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Sample records for brain inflammatory response

  1. Attenuated inflammatory response in aged mice brains following stroke.

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    Matthias W Sieber

    Full Text Available BACKGROUND: Increased age is a major risk factor for stroke incidence, post-ischemic mortality, and severe and long-term disability. Stroke outcome is considerably influenced by post-ischemic mechanisms. We hypothesized that the inflammatory response following an ischemic injury is altered in aged organisms. METHODS AND RESULTS: To that end, we analyzed the expression pattern of pro-inflammatory cytokines (TNF, IL-1α, IL-1β, IL-6, anti-inflammatory cytokines (IL-10, TGFβ1, and chemokines (Mip-1α, MCP-1, RANTES of adult (2 months and aged (24 months mice brains at different reperfusion times (6 h, 12 h, 24 h, 2 d, 7 d following transient occlusion of the middle cerebral artery. The infarct size was assessed to monitor possible consequences of an altered inflammatory response in aged mice. Our data revealed an increased neuro-inflammation with age. Above all, we found profound age-related alterations in the reaction to stroke. The response of pro-inflammatory cytokines (TNF, and IL-1β and the level of chemokines (Mip-1α, and MCP-1 were strongly diminished in the aged post-ischemic brain tissue. IL-6 showed the strongest age-dependent decrease in its post-ischemic expression profile. Anti-inflammatory cytokines (TGFβ1, and IL-10 revealed no significant age dependency after ischemia. Aged mice brains tend to develop smaller infarcts. CONCLUSION: The attenuated inflammatory response to stroke in aged animals may contribute to their smaller infarcts. The results presented here highlight the importance of using aged animals to investigate age-associated diseases like stroke, and should be considered as a major prerequisite in the development of age-adjusted therapeutic interventions.

  2. Strongly compromised inflammatory response to brain injury in interleukin-6-deficient mice

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    Penkowa, M; Moos, T; Carrasco, J;

    1999-01-01

    Injury to the central nervous system (CNS) elicits an inflammatory response involving activation of microglia, brain macrophages, and astrocytes, processes likely mediated by the release of proinflammatory cytokines. In order to determine the role of interleukin-6 (IL-6) during the inflammatory...... response in the brain following disruption of the blood-brain barrier (BBB), we examined the effects of a focal cryo injury to the fronto-parietal cortex in interleukin-6-deficient (IL-6-/-) and normal (IL-6+/+) mice. In IL-6+/+ mice, brain injury resulted in the appearance of brain macrophages...

  3. Acute, regional inflammatory response after traumatic brain injury: Implications for cellular therapy

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    Harting, Matthew T.; jimenez, fernando; Adams, Sasha D.; Mercer, David W.; Cox, Charles S.

    2008-01-01

    While cellular therapy has shown promise in the management of traumatic brain injury (TBI), microenvironment interactions between the intracerebral milieu and therapeutic stem cells are poorly understood. We sought to characterize the acute, regional inflammatory response after TBI.

  4. Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury

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    Quintana, Albert; Giralt, Mercedes; Rojas, Santiago

    2005-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via intracell......Tumor necrosis factor-alpha (TNF-alpha) is one of the mediators dramatically increased after traumatic brain injury that leads to the activation, proliferation, and hypertrophy of mononuclear, phagocytic cells and gliosis. Eventually, TNF-alpha can induce both apoptosis and necrosis via...... signaling also affected the expression of apoptosis/cell death-related genes (Fas, Rip, p53), matrix metalloproteinases (MMP3, MMP9, MMP12), and their inhibitors (TIMP1), suggesting a role of TNFR1 in extracellular matrix remodeling after injury. However, GDNF, NGF, and BDNF expression were not affected...... by TNFR1 deficiency. Overall, these results suggest that TNFR1 is involved in the early establishment of the inflammatory response and that its deficiency causes a decreased inflammatory response and tissue damage following brain injury....

  5. Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice.

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    Ralph Timaru-Kast

    Full Text Available After traumatic brain injury (TBI elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months and old (21 months male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2% compared to young (0%. This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1β expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral

  6. Acetylcholinesterase loosens the brain's cholinergic anti-inflammatory response and promotes epileptogenesis

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    Yehudit eGnatek

    2012-05-01

    Full Text Available Recent studies show a key role of brain inflammation in epilepsy. However, the mechanisms controlling brain immune response are only partly understood. In the periphery, acetylcholine (ACh release by the vagus nerve restrains inflammation by inhibiting the activation of leukocytes. Recent reports suggested a similar anti-inflammatory effect for ACh in the brain. Since brain cholinergic dysfunction are documented in epileptic animals, we explored changes in brain cholinergic gene expression and associated immune response during pilocarpine-induced epileptogenesis. Levels of acetylcholinesterase (AChE and inflammatory markers were measured using real-time RT-PCR, in-situ hybridization and immunostaining in wild type (WT and transgenic mice over-expressing the "synaptic" splice variant AChE-S (TgS. One month following pilocarpine, mice were video-monitored for spontaneous seizures. To test directly the effect of ACh on the brain's innate immune response, cytokines expression levels were measured in acute brain slices treated with cholinergic agents. We report a robust upregulation of AChE as early as 48 hrs following pilocarpine-induced status epilepticus (SE. AChE was expressed in hippocampal neurons, microglia and endothelial cells but rarely in astrocytes. TgS mice overexpressing AChE showed constitutive increased microglial activation, elevated levels of pro-inflammatory cytokines 48 hrs after SE and accelerated epileptogenesis compared to their WT counterparts. Finally we show a direct, muscarine-receptor dependant, nicotine-receptor independent anti-inflammatory effect of ACh in brain slices maintained ex vivo. Our work demonstrates for the first time, that ACh directly suppresses brain innate immune response and that AChE up-regulation after SE is associated with enhanced immune response, facilitating the epileptogenic process. Our results highlight the cholinergic system as a potential new target for the prevention of seizures and epilepsy.

  7. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs.

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    Perez-Caballero, L; Pérez-Egea, R; Romero-Grimaldi, C; Puigdemont, D; Molet, J; Caso, J-R; Mico, J-A; Pérez, V; Leza, J-C; Berrocoso, E

    2014-05-01

    Deep brain stimulation (DBS) in the subgenual cingulated gyrus (SCG) is a promising new technique that may provide sustained remission in resistant major depressive disorder (MDD). Initial studies reported a significant early improvement in patients, followed by a decline within the first month of treatment, an unexpected phenomenon attributed to potential placebo effects or a physiological response to probe insertion that remains poorly understood. Here we characterized the behavioural antidepressant-like effect of DBS in the rat medial prefrontal cortex, focusing on modifications to rodent SCG correlate (prelimbic and infralimbic (IL) cortex). In addition, we evaluated the early outcome of DBS in the SCG of eight patients with resistant MDD involved in a clinical trial. We found similar antidepressant-like effects in rats implanted with electrodes, irrespective of whether they received electrical brain stimulation or not. This effect was due to regional inflammation, as it was temporally correlated with an increase of glial-fibrillary-acidic-protein immunoreactivity, and it was blocked by anti-inflammatory drugs. Indeed, inflammatory mediators and neuronal p11 expression also changed. Furthermore, a retrospective study indicated that the early response of MDD patients subjected to DBS was poorer when they received anti-inflammatory drugs. Our study demonstrates that electrode implantation up to the IL cortex is sufficient to produce an antidepressant-like effect of a similar magnitude to that observed in rats receiving brain stimulation. Moreover, both preclinical and clinical findings suggest that the use of anti-inflammatory drugs after electrode implantation may attenuate the early anti-depressive response in patients who are subjected to DBS.

  8. The Acute Inflammatory Response in Trauma / Hemorrhage and Traumatic Brain Injury: Current State and Emerging Prospects

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    Y Vodovotz

    2009-01-01

    Full Text Available Traumatic injury/hemorrhagic shock (T/HS elicits an acute inflammatory response that may result in death. Inflammation describes a coordinated series of molecular, cellular, tissue, organ, and systemic responses that drive the pathology of various diseases including T/HS and traumatic brain injury (TBI. Inflammation is a finely tuned, dynamic, highly-regulated process that is not inherentlydetrimental, but rather required for immune surveillance, optimal post-injury tissue repair, and regeneration. The inflammatory response is driven by cytokines and chemokines and is partiallypropagated by damaged tissue-derived products (Damage-associated Molecular Patterns; DAMP’s.DAMPs perpetuate inflammation through the release of pro-inflammatory cytokines, but may also inhibit anti-inflammatory cytokines. Various animal models of T/HS in mice, rats, pigs, dogs, and nonhumanprimates have been utilized in an attempt to move from bench to bedside. Novel approaches, including those from the field of systems biology, may yield therapeutic breakthroughs in T/HS andTBI in the near future.

  9. Low intensity microwave radiation induced oxidative stress, inflammatory response and DNA damage in rat brain.

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    Megha, Kanu; Deshmukh, Pravin Suryakantrao; Banerjee, Basu Dev; Tripathi, Ashok Kumar; Ahmed, Rafat; Abegaonkar, Mahesh Pandurang

    2015-12-01

    Over the past decade people have been constantly exposed to microwave radiation mainly from wireless communication devices used in day to day life. Therefore, the concerns over potential adverse effects of microwave radiation on human health are increasing. Until now no study has been proposed to investigate the underlying causes of genotoxic effects induced by low intensity microwave exposure. Thus, the present study was undertaken to determine the influence of low intensity microwave radiation on oxidative stress, inflammatory response and DNA damage in rat brain. The study was carried out on 24 male Fischer 344 rats, randomly divided into four groups (n=6 in each group): group I consisted of sham exposed (control) rats, group II-IV consisted of rats exposed to microwave radiation at frequencies 900, 1800 and 2450 MHz, specific absorption rates (SARs) 0.59, 0.58 and 0.66 mW/kg, respectively in gigahertz transverse electromagnetic (GTEM) cell for 60 days (2h/day, 5 days/week). Rats were sacrificed and decapitated to isolate hippocampus at the end of the exposure duration. Low intensity microwave exposure resulted in a frequency dependent significant increase in oxidative stress markers viz. malondialdehyde (MDA), protein carbonyl (PCO) and catalase (CAT) in microwave exposed groups in comparison to sham exposed group (pmicrowave exposed groups (pmicrowave exposed animal (pmicrowave exposed groups as compared to their corresponding values in sham exposed group (pmicrowave radiation induces oxidative stress, inflammatory response and DNA damage in brain by exerting a frequency dependent effect. The study also indicates that increased oxidative stress and inflammatory response might be the factors involved in DNA damage following low intensity microwave exposure.

  10. Titanium oxide (TiO2) nanoparticles in induction of apoptosis and inflammatory response in brain

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    Meena, Ramovatar; Kumar, Sumit; Paulraj, R.

    2015-01-01

    The ever increasing applications of engineered nanoparticles in 21st century cause serious concern about its potential health risks on living being. Regulatory health risk assessment of such particles has become mandatory for the safe use of nanomaterials in consumer products and medicines. In order to study the mechanism underlying the effects of nano-TiO2 (TiO2 nanoparticles) on the brain, wistar rats were administrated intravenously with various doses of nano-TiO2 (21 nm) through the caudal vein, once a week for 4 weeks and different parameters such as bioaccumulation of nano-TiO2, oxidative stress-mediated response, level of inflammatory markers such as NF-κB (p65), HSP 60, p38, nitric oxide, IFN-γ and TNF-α, and level of neurochemicals in brain as well as DNA damage and expression of apoptosis markers (p53, Bax, Bcl-2, and cyto c) were evaluated. Results show that the concentration of nano-TiO2 in the brain increased with increasing the doses of nano-TiO2. Oxidative stress and injury of the brain occurred as nano-TiO2 appeared to trigger a cascade of reactions such as inflammation, lipid peroxidation, decreases the activities of antioxidative enzymes and melatonin level, the reduction of glutamic acid, downregulated levels of acetylcholinesterase activities, and the increase in caspase-3 activity (a biomarker of apoptosis), DNA fragmentation, and apoptosis. It may be concluded that nano-TiO2 induces oxidative stress that leads to activation of inflammatory cytokines and an alteration in the level of neurotransmitters resulted in the induction of mitochondrial-mediated apoptosis.

