaches are discussed and alternative strategies are proposed to provide new insights. Activation of the ubiquitin proteasome system has generally been considered a cause of pulmonary cachexia, but current animal models lack specificity and evidence is lacking in nonsmall cell lung cancer and conflicting in chronic obstructive pulmonary disease patients. Recent studies have shown activation of the autophagy-lysosome pathway in both nonsmall cell lung cancer and chronic obstructive pulmonary disease. Myonuclear loss, as a consequence of increased apoptotic events in myofibers, has been suggested in cancer-cachexia-associated muscle atrophy. Plasma transfer on myotube cultures can be used to detect early inflammatory signals in patients and pr