  11. Post-treatment vascular leakage and inflammatory responses around brain cysts in porcine neurocysticercosis.

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    Siddhartha Mahanty

    2015-03-01

    Full Text Available Cysticidal treatment of neurocysticercosis, an infection of humans and pig brains with Taenia solium, results in an early inflammatory response directed to cysts causing seizures and focal neurological manifestations. Treatment-induced pericystic inflammation and its association with blood brain barrier (BBB dysfunction, as determined by Evans blue (EB extravasation, was studied in infected untreated and anthelmintic-treated pigs. We compared the magnitude and extent of the pericystic inflammation, presence of EB-stained capsules, the level of damage to the parasite, expression of genes for proinflammatory and regulatory cytokines, chemokines, and tissue remodeling by quantitative PCR assays between treated and untreated infected pigs and between EB-stained (blue and non stained (clear cysts. Inflammatory scores were higher in pericystic tissues from EB-stained cysts compared to clear cysts from untreated pigs and also from anthelmintic-treated pigs 48 hr and 120 hr after treatment. The degree of inflammation correlated with the severity of cyst wall damage and both increased significantly at 120 hours. Expression levels of the proinflammatory genes for IL-6, IFN-γ, TNF-α were higher in EB-stained cysts compared to clear cysts and unaffected brain tissues, and were generally highest at 120 hr. Additionally, expression of some markers of immunoregulatory activity (IL-10, IL-2Rα were decreased in EB-stained capsules. An increase in other markers for regulatory T cells (CTLA4, FoxP3 was found, as well as significant increases in expression of two metalloproteases, MMP1 and MMP2 at 48 hr and 120 hr post-treatment. We conclude that the increase in severity of the inflammation caused by treatment is accompanied by both a proinflammatory and a complex regulatory response, largely limited to pericystic tissues with compromised vascular integrity. Because treatment induced inflammation occurs in porcine NCC similar to that in human cases, this model

  12. Post-treatment vascular leakage and inflammatory responses around brain cysts in porcine neurocysticercosis.

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    Mahanty, Siddhartha; Orrego, Miguel Angel; Mayta, Holger; Marzal, Miguel; Cangalaya, Carla; Paredes, Adriana; Gonzales-Gustavson, Eloy; Arroyo, Gianfranco; Gonzalez, Armando E; Guerra-Giraldez, Cristina; García, Hector H; Nash, Theodore E

    2015-03-01

    Cysticidal treatment of neurocysticercosis, an infection of humans and pig brains with Taenia solium, results in an early inflammatory response directed to cysts causing seizures and focal neurological manifestations. Treatment-induced pericystic inflammation and its association with blood brain barrier (BBB) dysfunction, as determined by Evans blue (EB) extravasation, was studied in infected untreated and anthelmintic-treated pigs. We compared the magnitude and extent of the pericystic inflammation, presence of EB-stained capsules, the level of damage to the parasite, expression of genes for proinflammatory and regulatory cytokines, chemokines, and tissue remodeling by quantitative PCR assays between treated and untreated infected pigs and between EB-stained (blue) and non stained (clear) cysts. Inflammatory scores were higher in pericystic tissues from EB-stained cysts compared to clear cysts from untreated pigs and also from anthelmintic-treated pigs 48 hr and 120 hr after treatment. The degree of inflammation correlated with the severity of cyst wall damage and both increased significantly at 120 hours. Expression levels of the proinflammatory genes for IL-6, IFN-γ, TNF-α were higher in EB-stained cysts compared to clear cysts and unaffected brain tissues, and were generally highest at 120 hr. Additionally, expression of some markers of immunoregulatory activity (IL-10, IL-2Rα) were decreased in EB-stained capsules. An increase in other markers for regulatory T cells (CTLA4, FoxP3) was found, as well as significant increases in expression of two metalloproteases, MMP1 and MMP2 at 48 hr and 120 hr post-treatment. We conclude that the increase in severity of the inflammation caused by treatment is accompanied by both a proinflammatory and a complex regulatory response, largely limited to pericystic tissues with compromised vascular integrity. Because treatment induced inflammation occurs in porcine NCC similar to that in human cases, this model can be used to

  13. Hyperbaric oxygen therapy ameliorates local brain metabolism, brain edema and inflammatory response in a blast-induced traumatic brain injury model in rabbits.

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    Zhang, Yongming; Yang, Yanyan; Tang, Hong; Sun, Wenjiang; Xiong, Xiaoxing; Smerin, Daniel; Liu, Jiachuan

    2014-05-01

    Many studies suggest that hyperbaric oxygen therapy (HBOT) can provide some clinically curative effects on blast-induced traumatic brain injury (bTBI). The specific mechanism by which this occurs still remains unknown, and no standardized time or course of hyperbaric oxygen treatment is currently used. In this study, bTBI was produced by paper detonators equivalent to 600 mg of TNT exploding at 6.5 cm vertical to the rabbit's head. HBO (100% O2 at 2.0 absolute atmospheres) was used once, 12 h after injury. Magnetic resonance spectroscopy was performed to investigate the impact of HBOT on the metabolism of local injured nerves in brain tissue. We also examined blood-brain barrier (BBB) integrity, brain water content, apoptotic factors, and some inflammatory mediators. Our results demonstrate that hyperbaric oxygen could confer neuroprotection and improve prognosis after explosive injury by promoting the metabolism of local neurons, inhibiting brain edema, protecting BBB integrity, decreasing cell apoptosis, and inhibiting the inflammatory response. Furthermore, timely intervention within 1 week after injury might be more conducive to improving the prognosis of patients with bTBI.

  14. Inhibitory Effect on Cerebral Inflammatory Response following Traumatic Brain Injury in Rats: A Potential Neuroprotective Mechanism of N-Acetylcysteine

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    Gang Chen

    2008-01-01

    Full Text Available Although N-acetylcysteine (NAC has been shown to be neuroprotective for traumatic brain injury (TBI, the mechanisms for this beneficial effect are still poorly understood. Cerebral inflammation plays an important role in the pathogenesis of secondary brain injury after TBI. However, it has not been investigated whether NAC modulates TBI-induced cerebral inflammatory response. In this work, we investigated the effect of NAC administration on cortical expressions of nuclear factor kappa B (NF-κB and inflammatory proteins such as interleukin-1β (IL-1β, tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, and intercellular adhesion molecule-1 (ICAM-1 after TBI. As a result, we found that NF-κB, proinflammatory cytokines, and ICAM-1 were increased in all injured animals. In animals given NAC post-TBI, NF-κB, IL-1β, TNF-α, and ICAM-1 were decreased in comparison to vehicle-treated animals. Measures of IL-6 showed no change after NAC treatment. NAC administration reduced brain edema, BBB permeability, and apoptotic index in the injured brain. The results suggest that post-TBI NAC administration may attenuate inflammatory response in the injured rat brain, and this may be one mechanism by which NAC ameliorates secondary brain damage following TBI.

  15. Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response.

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    Yang, Yang; Zhang, Yan; Wang, Zhaotao; Wang, Shanshan; Gao, Mou; Xu, Ruxiang; Liang, Chunyang; Zhang, Hongtian

    2016-04-01

    The outcome of intracerebral hemorrhage (ICH) is mainly determined by the volume of the hemorrhage core and the secondary brain damage to penumbral tissues due to brain swelling, microcirculation disturbance and inflammation. The present study aims to investigate the protective effects of cerebrolysin on brain edema and inhibition of the inflammation response surrounding the hematoma core in the acute stage after ICH. The ICH model was induced by administration of type VII bacterial collagenase into the stratum of adult rats, which were then randomly divided into three groups: ICH + saline; ICH + Cerebrolysin (5 ml/kg) and sham. Cerebrolysin or saline was administered intraperitoneally 1 h post surgery. Neurological scores, extent of brain edema content and Evans blue dye extravasation were recorded. The levels of pro-inflammatory factors (IL-1β, TNF-α and IL-6) were assayed by Real-time PCR and Elisa kits. Aquaporin-4 (AQP4) and tight junction proteins (TJPs; claudin-5, occludin and zonula occluden-1) expression were measured at multiple time points. The morphological and intercellular changes were characterized by Electron microscopy. It is found that cerebrolysin (5 ml/kg) improved the neurological behavior and reduced the ipsilateral brain water content and Evans blue dye extravasation. After cerebrolysin treated, the levels of pro-inflammatory factors and AQP4 in the peri-hematomal areas were markedly reduced and were accompanied with higher expression of TJPs. Electron microscopy showed the astrocytic swelling and concentrated chromatin in the ICH group and confirmed the cell junction changes. Thus, early cerebrolysin treatment ameliorates secondary injury after ICH and promotes behavioral performance during the acute phase by reducing brain edema, inflammatory response, and blood-brain barrier permeability.

  16. Downregulation of an astrocyte-derived inflammatory protein, S100B, reduces vascular inflammatory responses in brains persistently infected with Borna disease virus.

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    Ohtaki, Naohiro; Kamitani, Wataru; Watanabe, Yohei; Hayashi, Yohei; Yanai, Hideyuki; Ikuta, Kazuyoshi; Tomonaga, Keizo

    2007-06-01

    Borna disease virus (BDV) is a neurotropic virus that causes a persistent infection in the central nervous system (CNS) of many vertebrate species. Although a severe reactive gliosis is observed in experimentally BDV-infected rat brains, little is known about the glial reactions contributing to the viral persistence and immune modulation in the CNS. In this regard, we examined the expression of an astrocyte-derived factor, S100B, in the brains of Lewis rats persistently infected with BDV. S100B is a Ca(2+)-binding protein produced mainly by astrocytes. A prominent role of this protein appears to be the promotion of vascular inflammatory responses through interaction with the receptor for advanced glycation end products (RAGE). Here we show that the expression of S100B is significantly reduced in BDV-infected brains despite severe astrocytosis with increased glial fibrillary acidic protein immunoreactivity. Interestingly, no upregulation of the expression of S100B, or RAGE, was observed in the persistently infected brains even when incited with several inflammatory stimuli, including lipopolysaccharide. In addition, expression of the vascular cell adhesion molecule 1 (VCAM-1), as well as the infiltration of encephalitogenic T cells, was significantly reduced in persistently infected brains in which an experimental autoimmune encephalomyelitis was induced by immunization with myelin-basic protein. Furthermore, we demonstrated that the continuous activation of S100B in the brain may be necessary for the progression of vascular immune responses in neonatally infected rat brains. Our results suggested that BDV infection may impair astrocyte functions via a downregulation of S100B expression, leading to the maintenance of a persistent infection.

  17. Inflammatory responses are not sufficient to cause delayed neuronal death in ATP-induced acute brain injury.

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    Hey-Kyeong Jeong

    Full Text Available BACKGROUND: Brain inflammation is accompanied by brain injury. However, it is controversial whether inflammatory responses are harmful or beneficial to neurons. Because many studies have been performed using cultured microglia and neurons, it has not been possible to assess the influence of multiple cell types and diverse factors that dynamically and continuously change in vivo. Furthermore, behavior of microglia and other inflammatory cells could have been overlooked since most studies have focused on neuronal death. Therefore, it is essential to analyze the precise roles of microglia and brain inflammation in the injured brain, and determine their contribution to neuronal damage in vivo from the onset of injury. METHODS AND FINDINGS: Acute neuronal damage was induced by stereotaxic injection of ATP into the substantia nigra pars compacta (SNpc and the cortex of the rat brain. Inflammatory responses and their effects on neuronal damage were investigated by immunohistochemistry, electron microscopy, quantitative RT-PCR, and stereological counting, etc. ATP acutely caused death of microglia as well as neurons in a similar area within 3 h. We defined as the core region the area where both TH(+ and Iba-1(+ cells acutely died, and as the penumbra the area surrounding the core where Iba-1(+ cells showed activated morphology. In the penumbra region, morphologically activated microglia arranged around the injury sites. Monocytes filled the damaged core after neurons and microglia died. Interestingly, neither activated microglia nor monocytes expressed iNOS, a major neurotoxic inflammatory mediator. Monocytes rather expressed CD68, a marker of phagocytic activity. Importantly, the total number of dopaminergic neurons in the SNpc at 3 h (∼80% of that in the contralateral side did not decrease further at 7 d. Similarly, in the cortex, ATP-induced neuron-damage area detected at 3 h did not increase for up to 7 d. CONCLUSIONS: Different cellular

  18. Effect of glutamate on inflammatory responses of intestine and brain after focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Lei Xu; Jie Sun; Ran Lu; Qing Ji; Jian-Guo Xu

    2005-01-01

    AIM: To study the modulation of glutamate on post-ischemic intestinal and cerebral inflammatory responses in a ischemic and excitotoxic rat model.METHODS: Adult male rats were subjected to bilateral carotid artery occlusion for 15 min and injection of monosodium glutamate intraperitoneally, to decapitate them at selected time points. Tumor necrosis factor alpha (TNF-α) level and nuclear factor kappa B (NF-κB) activity were determined by enzyme-linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA), respectively.Hemodynamic parameters were monitored continuously during the whole process of cerebral ischemia and reperfusion.RESULTS: Monosodium glutamate (MSG) treated rats displayed statistically significant high levels of TNF-α in cerebral and intestinal tissuess within the first 6 h of ischemia. The rats with cerebral ischemia showed a minor decrease of TNF-α production in cerebral and intestinal tissuess. The rats with cerebral ischemia and treated with MSG displayed statistically significant low levels of TNF-α in cerebral and intestinal tissues. These results correlated significantly with NF-κB production calculated at the same intervals. During experiment, the mean blood pressure and heart rates in all groups were stable.CONCLUSION: Glutamate is involved in the mechanism of intestinal and cerebral inflammation responses. The effects of glutamate on cerebral and intestinal inflammatory responses after ischemia are up-regulated at the transcriptional level,through the NF-κB signal transduction pathway.

  19. Titanium oxide (TiO{sub 2}) nanoparticles in induction of apoptosis and inflammatory response in brain

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    Meena, Ramovatar, E-mail: rammeenarv@gmail.com; Kumar, Sumit; Paulraj, R., E-mail: paulrajr@hotmail.com [Jawaharlal Nehru University, School of Environmental Sciences (India)

    2015-01-15

    The ever increasing applications of engineered nanoparticles in 21st century cause serious concern about its potential health risks on living being. Regulatory health risk assessment of such particles has become mandatory for the safe use of nanomaterials in consumer products and medicines. In order to study the mechanism underlying the effects of nano-TiO{sub 2} (TiO{sub 2} nanoparticles) on the brain, wistar rats were administrated intravenously with various doses of nano-TiO{sub 2} (21 nm) through the caudal vein, once a week for 4 weeks and different parameters such as bioaccumulation of nano-TiO{sub 2}, oxidative stress-mediated response, level of inflammatory markers such as NF-κB (p65), HSP 60, p38, nitric oxide, IFN-γ and TNF-α, and level of neurochemicals in brain as well as DNA damage and expression of apoptosis markers (p53, Bax, Bcl-2, and cyto c) were evaluated. Results show that the concentration of nano-TiO{sub 2} in the brain increased with increasing the doses of nano-TiO{sub 2}. Oxidative stress and injury of the brain occurred as nano-TiO{sub 2} appeared to trigger a cascade of reactions such as inflammation, lipid peroxidation, decreases the activities of antioxidative enzymes and melatonin level, the reduction of glutamic acid, downregulated levels of acetylcholinesterase activities, and the increase in caspase-3 activity (a biomarker of apoptosis), DNA fragmentation, and apoptosis. It may be concluded that nano-TiO{sub 2} induces oxidative stress that leads to activation of inflammatory cytokines and an alteration in the level of neurotransmitters resulted in the induction of mitochondrial-mediated apoptosis.

  20. 胎儿炎症反应与早产儿脑损伤%Fetal inflammatory response and brain injury in preterm newborns

    Institute of Scientific and Technical Information of China (English)

    马江林

    2014-01-01

    宫内感染后胎儿炎症反应在早产及早产儿脑损伤中发挥重要作用.胎儿炎症反应表现为胎儿循环中前炎症细胞因子增加.炎症信号可通过血脑屏障启动胎儿神经炎症反应,导致发育中大脑损伤.全面理解胎儿炎症反应有助于提出干预措施并改善早产儿神经发育结局.该文就胎儿炎症反应与早产儿脑损伤相关问题作一综述.%The fetal inflammatory response to intrauterine infection plays a crucial role in the pathogenesis of preterm birth and preterm brain injury.The fetal inflammatory response is characterized by elevated levels of proinflammatory cytokines in the fetal circulation.The inflammation signal is likely transmitted across the blood-brain barrier and initiates a neuroinflammatory response and triggers damage in the developing brain.A better understanding of the fetal inflammatory response will help design interventions to improve neurodevelopmental outcomes after preterm birth.This review summarizes researches of fetal inflammatory response and brain injury in the preterm newborn.

  1. Inflammatory diseases of the brain

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    Haehnel, Stefan (ed.) [University of Heidelberg Medical Center (Germany). Div. of Neuroradiology

    2009-07-01

    This book provides a comprehensive overview of inflammatory brain diseases from a neuroradiological point of view. Such diseases may be either infectious (e.g., viral encephalitis and pyogenic brain abscess) or non-infectious (e.g., multiple sclerosis), and many of these entities are becoming increasingly important for differential diagnosis, particularly in immunocompromised persons. Neuroimaging contributes greatly to the differentiation of infectious and noninfectious brain diseases and to the distinction between brain inflammation and other, for instance neoplastic, diseases. In order to ensure a standardized approach throughout the book, each chapter is subdivided into three principal sections: epidemiology, clinical presentation and therapy; imaging; and differential diagnosis. A separate chapter addresses technical and methodological issues and imaging protocols. All of the authors are recognized experts in their fields, and numerous high-quality and informative illustrations are included. This book will be of great value not only to neuroradiologists but also to neurologists, neuropediatricians, and general radiologists. (orig.)

  2. Inflammatory cytokines in the brain: does the CNS shape immune responses?

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    Owens, T; Renno, T; Taupin, V;

    1994-01-01

    Immune responses in the central nervous system (CNS) have traditionally been regarded as representing the intrusion of an unruly, ill-behaved mob of leukocytes into the well-ordered and organized domain of thought and reason. However, results accumulated over the past few years suggest that, far ...

  3. miR-203 protects microglia mediated brain injury by regulating inflammatory responses via feedback to MyD88 in ischemia.

    Science.gov (United States)

    Yang, Zhao; Zhong, Lina; Zhong, Shanchuan; Xian, Ronghua; Yuan, Bangqing

    2015-06-01

    Much evidence demonstrates that microglia mediated inflammatory responses play an important role in brain injury in ischemia. miRNA is the important factor in regulation of inflammation. However, the effect of miRNA in microglia mediated inflammatory responses has not been well studied. In the study, we demonstrate that miR-203 negatively regulates ischemia induced microglia activation by targeting MyD88, an important adapter protein involved in most Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) pathways. Through negative feedback, enforced expression of miR-203 or MyD88 siRNA silencing inhibits downstream NF-κβ signaling and microglia activation, thereby alleviating neuronal injury. These findings reveal that miR-203 represents a novel target regulating neuroinflammation and brain injury, thus offering a new therapeutical strategy for cerebral hypoxic diseases.

  4. Zinc or copper deficiency-induced impaired inflammatory response to brain trauma may be caused by the concomitant metallothionein changes

    DEFF Research Database (Denmark)

    Penkowa, Milena; Giralt, M.; Thomsen, Pernille Sjølin;

    2001-01-01

    damage to neurons as indicated by neuron specific enolase (NSE) ir, and the number of cells undergoing apoptosis (measured by TUNEL) was dramatically increased. Zinc deficiency significantly altered brain response to TBI, potentiating the microgliosis and reducing the astrogliosis, while increasing...

  5. Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis.

    Science.gov (United States)

    Kim, Soo Young; Buckwalter, Marion; Soreq, Hermona; Vezzani, Annamaria; Kaufer, Daniela

    2012-11-01

    The protection of the brain from blood-borne toxins, proteins, and cells is critical to the brain's normal function. Accordingly, a compromise in the blood-brain barrier (BBB) function accompanies many neurologic disorders, and is tightly associated with brain inflammatory processes initiated by both infiltrating leukocytes from the blood, and activation of glial cells. Those inflammatory processes contribute to determining the severity and prognosis of numerous neurologic disorders, and can both cause, and result from BBB dysfunction. In this review we examine the role of BBB and inflammatory responses, in particular activation of transforming grown factor β (TGFβ) signaling, in epilepsy, stroke, and Parkinson's disease.

  6. Brain Injury and Inflammatory Response to Umbilical Cord Occlusions Is Limited With Worsening Acidosis in the Near-Term Ovine Fetus.

    Science.gov (United States)

    Xu, Alex; Matushewski, Brad; Nygard, Karen; Hammond, Robert; Frasch, Martin G; Richardson, Bryan S

    2016-07-01

    We hypothesized that repetitive umbilical cord occlusions (UCOs) with worsening fetal acidemia will lead to an inflammatory response within the brain and thereby brain injury which will be exacerbated by chronic hypoxemia and low-grade infection. Chronically instrumented fetal sheep served as controls (N = 10) or underwent repeated UCOs for up to 4 hours or until arterial pH was 55% and pH approaching 7.00 for all 3 UCO groups. However, there was no significant effect on measures of brain inflammation or injury, except in the LPS-UCO animals where TUNEL-positive cells were increased in the hippocampus, although small animal numbers in the hypoxic-UCO group may have limited the ability to detect significance in their TUNEL cell findings. We were therefore unable to confirm our working hypothesis since the near-term ovine fetal brain showed remarkable tolerance for these cord occlusion insults and likely involving protective metabolic mechanisms, despite the severe acidemia noted.

  7. NLRP3-inflammasome activating DAMPs stimulate an inflammatory response in glia in the absence of priming which contributes to brain inflammation after injury

    Directory of Open Access Journals (Sweden)

    Catherine Diane Savage

    2012-09-01

    Full Text Available Inflammation in the absence of infection (sterile inflammation contributes to acute injury and chronic disease. Cerebral ischaemia is a devastating condition in which the primary injury is caused by reduced blood supply and is therefore sterile. The cytokine interleukin-1β (IL-1β is a key contributor to ischaemic brain injury and central inflammatory responses. The release of IL-1β is regulated by the protease caspase-1, and its activating complex, the inflammasome. Of the known inflammasomes the best characterised, and one that is perceived to sense sterile injury is formed by a pattern recognition receptor called NLRP3. A key feature of NLRP3-inflammasome dependent responses in vitro in macrophages is the requirement of an initial priming stimulus by a pathogen (PAMP, or damage associated molecular pattern (DAMP respectively. We sought to determine the inflammatory responses of NLRP3-activating DAMPs on brain derived mixed glial cells in the absence of an initial priming stimulus in vitro. In cultured mouse mixed glia the DAMPs ATP, MSU and CPPD crystals had no effect on the expression of IL-1α or IL-1β and induced release only when the cells were primed with a PAMP. In the absence of priming, these DAMPs did however induce inflammation via the production of IL-6 and CXCL1, and the release of the lysosomal protease cathepsin B. Furthermore, the acute phase protein serum amyloid A (SAA acted as a priming stimulus on glial cells resulting in levels of IL-1 expression comparable to those induced by the PAMP LPS. In vivo, after cerebral ischaemia, IL-1 production contributed to increased IL-6 and CXCL1 since these cytokines were profoundly reduced in the ischaemic hemispheres from IL-1α/β double KO mice, although injury-induced cytokine responses were not abolished. Thus, DAMPs augment brain inflammation by directly stimulating production of glial derived inflammatory mediators. This is markedly enhanced by DAMP-induced IL-1-release

  8. Melatonin Counteracts at a Transcriptional Level the Inflammatory and Apoptotic Response Secondary to Ischemic Brain Injury Induced by Middle Cerebral Artery Blockade in Aging Rats.

    Science.gov (United States)

    Paredes, Sergio D; Rancan, Lisa; Kireev, Roman; González, Alberto; Louzao, Pedro; González, Pablo; Rodríguez-Bobada, Cruz; García, Cruz; Vara, Elena; Tresguerres, Jesús A F

    2015-01-01

    Aging increases oxidative stress and inflammation. Melatonin counteracts inflammation and apoptosis. This study investigated the possible protective effect of melatonin on the inflammatory and apoptotic response secondary to ischemia induced by blockade of the right middle cerebral artery (MCA) in aging male Wistar rats. Animals were subjected to MCA obstruction. After 24 h or 7 days of procedure, 14-month-old nontreated and treated rats with a daily dose of 10 mg/kg melatonin were sacrificed and right and left hippocampus and cortex were collected. Rats aged 2 and 6 months, respectively, were subjected to the same brain injury protocol, but they were not treated with melatonin. mRNA expression of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX), glial fibrillary acidic protein (GFAP), B-cell lymphoma 2 (Bcl-2), and sirtuin 1 was measured by reverse transcription-polymerase chain reaction. In nontreated animals, a significant time-dependent increase in IL-1β, TNF-α, BAD, and BAX was observed in the ischemic area of both hippocampus and cortex, and to a lesser extent in the contralateral hemisphere. Hippocampal GFAP was also significantly elevated, while Bcl-2 and sirtuin 1 decreased significantly in response to ischemia. Aging aggravated these changes. Melatonin administration was able to reverse significantly these alterations. In conclusion, melatonin may ameliorate the age-dependent inflammatory and apoptotic response secondary to ischemic cerebral injury.

  9. Chemotactic and inflammatory responses in the liver and brain are associated with pathogenesis of Rift Valley fever virus infection in the mouse.

    Directory of Open Access Journals (Sweden)

    Kimberly K Gray

    Full Text Available Rift Valley fever virus (RVFV is a major human and animal pathogen associated with severe disease including hemorrhagic fever or encephalitis. RVFV is endemic to parts of Africa and the Arabian Peninsula, but there is significant concern regarding its introduction into non-endemic regions and the potentially devastating effect to livestock populations with concurrent infections of humans. To date, there is little detailed data directly comparing the host response to infection with wild-type or vaccine strains of RVFV and correlation with viral pathogenesis. Here we characterized clinical and systemic immune responses to infection with wild-type strain ZH501 or IND vaccine strain MP-12 in the C57BL/6 mouse. Animals infected with live-attenuated MP-12 survived productive viral infection with little evidence of clinical disease and minimal cytokine response in evaluated tissues. In contrast, ZH501 infection was lethal, caused depletion of lymphocytes and platelets and elicited a strong, systemic cytokine response which correlated with high virus titers and significant tissue pathology. Lymphopenia and platelet depletion were indicators of disease onset with indications of lymphocyte recovery correlating with increases in G-CSF production. RVFV is hepatotropic and in these studies significant clinical and histological data supported these findings; however, significant evidence of a pro-inflammatory response in the liver was not apparent. Rather, viral infection resulted in a chemokine response indicating infiltration of immunoreactive cells, such as neutrophils, which was supported by histological data. In brains of ZH501 infected mice, a significant chemokine and pro-inflammatory cytokine response was evident, but with little pathology indicating meningoencephalitis. These data suggest that RVFV pathogenesis in mice is associated with a loss of liver function due to liver necrosis and hepatitis yet the long-term course of disease for those that

  10. Gene expression profiling in brain of mice exposed to the marine neurotoxin ciguatoxin reveals an acute anti-inflammatory, neuroprotective response

    Directory of Open Access Journals (Sweden)

    Ryan James C

    2010-08-01

    Full Text Available Abstract Background Ciguatoxins (CTXs are polyether marine neurotoxins and potent activators of voltage-gated sodium channels. This toxin is carried by multiple reef-fish species and human consumption of ciguatoxins can result in an explosive gastrointestinal/neurologic illness. This study characterizes the global transcriptional response in mouse brain to a symptomatic dose of the highly toxic Pacific ciguatoxin P-CTX-1 and additionally compares this data to transcriptional profiles from liver and whole blood examined previously. Adult male C57/BL6 mice were injected with 0.26 ng/g P-CTX-1 while controls received only vehicle. Animals were sacrificed at 1, 4 and 24 hrs and transcriptional profiling was performed on brain RNA with Agilent whole genome microarrays. RT-PCR was used to independently validate gene expression and the web tool DAVID was used to analyze gene ontology (GO and molecular pathway enrichment of the gene expression data. Results A pronounced 4°C hypothermic response was recorded in these mice, reaching a minimum at 1 hr and lasting for 8 hrs post toxin exposure. Ratio expression data were filtered by intensity, fold change and p-value, with the resulting data used for time course analysis, K-means clustering, ontology classification and KEGG pathway enrichment. Top GO hits for this gene set included acute phase response and mono-oxygenase activity. Molecular pathway analysis showed enrichment for complement/coagulation cascades and metabolism of xenobiotics. Many immediate early genes such as Fos, Jun and Early Growth Response isoforms were down-regulated although others associated with stress such as glucocorticoid responsive genes were up-regulated. Real time PCR confirmation was performed on 22 differentially expressed genes with a correlation of 0.9 (Spearman's Rho, p Conclusions Many of the genes differentially expressed in this study, in parallel with the hypothermia, figure prominently in protection against

  11. Airborne inflammatory factors: "from the nose to the brain".

    Science.gov (United States)

    Tonelli, Leonardo H; Postolache, Teodor T

    2010-01-01

    The intranasal pathway is a direct route of communication between the environment and the brain. This pathway is currently used for the delivery of several experimental therapeutic peptides and vaccines because it bypasses the blood brain barrier. It is also a route of entrance to the brain for several viruses and toxic substances. Airborne infectious, allergic and pollution agents are among the most common inflammatory factors which may affect brain function via the brain-nose interface. The inflammatory processes triggered in the upper respiratory tract by these agents are positioned to influence the immune response of the brain and therefore, influence its function and alter behavior. Several clinical and epidemiological studies find an association between inflammatory factors affecting the intranasal pathway and neurological disorders such as multiple sclerosis, Alzheimer and Parkinson diseases as well as mental disorders including anxiety and mood disorders. However the mechanisms of interaction between the immune response in the nasal epithelium and the brain are poorly understood. This article discusses current evidence about these mechanisms and associations with neurological and mental diseases.

  12. Transcompartmental inflammatory responses in humans

    DEFF Research Database (Denmark)

    Plovsing, Ronni R; Berg, Ronan M G; Evans, Kevin A;

    2014-01-01

    OBJECTIVES: Transcompartmental signaling during early inflammation may lead to propagation of disease to other organs. The time course and the mechanisms involved are still poorly understood. We aimed at comparing acute transcompartmental inflammatory responses in humans following...... measured. MEASUREMENTS AND MAIN RESULTS: IV endotoxin elicited a systemic inflammatory response with a time-dependent increase and peak in tumor necrosis factor-α, interleukin-6, and leukocyte counts (all p ...-α, interleukin-6, and albumin (all p inflammatory response was observed after 2-4 hours, with no change in plasma tumor necrosis factor-α. CONCLUSIONS: Acute lung or systemic inflammation in humans is followed by a transcompartmental proinflammatory response, the degree and differential...

  13. Attenuation of Brain Inflammatory Response after Focal Cerebral Ischemia/Reperfusion with Xuesaitong Injection(血塞通注射液) in Rats

    Institute of Scientific and Technical Information of China (English)

    HE Wei; XU Xiao-jun

    2006-01-01

    Objective: To investigate the neuro-protective effect of Xuesaitong Injection ( 血塞通注射液 ,XST) on brain inflammatory response after transient focal cerebral ischemia/reperfusion in rats. Methods:Focal cerebral ischemia/reperfusion models of male rats were induced by transient occlusion for 2 h of middle cerebral artery (MCA) which was followed by 24 h reperfusion. XST was administered through intraperitoneal injection of 25 mg/kg or 50 mg/kg at 4 h after the onset of ischemia. After reperfusion for 24 h, the neurological function score was evaluated, the brain edema was detected with dry-wet weight method, the myeloperoxidase (MPO) activity and the expression of intercellular adhesion molecule-1 (ICAM-1) of ischemic cerebral cortex and caudate putamen was determined by spectrophotometry and immunohistochemistry respectively. Results: XST not only lowered neurological function score at the dose of 50 mg/kg, but reduced brain edema and inhibited MPO activity and ICAM-1 expression as compared with the ischemia/reperfusion model group ( P<0.01 ). Conclusion: XST has a definite effect on inhibiting the expression of ICAM-1 and neutrophil infiltration in rats with cerebral ischemia/reperfusion when treatment started at 4 h after ischemia onset, and also attenuates inflammation in the infarcted cerebral area.neutrophil, intercellular adhesion molecule-1 of ischemic cerebral cortex and caudate putamen was determined by spectrophotometry and immunohistochemistry respectively. Results: XST not only lowered neurological function score at the dose of 50 mg/kg, but reduced brain edema and inhibited MPO activity and ICAM-1 expression as compared with the ischemia/reperfusion model group ( P<0.01 ). Conclusion: XST has a definite effect on inhibiting the expression of ICAM-1 and neutrophil infiltration in rats with cerebral ischemia/reperfusion when treatment started at 4 h after ischemia onset, and also attenuates inflammation in the infarcted cerebral area.

  14. Inflammatory bowel diseases: a dysfunction of brain-gut interactions?

    Science.gov (United States)

    Bonaz, B

    2013-09-01

    The gut has the capacity to function as an autonomous organ. However, in normal conditions, the gut and the central nervous system talk to each other through the autonomic nervous system (ANS), represented by the sympathetic (i.e. the splanchnic nerves) and the parasympathetic nervous system (i.e. the vagus nerve and the sacral parasympathetic pelvic nerves). The brain is able to integrate inputs coming from the digestive tract inside a central autonomic network organized around the hypothalamus, limbic system and cerebral cortex and in return to modify the ANS and the hypothalamic pituitary adrenal axis (HPA axis). An abnormal functioning of these brain-gut interactions has been described in irritable bowel syndrome (IBS) classically considered as a biopsychosocial model where stress plays a promoting role. Inflammatory bowel diseases (IBD) result from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. In this article we review the current knowledge on the possible involvement of a dysfunction of brain-gut interactions in the pathogeny of IBD as represented by a dysfunction of the ANS, an abnormal HPA axis and cholinergic anti-inflammatory pathway, a deleterious effect of stress and depression as well as an abnormal coupling of the prefrontal cortex-amygdala complex and an abnormal relation between the microbiota and the brain as pro-inflammatory factors. Therapeutic approaches with the aim to restore an equilibrium of these brain-gut interactions are of interest.

  15. Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures

    DEFF Research Database (Denmark)

    Penkowa, M; Molinero, A; Carrasco, J

    2001-01-01

    , and caused a significant mortality (62%) only in the latter mice, indicating that interleukin-6 deficiency increased the susceptibility to kainic acid-induced brain damage. To compare the histopathological damage caused to the brain, control and interleukin-6 null mice were administered 8.75mg/kg kainic acid...... morphological hippocampal damage, oxidative stress and apoptotic neuronal death were increased. Since metallothionein-I+II levels were lower, and those of inducible nitric oxide synthase higher, these concomitant changes are likely to contribute to the observed increased oxidative stress and neuronal death...

  16. Impaired inflammatory response and increased oxidative stress and neurodegeneration after brain injury in interleukin-6-deficient mice

    DEFF Research Database (Denmark)

    Penkowa, M; Giralt, M; Carrasco, J;

    2000-01-01

    showed higher levels of MDA, NITT, and iNOS than did normal mice. Concomitantly, in IL-6KO mice the number of apoptotic neurons was significantly increased as judged by TUNEL staining, and regeneration of the tissue was delayed relative to normal mice. The changes in neuronal tissue damage and in brain...

  17. Silver and titanium dioxide nanoparticles alter oxidative/inflammatory response and renin-angiotensin system in brain.

    Science.gov (United States)

    Krawczyńska, Agata; Dziendzikowska, Katarzyna; Gromadzka-Ostrowska, Joanna; Lankoff, Anna; Herman, Andrzej Przemysław; Oczkowski, Michał; Królikowski, Tomasz; Wilczak, Jacek; Wojewódzka, Maria; Kruszewski, Marcin

    2015-11-01

    The study was designed to examine the effects of silver AgNPs, 20 nm) and titanium dioxide (Aeroxide(®) P25 TiO2NPs, 21 nm) nanoparticles on brain oxidative stress parameters, its antioxidant potential and brain renin-angiotensin system (RAS) in vivo. The analysis was performed 28 days after single dose injection of TiO2NPs and AgNPs (10 or 5 mg/kg body weight, respectively). The AgNPs, but not TiO2NPs, administration resulted in decreased lipid and cholesterol peroxidation. Antioxidant enzymes gene expression and/or activity were changed differently for TiO2NPs and AgNPs group. The TiO2NPs decreased aromatase gene expression, and glutathione peroxidase and reductase activities. In AgNPs group the sodium dismutase 1 and glutathione reductase mRNA levels were decreased as opposed to their activities. Both NPs altered the expression of brain RAS genes (angiotensinogen, renin, angiotensin I converting enzyme 1 and 2), but only TiO2NPs caused similar changes on protein level. The expression of amyloid beta precursor protein gene was not altered by any kind of injected NPs. The TiO2NPs were more potent modulator of gene expression in the brain than AgNPs, despite the two times lower dosage. These results suggest that AgNPs and TiO2NPs exposure may modulate the brain function, but with different strength.

  18. Inflammatory response and extracorporeal circulation.

    Science.gov (United States)

    Kraft, Florian; Schmidt, Christoph; Van Aken, Hugo; Zarbock, Alexander

    2015-06-01

    Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery.

  19. Systemic inflammatory response syndrome following burns is mediated by brain natriuretic peptide/natriuretic peptide A receptor-induced shock factor 1 signaling pathway.

    Science.gov (United States)

    Xu, Yang-Cheng; Luo, Cheng-Qun; Li, Xiong

    2016-10-01

    The aim of this study was to determine whether systemic inflammatory response syndrome (SIRS) in burn patients is mediated by the brain natriuretic peptide (BNP)/natriuretic peptide A receptor (NPRA)-induced heat shock factor 1 (HSF-1) signalling pathway. Mononuclear cells (MNCs) that were isolated from patients with burn injuries and SIRS mouse models and a RAW264.7 cell line were treated with normal serum or serum obtained from animals with burn injuries. In parallel, small hairpin RNAs (shRNAs) against BNP or NPRA were transfected in both cell types. Western blotting (WB) and enzyme-linked immunosorbent assay (ELISA) were used to detect protein expression and inflammatory factor levels, respectively. We found that interleukin (IL)-12, tumour necrosis factor (TNF)-α, C-reactive protein (CRP), and BNP levels were increased and IL-10 levels were decreased in the plasma and MNCs in vivo in the animal model of SIRS. Additionally, NPRA was upregulated, whereas HSF-1 was downregulated in monocytes in vivo. Treatment of RAW264.7 cells with burn serum or BNP induced IL-12, TNF-α, and CRP secretion as well as HSF-1 expression. Finally, silencing BNP with shRNA interrupted the effect of burn serum on RAW264.7 cells, and silencing NPRA blocked burn serum- and BNP-mediated changes in RAW264.7 cells. These results suggest that the interaction of NPRA with BNP secreted from circulatory MNCs as well as mononuclear macrophages leads to inflammation via HSF-1 during SIRS development following serious burn injury.

  20. Structural brain lesions in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Can; Dolapcioglu; Hatice; Dolapcioglu

    2015-01-01

    Central nervous system(CNS) complications or manifes-tations of inflammatory bowel disease deserve particular attention because symptomatic conditions can require early diagnosis and treatment, whereas unexplained manifestations might be linked with pathogenic me-chanisms. This review focuses on both symptomatic and asymptomatic brain lesions detectable on imaging studies, as well as their frequency and potential mecha-nisms. A direct causal relationship between inflammatory bowel disease(IBD) and asymptomatic structural brain changes has not been demonstrated, but several possible explanations, including vasculitis, thromboembolism and malnutrition, have been proposed. IBD is associated with a tendency for thromboembolisms; therefore, cerebro-vascular thromboembolism represents the most frequent and grave CNS complication. Vasculitis, demyelinating conditions and CNS infections are among the other CNS manifestations of the disease. Biological agents also represent a risk factor, particularly for demyelination. Identification of the nature and potential mechanisms of brain lesions detectable on imaging studies would shed further light on the disease process and could improve patient care through early diagnosis and treatment.

  1. Low intracellular ATP levels exacerbate carcinogen-induced inflammatory stress response and inhibit in vitro tubulogenesis in human brain endothelial cells

    Directory of Open Access Journals (Sweden)

    Elizabeth Tahanian

    2011-01-01

    Full Text Available Elizabeth Tahanian, Sabrina Peiro, Borhane AnnabiLaboratoire d'Oncologie Moléculaire, Centre de Recherche BioMED, Département de Chimie, Université du Québec à Montréal, Montréal, Québec, CanadaAbstract: Solid tumor development requires angiogenesis and is correlated to the expression of inflammatory markers through cellular metabolic and energetic adaptation. While high glycolysis rates enable the cancer cell compartment to generate adenosine triphosphate (ATP, very little is known about the impact of low intracellular ATP concentrations within the vascular endothelial cell compartment, which is responsible for tumor angiogenesis. Here, we investigated the effect of 2-deoxy-D-glucose (2-DG, a glucose analog that inhibits glycolysis through intracellular ATP depletion, on human brain microvascular endothelial cell (HBMEC angiogenic properties. While preformed capillaries remained unaffected, we found that in vitro tubulogenesis was dose-dependently decreased by 2-DG and that this correlated with reduced intracellular ATP levels. Procarcinogenic signaling was induced with phorbol 12-myristate 13-acetate (PMA and found to trigger the proinflammatory marker cyclooxygenase-2 (COX-2 and endoplasmic reticulum (ER stress marker GRP78 expression, whose inductions were potentiated when PMA was combined with 2-DG treatment. Inversely, PMA-induced matrix-metalloproteinase-9 (MMP-9 gene expression and protein secretion were abrogated in the presence of 2-DG, and this can be partially explained by reduced nuclear factor-κB signaling. Collectively, we provide evidence for an intracellular ATP requirement in order for tubulogenesis to occur, and we link increases in ER stress to inflammation. A better understanding of the metabolic adaptations of the vascular endothelial cells that mediate tumor vascularization will help the development of new drugs and therapies.Keywords: endoplasmic reticulum stress, MMP-9, COX-2, 2-deoxy-D-glucose, endothelial

  2. Inflammatory Response to Sorbent Hemodialysis.

    Science.gov (United States)

    Rosales, Laura; Thijssen, Stephan; Kruse, Anja; Sipahioglu, Murat Hairy; Hirachan, Padam; Raimann, Jochen G; Kuntsevich, Viktoriya; Carter, Mary; Levin, Nathan W; Kotanko, Peter

    2015-01-01

    Inflammation is common and associated with morbidity and mortality in hemodialysis (HD) patients. Exposure to endotoxin contained in the dialysate may trigger inflammation. Dialysate volume is substantially reduced in sorbent HD compared with standard single-pass dialysis. In this prospective study (Clinicaltrials.gov, number: NCT00788905), we compared the inflammatory response to single-pass and sorbent HD. Patients receiving single-pass HD were studied during 1 week of sorbent HD (Allient system; Renal Solutions, Warrendale, PA) and 1 week of single-pass HD. Patients were dialyzed using high-flux polysulfone dialyzers. Midweek pre- and post-HD serum levels of high-sensitivity C-reactive protein, interleukin (IL)-1β, IL-6, IL-10, interferon gamma, tumor necrosis factor alpha (TNF-α), and eotaxin were determined and their intradialytic change corrected for hemoconcentration during single-pass HD and sorbent HD compared by paired t-test. We enrolled 18 patients, nine completed the study. Although TNF-α decreased during both single-pass and sorbent HD (p < 0.001), none of the other biomarkers changed significantly during HD. We observed no difference between single-pass and sorbent HD. For the markers investigated in this study, there was no difference in the acute intradialytic inflammatory response to single-pass or sorbent HD.

  3. Sphingosine 1 Phosphate at the Blood Brain Barrier: Can the Modulation of S1P Receptor 1 Influence the Response of Endothelial Cells and Astrocytes to Inflammatory Stimuli?

    Directory of Open Access Journals (Sweden)

    Simona F Spampinato

    Full Text Available The ability of the Blood Brain Barrier (BBB to maintain proper barrier functions, keeping an optimal environment for central nervous system (CNS activity and regulating leukocytes' access, can be affected in CNS diseases. Endothelial cells and astrocytes are the principal BBB cellular constituents and their interaction is essential to maintain its function. Both endothelial cells and astrocytes express the receptors for the bioactive sphingolipid S1P. Fingolimod, an immune modulatory drug whose structure is similar to S1P, has been approved for treatment in multiple sclerosis (MS: fingolimod reduces the rate of MS relapses by preventing leukocyte egress from the lymph nodes. Here, we examined the ability of S1P and fingolimod to act on the BBB, using an in vitro co-culture model that allowed us to investigate the effects of S1P on endothelial cells, astrocytes, and interactions between the two. Acting selectively on endothelial cells, S1P receptor signaling reduced cell death induced by inflammatory cytokines. When acting on astrocytes, fingolimod treatment induced the release of a factor, granulocyte macrophage colony-stimulating factor (GM-CSF that reduced the effects of cytokines on endothelium. In an in vitro BBB model incorporating shear stress, S1P receptor modulation reduced leukocyte migration across the endothelial barrier, indicating a novel mechanism that might contribute to fingolimod efficacy in MS treatment.

  4. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

    Science.gov (United States)

    Borovikova, Lyudmila V.; Ivanova, Svetlana; Zhang, Minghuang; Yang, Huan; Botchkina, Galina I.; Watkins, Linda R.; Wang, Haichao; Abumrad, Naji; Eaton, John W.; Tracey, Kevin J.

    2000-05-01

    Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

  5. Systemic inflammatory response following acute myocardial infarction.

    Science.gov (United States)

    Fang, Lu; Moore, Xiao-Lei; Dart, Anthony M; Wang, Le-Min

    2015-05-01

    Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns, activating complement and toll-like receptor/interleukin-1 signaling, and triggering an intense inflammatory response. Inflammasomes also recognize danger signals and mediate sterile inflammatory response following acute myocardial infarction (AMI). Inflammatory response serves to repair the heart, but excessive inflammation leads to adverse left ventricular remodeling and heart failure. In addition to local inflammation, profound systemic inflammation response has been documented in patients with AMI, which includes elevation of circulating inflammatory cytokines, chemokines and cell adhesion molecules, and activation of peripheral leukocytes and platelets. The excessive inflammatory response could be caused by a deregulated immune system. AMI is also associated with bone marrow activation and spleen monocytopoiesis, which sustains a continuous supply of monocytes at the site of inflammation. Accumulating evidence has shown that systemic inflammation aggravates atherosclerosis and markers for systemic inflammation are predictors of adverse clinical outcomes (such as death, recurrent myocardial infarction, and heart failure) in patients with AMI.

  6. Systemic inflammatory response following acute myocardial infarction

    Institute of Scientific and Technical Information of China (English)

    Lu FANG; Xiao-Lei Moore; Anthony M Dart; Le-Min WANG

    2015-01-01

    Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns, activating complement and toll-like receptor/interleukin-1 signaling, and triggering an intense inflammatory response. Inflammasomes also recognize danger signals and mediate sterile inflammatory response following acute myocardial infarction (AMI). Inflammatory response serves to repair the heart, but excessive inflammation leads to adverse left ventricular remodeling and heart failure. In addition to local inflammation, profound systemic inflammation response has been documented in patients with AMI, which includes elevation of circulating inflammatory cytokines, chemokines and cell adhesion molecules, and activation of peripheral leukocytes and platelets. The excessive inflammatory response could be caused by a deregulated immune system. AMI is also associated with bone marrow activation and spleen monocytopoiesis, which sustains a continuous supply of monocytes at the site of inflammation. Accumulating evidence has shown that systemic inflammation aggravates atherosclerosis and markers for systemic inflammation are predictors of adverse clinical outcomes (such as death, recurrent myocardial in-farction, and heart failure) in patients with AMI.

  7. Inflammatory response and the endothelium.

    Science.gov (United States)

    Meroni, P L; Borghi, M O; Raschi, E; Ventura, D; Sarzi Puttini, P C; Atzeni, F; Lonati, L; Parati, G; Tincani, A; Mari, D; Tedesco, F

    2004-01-01

    Antiphospholipid-mediated endothelium perturbation plays a role in antiphospholipid syndrome (APS)-associated vasculopathy. Antiphospholipid antibodies activate endothelium both in vitro and in vivo experimental models by inducing a pro-inflammatory/-coagulant phenotype; the antibodies recognize beta2 glycoprotein I (beta2GPI) on human endothelial cells (EC) from different parts of the vasculature. In spite of such large in vitro evidence, few studies have addressed the issue whether or not a comparable endothelial perturbation might be detectable in vivo. We investigated several indirect ex vivo parameters of endothelial dysfunction: plasma levels of soluble adhesion molecules (sADM), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays. The study included: patients with primary antiphospholipid syndrome (n=32), with the syndrome secondary to non-active systemic lupus erythematosus (SLE, n=10), six patients with persistent antiphospholipid positivity at medium/high titre without any clinical manifestation of the syndrome. Fifty-two age and sex matched healthy subjects have been enrolled as controls. In addition, circulating endothelial cells identified by flow cytometry and the brachial artery flow-mediated vasodilation (FMV) were evaluated in 26 patients (20 primary and 6 lupus syndromes) and 30 healthy controls. Plasma levels of soluble adhesion molecules did not differ from controls, while a significant increase in von Willebrand factor titres (P<0.05) was found. No significant difference was found regarding the number of circulating endothelial cells and flow-mediated vasodilation. As a whole, these findings do suggest that antiphospholipid antibodies per se are not able to support a full-blown endothelial perturbation in vivo. As shown in antiphospholipid syndrome experimental animal models, a two-hit hypothesis is suggested.

  8. Lateral fluid percussion injury of the brain induces CCL20 inflammatory chemokine expression in rats

    OpenAIRE

    2011-01-01

    Abstract Background Traumatic brain injury (TBI) evokes a systemic immune response including leukocyte migration into the brain and release of pro-inflammatory cytokines; however, the mechanisms underlying TBI pathogenesis and protection are poorly understood. Due to the high incidence of head trauma in the sports field, battlefield and automobile accidents identification of the molecular signals involved in TBI progression is critical for the development of novel therapeutics. Methods In thi...

  9. Cardiovascular disease management through restrained inflammatory responses.

    Science.gov (United States)

    Jabir, Nasimudeen R; Tabrez, Shams

    2016-01-01

    Cardio vascular disease (CVD) is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries and remains the leading cause of death worldwide. Vascular inflammation and associated ongoing inflammatory responses have been considered as the critical culprits in the pathogenesis of CVD. Moreover, the activation of inflammatory pathways is not confined to coronary lesions only but involves the activation of neutrophils, monocytes and lymphocytes in peripheral blood. In view of high mortality rate associated with this devastated disease, it is essential that CVD and related complications should be taken care off at its earliest. To achieve that goal, some inflammatory mediators could be potentially targeted. In the current article, we will highlight targeting some inflammatory mediators viz. IL-1, IL-6, TNF-α etc for CVD management. As far as our knowledge goes, we are for the first time reporting the targeting inflammatory mediators especially IL-1, IL-6 and TNF-α together in a single article. Based on our review, we believe that scientific community will come up with certain anti-inflammatory agents against atherosclerosis in near future and hopefully that will be used for the successful management of CVD patients.

  10. Effect of Lead (Pb on Inflammatory Processes in the Brain

    Directory of Open Access Journals (Sweden)

    Karina Chibowska

    2016-12-01

    Full Text Available That the nervous system is the main target of lead (Pb has long been considered an established fact until recent evidence has linked the Pb effect on the immune system to the toxic effects of Pb on the nervous system. In this paper, we present recent literature reports on the effect of Pb on the inflammatory processes in the brain, particularly the expression of selected cytokines in the brain (interleukin 6, TGF-β1, interleukin 16, interleukin 18, and interleukin 10; expression and activity of enzymes participating in the inflammatory processes, such as cyclooxygenase 2, caspase 1, nitrogen oxide synthase (NOS 2 and proteases (carboxypeptidases, metalloproteinases and chymotrypsin; and the expression of purine receptors P2X4 and P2X7. A significant role in the development of inflammatory processes in the brain is also played by microglia (residual macrophages in the brain and the spinal cord, which act as the first line of defense in the central nervous system, and astrocytes—Whose most important function is to maintain homeostasis for the proper functioning of neurons. In this paper, we also present evidence that exposure to Pb may result in micro and astrogliosis by triggering TLR4-MyD88-NF-κB signaling cascade and the production of pro-inflammatory cytokines.

  11. Natural Products: Insights into Leishmaniasis Inflammatory Response

    Science.gov (United States)

    Rodrigues, Igor A.; Mazotto, Ana Maria; Cardoso, Verônica; Alves, Renan L.; Amaral, Ana Claudia F.; Silva, Jefferson Rocha de Andrade; Pinheiro, Anderson S.; Vermelho, Alane B.

    2015-01-01

    Leishmaniasis is a vector-borne disease that affects several populations worldwide, against which there are no vaccines available and the chemotherapy is highly toxic. Depending on the species causing the infection, the disease is characterized by commitment of tissues, including the skin, mucous membranes, and internal organs. Despite the relevance of host inflammatory mediators on parasite burden control, Leishmania and host immune cells interaction may generate an exacerbated proinflammatory response that plays an important role in the development of leishmaniasis clinical manifestations. Plant-derived natural products have been recognized as bioactive agents with several properties, including anti-protozoal and anti-inflammatory activities. The present review focuses on the antileishmanial activity of plant-derived natural products that are able to modulate the inflammatory response in vitro and in vivo. The capability of crude extracts and some isolated substances in promoting an anti-inflammatory response during Leishmania infection may be used as part of an effective strategy to fight the disease. PMID:26538837

  12. Lateral fluid percussion injury of the brain induces CCL20 inflammatory chemokine expression in rats

    Directory of Open Access Journals (Sweden)

    Das Mahasweta

    2011-10-01

    Full Text Available Abstract Background Traumatic brain injury (TBI evokes a systemic immune response including leukocyte migration into the brain and release of pro-inflammatory cytokines; however, the mechanisms underlying TBI pathogenesis and protection are poorly understood. Due to the high incidence of head trauma in the sports field, battlefield and automobile accidents identification of the molecular signals involved in TBI progression is critical for the development of novel therapeutics. Methods In this report, we used a rat lateral fluid percussion impact (LFPI model of TBI to characterize neurodegeneration, apoptosis and alterations in pro-inflammatory mediators at two time points within the secondary injury phase. Brain histopathology was evaluated by fluoro-jade (FJ staining and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL assay, polymerase chain reaction (qRT PCR, enzyme linked immunosorbent assay (ELISA and immunohistochemistry were employed to evaluate the CCL20 gene expression in different tissues. Results Histological analysis of neurodegeneration by FJ staining showed mild injury in the cerebral cortex, hippocampus and thalamus. TUNEL staining confirmed the presence of apoptotic cells and CD11b+ microglia indicated initiation of an inflammatory reaction leading to secondary damage in these areas. Analysis of spleen mRNA by PCR microarray of an inflammation panel led to the identification of CCL20 as an important pro-inflammatory signal upregulated 24 h after TBI. Although, CCL20 expression was observed in spleen and thymus after 24h of TBI, it was not expressed in degenerating cortex or hippocampal neurons until 48 h after insult. Splenectomy partially but significantly decreased the CCL20 expression in brain tissues. Conclusion These results demonstrate that the systemic inflammatory reaction to TBI starts earlier than the local brain response and suggest that spleen- and/ or thymus-derived CCL20 might play a role in

  13. Pharmacologic Strategies for Combating the Inflammatory Response

    OpenAIRE

    Landis, Clive

    2007-01-01

    The “systemic inflammatory response” is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance ...

  14. 5′-Adenosine Monophosphate-Induced Hypothermia Attenuates Brain Ischemia/Reperfusion Injury in a Rat Model by Inhibiting the Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Yi-Feng Miao

    2015-01-01

    Full Text Available Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5′-adenosine monophosphate (5′-AMP, a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5′-AMP-induced hypothermia (AIH may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9, interleukin-1 receptor (IL-1R, tumor necrosis factor receptor (TNFR, and Toll-like receptor (TLR protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL- positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5′-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia.

  15. Certain types of iron oxide nanoparticles are not suited to passively target inflammatory cells that infiltrate the brain in response to stroke

    Science.gov (United States)

    Harms, Christoph; Datwyler, Anna Lena; Wiekhorst, Frank; Trahms, Lutz; Lindquist, Randall; Schellenberger, Eyk; Mueller, Susanne; Schütz, Gunnar; Roohi, Farnoosh; Ide, Andreas; Füchtemeier, Martina; Gertz, Karen; Kronenberg, Golo; Harms, Ulrike; Endres, Matthias; Dirnagl, Ulrich; Farr, Tracy D

    2013-01-01

    Intravenous administration of iron oxide nanoparticles during the acute stage of experimental stroke can produce signal intensity changes in the ischemic region. This has been attributed, albeit controversially, to the infiltration of iron-laden blood-borne macrophages. The properties of nanoparticles that render them most suitable for phagocytosis is a matter of debate, as is the most relevant timepoint for administration. Both of these questions are examined in the present study. Imaging experiments were performed in mice with 30 minutes of middle cerebral artery occlusion (MCAO). Iron oxide nanoparticles with different charges and sizes were used, and mice received 300 μmol Fe/kg intravenously: either superparamagnetic iron oxide nanoparticles (SPIOs), ultrasmall SPIOs, or very small SPIOs. The particles were administered 7 days before MCAO, at the time of reperfusion, or 72 hours after MCAO. Interestingly, there was no observable signal change in the ischemic brains that could be attributed to iron. Furthermore, no Prussian blue-positive cells were found in the brains or blood leukocytes, despite intense staining in the livers and spleens. This implies that the nanoparticles selected for this study are not phagocytosed by blood-borne leukocytes and do not enter the ischemic mouse brain. PMID:23443176

  16. Markers of systemic inflammatory response in coxarthrosis

    Directory of Open Access Journals (Sweden)

    Korshunov G.V.

    2013-12-01

    Full Text Available Objective: to detect markers of the systemic inflammatory response syndrome in patients with coxarthrosis by means of assessment of the status of the hemostasis system, endothelium function and inflammation intensity. Material and Methods. The indices of the plasmatic hemostasis, levels of VCAM-1, ICAM-1, ELAM-1, VEGF-A, neop-terin were analyzed. Results. It has been found that among the patients with hip coxarthrosis a group of patients (47% with endothelium dysfunction, cellular immunity activation, a high content of Soluble Fibrin Monomer Complex and D-dimers and a group of patients (53% without any abnormalities in these parameters should be differentiated. Conclusion. Among the patients with hip coxarthrosis a group with signs of a systemic inflammatory response syndrome (occurrence of endothelium dysfunction, cellular immunity activation, a high content of Soluble Fibrin Monomer Complex and D-dimers and a group of patients with reference values of these parameters can be determined. The markers of the systemic inflammatory response syndrome in cases with hip osteoarthrosis are Soluble Fibrin Monomer Complex and D-dimers, high levels of intercellular adhesion molecule-1 (slCAM-1, vascular cell adhesion molecule-2 (sVCAM-1, cell adhesion E-selectin-1 (ELAM-1 and Neopterin (Np.

  17. 创伤性脑损伤炎症反应研究进展%Research progress in inflammatory response following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    章翔; 程岗

    2011-01-01

    @@ 创伤性脑损伤(traumatic brain injury,TBI)是灾害性颅脑伤致死、致残的主要原因,美国每年约有150万TBI者,其中99 000人永久性致残,约有50 000人死亡[q].随着对TBI研究的深入,已知TBI是一种由多种细胞和分子通路参与、包括炎症反应在内的复杂神经性疾病.

  18. Neuroimmune regulation of inflammatory responses in inflammatory bowel disease

    NARCIS (Netherlands)

    Rijnierse, Anneke

    2006-01-01

    The term inflammatory bowel disease (IBD) is used to describe chronic inflammatory conditions of the gastro-intestinal tract. Patients suffer from abdominal pain, diarrhea, rectal bleeding and a substantial personal burden. The etiology of IBD is gradually being unraveled but remains a complex inter

  19. Analyzing inflammatory response as excitable media

    Science.gov (United States)

    Yde, Pernille; Høgh Jensen, Mogens; Trusina, Ala

    2011-11-01

    The regulatory system of the transcription factor NF-κB plays a great role in many cell functions, including inflammatory response. Interestingly, the NF-κB system is known to up-regulate production of its own triggering signal—namely, inflammatory cytokines such as TNF, IL-1, and IL-6. In this paper we investigate a previously presented model of the NF-κB, which includes both spatial effects and the positive feedback from cytokines. The model exhibits the properties of an excitable medium and has the ability to propagate waves of high cytokine concentration. These waves represent an optimal way of sending an inflammatory signal through the tissue as they create a chemotactic signal able to recruit neutrophils to the site of infection. The simple model displays three qualitatively different states; low stimuli leads to no or very little response. Intermediate stimuli leads to reoccurring waves of high cytokine concentration. Finally, high stimuli leads to a sustained high cytokine concentration, a scenario which is toxic for the tissue cells and corresponds to chronic inflammation. Due to the few variables of the simple model, we are able to perform a phase-space analysis leading to a detailed understanding of the functional form of the model and its limitations. The spatial effects of the model contribute to the robustness of the cytokine wave formation and propagation.

  20. Collective cell migration during inflammatory response

    Science.gov (United States)

    Wu, Di; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    Wound scratch healing assays of endothelial cell monolayers is a simple model to study collective cell migration as a function of biological signals. A signal of particular interest is the immune response, which after initial wounding in vivo causes the release of various inflammatory factors such as tumor necrosis alpha (TNF-α). TNF-α is an innate inflammatory cytokine that can induce cell growth, cell necrosis, and change cell morphology. We studied the effects of TNF-α on collective cell migration using the wound healing assays and measured several migration metrics, such as rate of scratch closure, velocities of leading edge and bulk cells, closure index, and velocity correlation functions between migrating cells. We observed that TNF-α alters all migratory metrics as a function of the size of the scratch and TNF-α content. The changes observed in migration correlate with actin reorganization upon TNF-α exposure.

  1. Inflammatory transcription factors as activation markers and functional readouts in immune-to-brain communication.

    Science.gov (United States)

    Rummel, Christoph

    2016-05-01

    Immune-to-brain communication pathways involve humoral mediators, including cytokines, central modulation by neuronal afferents and immune cell trafficking to the brain. During systemic inflammation these pathways contribute to mediating brain-controlled sickness symptoms including fever. Experimentally, activation of these signaling pathways can be mimicked and studied when injecting animals with pathogen associated molecular patterns (PAMPS). One central component of the brain inflammatory response, which leads, for example, to fever induction, is transcriptional activation of brain cells via cytokines and PAMPS. We and others have studied the spatiotemporal activation and the physiological significance of transcription factors for the induction of inflammation within the brain and the manifestation of fever. Evidence has revealed a role of nuclear factor (NF)κB in the initiation, signal transducer and activator of transcription (STAT)3 in the maintenance and NF-interleukin (IL)6 in the maintenance or even termination of brain-inflammation and fever. Moreover, psychological stressors, such as exposure to a novel environment, leads to increased body core temperature and genomic NF-IL6-activation, suggesting a potential use of NF-IL6-immunohistochemistry as a multimodal brain cell activation marker and a role for NF-IL6 for differential brain activity. In addition, the nutritional status, as reflected by circulating levels of the cytokine-like hormone leptin, influence immune-to-brain communication and age-dependent changes in LPS-induced fever. Overall, transcription factors remain therapeutically important targets for the treatment of brain-inflammation and fever induction during infectious/non-infectious inflammatory and psychological stress. However, the exact physiological role and significance of these transcription factors requires to be further investigated.

  2. Blockade of Glutamine Synthetase Enhances Inflammatory Response in Microglial Cells

    Science.gov (United States)

    Palmieri, Erika M.; Menga, Alessio; Lebrun, Aurore; Hooper, Douglas C.; Butterfield, D. Allan

    2017-01-01

    Abstract Aims: Microglial cells are brain-resident macrophages engaged in surveillance and maintained in a constant state of relative inactivity. However, their involvement in autoimmune diseases indicates that in pathological conditions microglia gain an inflammatory phenotype. The mechanisms underlying this change in the microglial phenotype are still unclear. Since metabolism is an important modulator of immune cell function, we focused our attention on glutamine synthetase (GS), a modulator of the response to lipopolysaccharide (LPS) activation in other cell types, which is expressed by microglia. Results: GS inhibition enhances release of inflammatory mediators of LPS-activated microglia in vitro, leading to perturbation of the redox balance and decreased viability of cocultured neurons. GS inhibition also decreases insulin-mediated glucose uptake in microglia. In vivo, microglia-specific GS ablation enhances expression of inflammatory markers upon LPS treatment. In the spinal cords from experimental autoimmune encephalomyelitis (EAE), GS expression levels and glutamine/glutamate ratios are reduced. Innovation: Recently, metabolism has been highlighted as mediator of immune cell function through the discovery of mechanisms that (behind these metabolic changes) modulate the inflammatory response. The present study shows for the first time a metabolic mechanism mediating microglial response to a proinflammatory stimulus, pointing to GS activity as a master modulator of immune cell function and thus unraveling a potential therapeutic target. Conclusions: Our study highlights a new role of GS in modulating immune response in microglia, providing insights into the pathogenic mechanisms associated with inflammation and new strategies of therapeutic intervention. Antioxid. Redox Signal. 26, 351–363. PMID:27758118

  3. Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway

    Institute of Scientific and Technical Information of China (English)

    Xiaojie Liu; Zhigang Mei; Jingping Qian; Yongbao Zeng; Mingzhi Wang

    2013-01-01

    Puerarin, a major isoflavonoid derived from the Chinese medical herb radix puerariae (Gegen), has been reported to inhibit neuronal apoptosis and play an anti-inflammatory role in focal cerebral ischemia model rats. Recent findings regarding stroke pathophysiology have recognized that an-ti-inflammation is an important target for the treatment of ischemic stroke. The cholinergic an-ti-inflammatory pathway is a highly robust neural-immune mechanism for inflammation control. This study was to investigate whether activating the cholinergic anti-inflammatory pathway can be in-volved in the mechanism of inhibiting the inflammatory response during puerarin-induced cerebral ischemia/reperfusion in rats. Results showed that puerarin pretreatment (intravenous injection) re-duced the ischemic infarct volume, improved neurological deficit after cerebral ischemia/reperfusion and decreased the levels of interleukin-1β, interleukin-6 and tumor necrosis factor-αin brain tissue. Pretreatment with puerarin (intravenous injection) attenuated the inflammatory response in rats, which was accompanied by janus-activated kinase 2 (JAK2) and signal transducers and activators of transcription 3 (STAT3) activation and nuclear factor kappa B (NF-κB) inhibition. These observa-tions were inhibited by the alpha7 nicotinic acetylcholine receptor (α7nAchR) antagonistα-bungarotoxin (α-BGT). In addition, puerarin pretreatment increased the expression of α7nAchR mRNA in ischemic cerebral tissue. These data demonstrate that puerarin pretreatment strongly protects the brain against cerebral ischemia/reperfusion injury and inhibits the inflammatory re-sponse. Our results also indicated that the anti-inflammatory effect of puerarin may partly be me-diated through the activation of the cholinergic anti-inflammatory pathway.

  4. Inhibitory Effect of Progesterone on Inflammatory Factors After Experimental Traumatic Brain Injury

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in young people. Inflammatory cytokines play an important part in the pathophysiology of TBI. Recent studies demonstrate that progesterone significantly reduces cerebral edema and enhances functional recovery from TBI and stroke in several animal models. This study was designed to investigate the inhibitory effect of progesterone on inflammatory response after traumatic brain injury. Methods Progesterone was injected intraperitoneally using rats as a model of traumatic brain injury,and Western blot technique was applied to detect the expression of three inflammation-related factors:nuclear factor kappa B p65 (NFk B p65),glial fibrillary acidic protein (GFAP),and tumor necrosis factor-α (TNF-α). The water content of injured brain was also examined. A neurological severity score was recorded to evaluate the effect of progesterone on neurodeficit recovery. Results NFk B p65,GFAP,and TNF-α were increased in all injured animals. In rats treated with progesterone,the expression level of NFkB p65 and TNF-α were reduced significantly in comparison with vehicle-treated rats. However,progesterone did not alter the expression of GFAP in the injured rats. Progesterone also reduced the water content of injured brain and the lesion volume. In addition,progesterone-treated injured rats showed significant improvements in the Neurological Severity Score test,compared with vehicle-treated ones.Conclusions Progesterone inhibits the inflammatory response after experimental traumatic brain injury and mitigates the severity of brain damage.

  5. Scorpion Venom and the Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Vera L. Petricevich

    2010-01-01

    Full Text Available Scorpion venoms consist of a complex of several toxins that exhibit a wide range of biological properties and actions, as well as chemical compositions, toxicity, and pharmacokinetic and pharmacodynamic characteristics. These venoms are associated with high morbility and mortality, especially among children. Victims of envenoming by a scorpion suffer a variety of pathologies, involving mainly both sympathetic and parasympathetic stimulation as well as central manifestations such as irritability, hyperthermia, vomiting, profuse salivation, tremor, and convulsion. The clinical signs and symptoms observed in humans and experimental animals are related with an excessive systemic host inflammatory response to stings and stings, respectively. Although the pathophysiology of envenomation is complex and not yet fully understood, venom and immune responses are known to trigger the release of inflammatory mediators that are largely mediated by cytokines. In models of severe systemic inflammation produced by injection of high doses of venom or venoms products, the increase in production of proinflammatory cytokines significantly contributes to immunological imbalance, multiple organ dysfunction and death. The cytokines initiate a cascade of events that lead to illness behaviors such as fever, anorexia, and also physiological events in the host such as activation of vasodilatation, hypotension, and increased of vessel permeability.

  6. Neuroendocrine Inflammatory Responses in Overweight/Obese Infants

    Science.gov (United States)

    de Andrade, Camila Alves; Oliveira, Katherine Simone Caires; Tossige-Gomes, Rosalina; Rocha-Vieira, Etel; Neves, Camila Danielle Cunha; Vieira, Érica Leandro Marciano; Leite, Hércules Ribeiro; Oliveira, Murilo Xavier; Júnior, Antônio Lúcio Teixeira; Coimbra, Cândido Celso

    2016-01-01

    Childhood obesity is related to a cascade of neuroendocrine inflammatory changes. However, there remains a gap in the current literature regarding the possible occurrence of these changes in overweight/obese infants. The objective of this study was to evaluate adipokines, cortisol, brain-derived neurotrophic factor (BDNF) and redox status in overweight/obese infants versus normal-weight peers. A cross-sectional study was conducted with 50 infants (25 in the overweight/obese group and 25 in the normal-weight group) between 6 and 24 months. Plasma levels of leptin, adiponectin, resistin, soluble tumor necrosis factor (TNF) receptors, chemokines, BDNF, serum cortisol and redox status were measured. Unpaired Student's t-test was used to analyze the results and a probability of p<0.05 was acceptable for rejection of the null hypothesis. The Pearson correlation was used to verify the association between the biomarkers analyzed in each group. Plasma levels of leptin (p = 0.0001), adiponectin (p = 0.0007) and BDNF (p = 0.003), and serum cortisol (p = 0.048) were significantly higher in overweight/obese infants than normal-weight infants. In contrast, the concentration of thiobarbituric acid reactive substances (TBARS) (p = 0.004), and catalase (p = 0.045) and superoxide dismutase activity (p = 0.02) were lower in overweight/obese infants than normal-weight peers. All the results together indicate neuroendocrine inflammatory response changes in overweight/obese infants between 6 and 24 months. Although there is already an environment that predisposes for a subsequent pro-inflammatory response, neuroendocrine secretion changes that permit the control of the inflammatory process in this age interval can be observed. PMID:27907172

  7. Using optogenetics to translate the "inflammatory dialogue" between heart and brain in the context of stress

    Institute of Scientific and Technical Information of China (English)

    Jinbo Cheng; Jie Zhang; Caiyi Lu; Liping Wang

    2012-01-01

    Inflammatory processes are an integral part of the stress response and are likely to result from a programmed adaptation that is vital to the organism's survival and well-being.The whole inflammatory response is mediated by largely overlapping circuits in the limbic forebrain,hypothalamus and brainstem,but is also under the control of the neuroendocrine and autonomic nervous systems.Genetically predisposed individuals who fail to tune the respective contributions of the two systems in accordance with stressor modality and intensity after adverse experiences can be at risk for stress-related psychiatric disorders and cardiovascular diseases.Altered glucocorticoid (GC) homeostasis due to GC resistance leads to the failure of neural and negative feedback regulation of the hypothalamic-pituitary-adrenal axis during chronic inflammation,and this might be the mechanism underlying the ensuing brain and heart diseases and the high prevalence of co-morbidity between the two systems.By the combined use of light and genetically-encoded lightsensitive proteins,optogenetics allows cell-type-specific,fast (millisecond-scale) control of precisely defined events in biological systems.This method is an important breakthrough to explore the causality between neural activity patterns and behavioral profiles relevant to anxiety,depression,autism and schizophrenia.Optogenetics also helps to understand the "inflammatory dialogue",the inflammatory processes in psychiatric disorders and cardiovascular diseases,shared by heart and brain in the context of stress.

  8. Transport induced inflammatory responses in horses.

    Science.gov (United States)

    Wessely-Szponder, J; Bełkot, Z; Bobowiec, R; Kosior-Korzecka, U; Wójcik, M

    2015-01-01

    Deleterious response to road transport is an important problem in equine practice. It determines different physiological, immunological and metabolic changes which lead to increased susceptibility to several disorders such as pneumonia, diarrhea, colics, laminitis, injuries and rhabdomyolisis. The aim of our study was to look for possible relationships between transportation of female young and older horses over a long and short distance and an inflammatory state reflected by an increase of acute phase protein concentration, oxidative stress and muscle injury. The study was conducted on 24 cold-blooded female horses divided into four groups. Six fillies aged 6-18 months and six mares aged 10-12 years were transported over the distance of about 550 km, six fillies aged 6-18 months and six mares aged 10-12 years were transported over the distance of about 50 km. Plasma and serum were obtained from blood samples taken before transportation (T0), immediately after transportation (T1) and at an abattoir during slaughter (T2). In these samples fibrinogen, MDA, AST and CK were assessed. Fibrinogen increased in all studied groups especially in fillies after long distance transportation, where it reached 205±7.07 mg/dl before transportation, 625±35.35 mg/dl after transportation, and 790±14.14 mg/dl during slaughter. MDA concentrations rose after transportation and reached the maximal level during slaughter. CK activity was more elevated after short transportation in younger horses, whereas initial activity of AST was higher in older horses. We estimated that intensified responses from acute phase, oxidative stress and muscle injury parameters indicated an inflammatory state.

  9. Divergent responses of inflammatory mediators within the amygdala and medial prefrontal cortex to acute psychological stress.

    Science.gov (United States)

    Vecchiarelli, Haley A; Gandhi, Chaitanya P; Gray, J Megan; Morena, Maria; Hassan, Kowther I; Hill, Matthew N

    2016-01-01

    There is now a growing body of literature that indicates that stress can initiate inflammatory processes, both in the periphery and brain; however, the spatiotemporal nature of this response is not well characterized. The aim of this study was to examine the effects of an acute psychological stress on changes in mRNA and protein levels of a wide range of inflammatory mediators across a broad temporal range, in key corticolimbic brain regions involved in the regulation of the stress response (amygdala, hippocampus, hypothalamus, medial prefrontal cortex). mRNA levels of inflammatory mediators were analyzed immediately following 30min or 120min of acute restraint stress and protein levels were examined 0h through 24h post-termination of 120min of acute restraint stress using both multiplex and ELISA methods. Our data demonstrate, for the first time, that exposure to acute psychological stress results in an increase in the protein level of several inflammatory mediators in the amygdala while concomitantly producing a decrease in the protein level of multiple inflammatory mediators within the medial prefrontal cortex. This pattern of changes seemed largely restricted to the amygdala and medial prefrontal cortex, with stress producing few changes in the mRNA or protein levels of inflammatory mediators within the hippocampus or hypothalamus. Consistent with previous research, stress resulted in a general elevation in multiple inflammatory mediators within the circulation. These data indicate that neuroinflammatory responses to stress do not appear to be generalized across brain structures and exhibit a high degree of spatiotemporal specificity. Given the impact of inflammatory signaling on neural excitability and emotional behavior, these data may provide a platform with which to explore the importance of inflammatory signaling within the prefrontocortical-amygdala circuit in the regulation of the neurobehavioral responses to stress.

  10. [Therapeutic responsiveness in chronic inflammatory demyelinating polyradiculoneuropathy].

    Science.gov (United States)

    Iijima, Masahiro

    2011-11-01

    CIDP is autoimmune-associated peripheral neuropathy characterized by motor and sensory disturbances in each limb. While various phenotypes have been reported in CIDP, the essential pathogenesis is not elucidated yet. Clinicopathological study indicated axonal dysfunction (muscle atrophy and decreased compound muscular action potentials) is one of the most important factors in IVIg Non-responders. Furthermore, single nucleotide polymorphism (SNP) haplotype/diplotype analysis within a linkage disequilibrium block indicates transient axonal glycoprotein 1 (TAG-1), which controls proper distribution of potassium channels in juxtaparanode, is an important factor for IVIg responsiveness. Gene expression analysis of biopsied nerves supported the hypothesis that CIDP pathogenesis is involved in humoral and cellular immune system. With respect to IVIg responsiveness, expression profiles indicate whole CIDP patients need conventional immune-modulating therapies in somewhat, while we should re-consider how to use them. From aspects of gene expression results, Non-responders need not only conventional immune-modulating therapies but also other original modalities which could intervene the pathogenesis except Schwann/inflammatory cells while Responders with IVIg dependence should need stronger and longer immune-suppression.

  11. Incidence of systemic inflammatory response syndrome after endovascular aortic repair

    DEFF Research Database (Denmark)

    De La Motte, L; Vogt, K; Jensen, Leif Panduro;

    2011-01-01

    The aim of this study was to estimate the incidence of the post-implantation syndrome/systemic inflammatory response syndrome (SIRS) after endovascular aortic repair.......The aim of this study was to estimate the incidence of the post-implantation syndrome/systemic inflammatory response syndrome (SIRS) after endovascular aortic repair....

  12. The influence of biomaterials on inflammatory responses to cardiopulmonary bypass.

    Science.gov (United States)

    Courtney, J M; Matata, B M; Yin, H Q; Esposito, A; Mahiout, A; Taggart, D P; Lowe, G D

    1996-05-01

    The nature of cardiopulmonary bypass and the complexity of the inflammatory response make the detection and interpretation of a biomaterial influence difficult. However, if mediation of the inflammatory response is considered to be an appropriate clinical goal, alteration to the biomaterial influence merits further investigation.

  13. Lipocalin-2 protects the brain during inflammatory conditions.

    Science.gov (United States)

    Kang, S S; Ren, Y; Liu, C-C; Kurti, A; Baker, K E; Bu, G; Asmann, Y; Fryer, J D

    2017-01-10

    Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2(-/-) mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in wild-type (WT) mice injected with LPS, Lcn2(-/-) mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared with WT mice injected with LPS, Lcn2(-/-) mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, nucleotide-binding oligomerization domain-like receptor signaling and Janus kinase-signal transducer and activator of transcription signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae.Molecular Psychiatry advance online publication, 10 January 2017; doi:10.1038/mp.2016.243.

  14. Action of Antiproteases on the Inflammatory Response in Acute Pancreatitis

    Directory of Open Access Journals (Sweden)

    Chun-Chia Chen

    2007-07-01

    Full Text Available The spectrum of acute pancreatitis ranges from mild edematous disease to a severe necrotizing process which is usually accompanied by local or systemic complications and even mortality. Early deaths (within the first week due to severe acute pancreatitis are generally caused by massive inflammatory responses which result in multiple organ failure. Although the exact mechanisms which trigger the inflammatory and necrotizing processes are not completely understood, it is generally accepted that autodigestion and activated leukocytes play important roles in the pathogenesis of acute pancreatitis. Proinflammatory cytokines are associated with systemic inflammatory response syndrome and multiple organ failure syndrome in acute pancreatitis. A compensatory anti-inflammatory response occurs in parallel with systemic inflammatory response syndrome. Trypsin secreted by the pancreatic acinar cells activates proteaseactivated receptor-2 which can result in the production of cytokines. Protease inhibitors such as aprotinin, gabexate mesilate, nafamostat mesilate, ulinastatin, etc. can inhibit the various enzymes and inflammatory response in experimental and clinical studies. Thus, protease inhibitors have been considered as a potential treatment to inhibit the pancreatic inflammation in acute pancreatitis. The beneficial effects of antiproteases on experimental severe acute pancreatitis may be, in part, due to the modulation of inflammatory cytokine responses. The effect of protease inhibitors on the inflammatory response in human acute pancreatitis deserves further study.

  15. Multiplex analyte assays to characterize different dementias: brain inflammatory cytokines in poststroke and other dementias.

    Science.gov (United States)

    Chen, Aiqing; Oakley, Arthur E; Monteiro, Maria; Tuomela, Katri; Allan, Louise M; Mukaetova-Ladinska, Elizabeta B; O'Brien, John T; Kalaria, Raj N

    2016-02-01

    possible specific involvement of immunosenescence in dementia pathogenesis. In contrast, CRP was not altered between dementia and nondementia subjects or between PSD and PSND. Our study provides evidence not only for the feasibility of tracking cytokines in postmortem brain tissue but also suggests differentially impaired inflammatory mechanisms underlying dementia including AD. There was a diminished inflammatory response, possibly reflecting immunosenescence and cerebral atrophy, in all dementias. Strategies to enhance anti-inflammatory cytokines and boost the immune system of the brain may be beneficial for preventing cognitive dysfunction, especially after stroke.

  16. Virus Infections on Prion Diseased Mice Exacerbate Inflammatory Microglial Response

    Science.gov (United States)

    Lins, Nara; Mourão, Luiz; Trévia, Nonata; Passos, Aline; Farias, José Augusto; Assunção, Jarila; Bento-Torres, João; Consentino Kronka Sosthenes, Marcia; Diniz, José Antonio Picanço; Vasconcelos, Pedro Fernando da Costa

    2016-01-01

    We investigated possible interaction between an arbovirus infection and the ME7 induced mice prion disease. C57BL/6, females, 6-week-old, were submitted to a bilateral intrahippocampal injection of ME7 prion strain (ME7) or normal brain homogenate (NBH). After injections, animals were organized into two groups: NBH (n = 26) and ME7 (n = 29). At 15th week after injections (wpi), animals were challenged intranasally with a suspension of Piry arbovirus 0.001% or with NBH. Behavioral changes in ME7 animals appeared in burrowing activity at 14 wpi. Hyperactivity on open field test, errors on rod bridge, and time reduction in inverted screen were detected at 15th, 19th, and 20th wpi respectively. Burrowing was more sensitive to earlier hippocampus dysfunction. However, Piry-infection did not significantly affect the already ongoing burrowing decline in the ME7-treated mice. After behavioral tests, brains were processed for IBA1, protease-resistant form of PrP, and Piry virus antigens. Although virus infection in isolation did not change the number of microglia in CA1, virus infection in prion diseased mice (at 17th wpi) induced changes in number and morphology of microglia in a laminar-dependent way. We suggest that virus infection exacerbates microglial inflammatory response to a greater degree in prion-infected mice, and this is not necessarily correlated with hippocampal-dependent behavioral deficits. PMID:28003864

  17. Functional Roles of Syk in Macrophage-Mediated Inflammatory Responses

    Directory of Open Access Journals (Sweden)

    Young-Su Yi

    2014-01-01

    Full Text Available Inflammation is a series of complex biological responses to protect the host from pathogen invasion. Chronic inflammation is considered a major cause of diseases, such as various types of inflammatory/autoimmune diseases and cancers. Spleen tyrosine kinase (Syk was initially found to be highly expressed in hematopoietic cells and has been known to play crucial roles in adaptive immune responses. However, recent studies have reported that Syk is also involved in other biological functions, especially in innate immune responses. Although Syk has been extensively studied in adaptive immune responses, numerous studies have recently presented evidence that Syk has critical functions in macrophage-mediated inflammatory responses and is closely related to innate immune response. This review describes the characteristics of Syk-mediated signaling pathways, summarizes the recent findings supporting the crucial roles of Syk in macrophage-mediated inflammatory responses and diseases, and discusses Syk-targeted drug development for the therapy of inflammatory diseases.

  18. Pronounced inflammatory response to endotoxaemia during nighttime

    DEFF Research Database (Denmark)

    Alamili, Mahdi; Bendtzen, Klaus; Lykkesfeldt, Jens

    2014-01-01

    endotoxaemia model. DESIGN AND METHODS: A cross-over study, where 12 healthy young men received E. coli endotoxin (lipopolysaccharide, LPS) 0.3 ng/kg at 12 noon and, on another day, at 12 midnight. Blood samples were analysed for pro- and anti-inflammatory cytokines: tumour-necrosis factor (TNF)-alpha, soluble...

  19. Systemic inflammatory responses following welding inhalation challenge test

    Directory of Open Access Journals (Sweden)

    Paula Kauppi

    2015-01-01

    Conclusions: Exposure to MS and SS welding fume resulted in a mild systemic inflammatory response. The particle concentration from the breathing zones correlated with the measurements inside the welding face shields.

  20. Platelets as Central Mediators of Systemic Inflammatory Responses

    OpenAIRE

    Smith, Tammy L; Weyrich, Andrew S.

    2010-01-01

    Systemic inflammatory responses are associated with high morbidity and mortality and represent a diverse and clinically challenging group of diseases. Platelets are increasingly linked to inflammation, in addition to their well-known roles in hemostasis and thrombosis. There is agreement that traditional functions of platelets, including adherence, aggregation, and secretion of preformed mediators, contribute to systemic inflammatory responses. However, emerging evidence indicates that platel...

  1. Macrophage Expression of Inflammatory Genes in Response to EMCV Infection

    Directory of Open Access Journals (Sweden)

    Zachary R. Shaheen

    2015-08-01

    Full Text Available The expression and production of type 1 interferon is the classic cellular response to virus infection. In addition to this antiviral response, virus infection also stimulates the production of proinflammatory mediators. In this review, the pathways controlling the induction of inflammatory genes and the roles that these inflammatory mediators contribute to host defense against viral pathogens will be discussed. Specific focus will be on the role of the chemokine receptor CCR5, as a signaling receptor controlling the activation of pathways leading to virus-induced inflammatory gene expression.

  2. The Role of Cytokines and Inflammatory Cells in Perinatal Brain Injury

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    Ryan M. McAdams

    2012-01-01

    Full Text Available Perinatal brain injury frequently complicates preterm birth and leads to significant long-term morbidity. Cytokines and inflammatory cells are mediators in the common pathways associated with perinatal brain injury induced by a variety of insults, such as hypoxic-ischemic injury, reperfusion injury, toxin-mediated injury, and infection. This paper examines our current knowledge regarding cytokine-related perinatal brain injury and specifically discusses strategies for attenuating cytokine-mediated brain damage.

  3. Pro-inflammatory cytokine regulation of P-glycoprotein in the developing blood-brain barrier.

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    Majid Iqbal

    Full Text Available Placental P-glycoprotein (P-gp acts to protect the developing fetus from exogenous compounds. This protection declines with advancing gestation leaving the fetus and fetal brain vulnerable to these compounds and potential teratogens in maternal circulation. This vulnerability may be more pronounced in pregnancies complicated by infection, which is common during pregnancy. Pro-inflammatory cytokines (released during infection have been shown to be potent inhibitors of P-gp, but nothing is known regarding their effects at the developing blood-brain barrier (BBB. We hypothesized that P-gp function and expression in endothelial cells of the developing BBB will be inhibited by pro-inflammatory cytokines. We have derived brain endothelial cell (BEC cultures from various stages of development of the guinea pig: gestational day (GD 50, 65 (term ~68 days and postnatal day (PND 14. Once these cultures reached confluence, BECs were treated with various doses (10(0-10(4 pg/mL of pro-inflammatory cytokines: interleukin-1β (IL-1β, interleukin-6 (IL-6 or tumor necrosis factor- α (TNF-α. P-gp function or abcb1 mRNA (encodes P-gp expression was assessed following treatment. Incubation of GD50 BECs with IL-1β, IL-6 or TNF-α resulted in no change in P-gp function. GD65 BECs displayed a dose-dependent decrease in function with all cytokines tested; maximal effects at 42%, 65% and 34% with IL-1β, IL-6 and TNF-α treatment, respectively (P<0.01. Inhibition of P-gp function by IL-1β, IL-6 and TNF-α was even greater in PND14 BECs; maximal effects at 36% (P<0.01, 84% (P<0.05 and 55% (P<0.01, respectively. Cytokine-induced reductions in P-gp function were associated with decreased abcb1 mRNA expression. These data suggest that BBB P-gp function is increasingly responsive to the inhibitory effects of pro-inflammatory cytokines, with increasing developmental age. Thus, women who experience infection and take prescription medication during pregnancy may expose the

  4. Inflammatory responses to Hydroxyapatite implants in middle ear in rats

    Institute of Scientific and Technical Information of China (English)

    YE Qing; JIANG Yi; WANG Xiao-yan; ZHENG Ke-fei

    2008-01-01

    Objective To study local inflammatory response after implantation of hydroxyapatite synthetic ossicular prosthesis. Methods Hydroxyapatite gantries were implanted in the bulla in 32 rats. Sham surgical procedures were performed in 10 rats as the control. Animals were sacrificed at 1 to 300 days after surgery. Bulla sections, stained with HE and Mallory's azan, were examined for numbers and percentages of various inflammatory cell types. Results Slightly more inflammatory reaction was seen in animals with the implant than in the controls, mostly during the early stage following the implantation procedure. Few inflammatory cells were observed at later times. There were satisfactory fibrosis in both implanted and control ears. Conclusion The results indicate that hydroxyapatite synthetic prosthesis is a biocompatible implantation material in the middle ear. Nonetheless, the presence of inflammatory reaction immediately following implantation implies that control of infection is important in the early times after the implantation procedure.

  5. Messengers without borders: mediators of systemic inflammatory response in AKI.

    Science.gov (United States)

    Ratliff, Brian B; Rabadi, May M; Vasko, Radovan; Yasuda, Kaoru; Goligorsky, Michael S

    2013-03-01

    The list of signals sent by an injured organ to systemic circulation, so-called danger signals, is growing to include multiple metabolites and secreted moieties, thus revealing a highly complex and integrated network of interlinked systemic proinflammatory and proregenerative messages. Emerging new data indicate that, apart from the well established local inflammatory response to AKI, danger signaling unleashes a cascade of precisely timed, interdependent, and intensity-gradated mediators responsible for development of the systemic inflammatory response. This fledgling realization of the importance of the systemic inflammatory response to the localized injury and inflammation is at the core of this brief overview. It has a potential to explain the additive effects of concomitant diseases or preexisting chronic conditions that can prime the systemic inflammatory response and exacerbate it out of proportion to the actual degree of acute kidney damage. Although therapies for ameliorating AKI per se remain limited, a potentially powerful strategy that could reap significant benefits in the future is to modulate the intensity of danger signals and consequently the systemic inflammatory response, while preserving its intrinsic proregenerative stimuli.

  6. Intranasal pyrrolidine dithiocarbamate decreases brain inflammatory mediators and provides neuroprotection after brain hypoxia-ischemia in neonatal rats.

    Science.gov (United States)

    Wang, Zhi; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2013-11-01

    Brain injury due to birth asphyxia is the major cause of death and long-term disabilities in newborns. We determined whether intranasal pyrrolidine dithiocarbamate (PDTC) could provide neuroprotection in neonatal rats after brain hypoxia-ischemia (HI). Seven-day old male and female Sprague-Dawley rats were subjected to brain HI. They were then treated with intranasal PDTC. Neurological outcomes were evaluated 7 or 30 days after the brain HI. Brain tissues were harvested 6 or 24 h after the brain HI for biochemical analysis. Here, PDTC dose-dependently reduced brain HI-induced brain tissue loss with an effective dose (ED)50 at 27 mg/kg. PDTC needed to be applied within 45 min after the brain HI for this neuroprotection. This treatment reduced brain tissue loss and improved neurological and cognitive functions assessed 30 days after the HI. PDTC attenuated brain HI-induced lipid oxidative stress, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells, and various inflammatory mediators in the brain tissues. Inhibition of inducible nitric oxide synthase after brain HI reduced brain tissue loss. Our results suggest that intranasal PDTC provides neuroprotection possibly via reducing inflammation and oxidative stress. Intranasal PDTC may have a potential to provide neuroprotection to human neonates after birth asphyxia.

  7. Translation Control: A Multifaceted Regulator of Inflammatory Response

    Science.gov (United States)

    Mazumder, Barsanjit; Li, Xiaoxia; Barik, Sailen

    2010-01-01

    A robust innate immune response is essential to the protection of all vertebrates from infection, but it often comes with the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue damage, resulting in myriad disorders, such as dermatitis, toxicshock, cardiovascular disease, acute pelvic and arthritic inflammatory diseases, and various infections. To prevent such pathologies, cells have evolved mechanisms to rapidly and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the most dominant and common mechanism is translational silencing, in which specific regulatory proteins or complexes are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the inflammatory protein(s). Enhancement of the silencing function may constitute a novel pharmacological approach to prevent immunity-related inflammation. PMID:20304832

  8. Amniotic fluid protein profiles of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria.

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    Marian Kacerovsky

    Full Text Available OBJECTIVE: This study aimed to evaluate the amniotic fluid protein profiles and the intensity of intraamniotic inflammatory response to Ureaplasma spp. and other bacteria, using the multiplex xMAP technology. METHODS: A retrospective cohort study was undertaken in the Department of Obstetrics and Gynecology, University Hospital Hradec Kralove, Czech Republic. A total of 145 pregnant women with preterm prelabor rupture of membranes between gestational age 24+0 and 36+6 weeks were included in the study. Amniocenteses were performed. The presence of Ureaplasma spp. and other bacteria was evaluated using 16S rRNA gene sequencing. The levels of specific proteins were determined using multiplex xMAP technology. RESULTS: The presence of Ureaplasma spp. and other bacteria in the amniotic fluid was associated with increased levels of interleukin (IL-6, IL-8, IL-10, brain-derived neurotropic factor, granulocyte macrophage colony stimulating factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and matrix metalloproteinasis-9. Ureaplasma spp. were also associated with increased levels of neurotropin-3 and triggering receptor expressed on myeloid cells-1. CONCLUSIONS: The presence of Ureaplasma spp. in the amniotic fluid is associated with a slightly different protein profile of inflammatory response, but the intensity of inflammatory response to Ureaplasma spp. is comparable with the inflammatory response to other bacteria.

  9. Law, Responsibility, and the Brain

    Science.gov (United States)

    Mobbs, Dean; Lau, Hakwan C.; Jones, Owen D.; Frith, Chris D.

    In perhaps the first attempt to link the brain to mental illness, Hippocrates elegantly wrote that it is the brain that makes us mad or delirious. Epitomizing one of the fundamental assumptions of contemporary neuroscience, Hippocrates' words resonate far beyond the classic philosophical puzzle of mind and body and posit that our behavior, no matter how monstrous, lies at the mercy of our brain's integrity. While clinicopathological observations have long pointed to several putative neurobiological systems as important in antisocial and violent criminal behavior, recent advances in brain-imaging have the potential to provide unparalleled insight. Consequently, brain-imaging studies have reinvigorated the neurophilosophical and legal debate of whether we are free agents in control of our own actions or mere prisoners of a biologically determined brain. In this chapter, we review studies pointing to brain dysfunction in criminally violent individuals and address a range of philosophical and practical issues concerning the use of brainimaging in court. We finally lay out several guidelines for its use in the legal system.

  10. Short and Long-Term Analysis and Comparison of Neurodegeneration and Inflammatory Cell Response in the Ipsilateral and Contralateral Hemisphere of the Neonatal Mouse Brain after Hypoxia/Ischemia

    Directory of Open Access Journals (Sweden)

    Kalpana Shrivastava

    2012-01-01

    Full Text Available Understanding the evolution of neonatal hypoxic/ischemic is essential for novel neuroprotective approaches. We describe the neuropathology and glial/inflammatory response, from 3 hours to 100 days, after carotid occlusion and hypoxia (8% O2, 55 minutes to the C57/BL6 P7 mouse. Massive tissue injury and atrophy in the ipsilateral (IL hippocampus, corpus callosum, and caudate-putamen are consistently shown. Astrogliosis peaks at 14 days, but glial scar is still evident at day 100. Microgliosis peaks at 3–7 days and decreases by day 14. Both glial responses start at 3 hours in the corpus callosum and hippocampal fissure, to progressively cover the degenerating CA field. Neutrophils increase in the ventricles and hippocampal vasculature, showing also parenchymal extravasation at 7 days. Remarkably, delayed milder atrophy is also seen in the contralateral (CL hippocampus and corpus callosum, areas showing astrogliosis and microgliosis during the first 72 hours. This detailed and long-term cellular response characterization of the ipsilateral and contralateral hemisphere after H/I may help in the design of better therapeutic strategies.

  11. Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

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    Zilka Norbert

    2012-03-01

    Full Text Available Abstract Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease.

  12. Hydrodynamic regulation of monocyte inflammatory response to an intracellular pathogen.

    Directory of Open Access Journals (Sweden)

    Shankar J Evani

    Full Text Available Systemic bacterial infections elicit inflammatory response that promotes acute or chronic complications such as sepsis, arthritis or atherosclerosis. Of interest, cells in circulation experience hydrodynamic shear forces, which have been shown to be a potent regulator of cellular function in the vasculature and play an important role in maintaining tissue homeostasis. In this study, we have examined the effect of shear forces due to blood flow in modulating the inflammatory response of cells to infection. Using an in vitro model, we analyzed the effects of physiological levels of shear stress on the inflammatory response of monocytes infected with chlamydia, an intracellular pathogen which causes bronchitis and is implicated in the development of atherosclerosis. We found that chlamydial infection alters the morphology of monocytes and trigger the release of pro-inflammatory cytokines TNF-α, IL-8, IL-1β and IL-6. We also found that the exposure of chlamydia-infected monocytes to short durations of arterial shear stress significantly enhances the secretion of cytokines in a time-dependent manner and the expression of surface adhesion molecule ICAM-1. As a functional consequence, infection and shear stress increased monocyte adhesion to endothelial cells under flow and in the activation and aggregation of platelets. Overall, our study demonstrates that shear stress enhances the inflammatory response of monocytes to infection, suggesting that mechanical forces may contribute to disease pathophysiology. These results provide a novel perspective on our understanding of systemic infection and inflammation.

  13. Pathophysiology of the systemic inflammatory response after major accidental trauma

    DEFF Research Database (Denmark)

    Brøchner, Anne Craveiro; Toft, Palle

    2009-01-01

    ABSTRACT: BACKGROUND: Purpose of the present study was to describe the pathophysiology of the systemic inflammatory response after major trauma and the timing of final reconstructive surgery. Methods: An unsystematic review of the medical literature was performed and articles pertaining to the in......ABSTRACT: BACKGROUND: Purpose of the present study was to describe the pathophysiology of the systemic inflammatory response after major trauma and the timing of final reconstructive surgery. Methods: An unsystematic review of the medical literature was performed and articles pertaining...... to the inflammatory response to trauma were obtained. The literature selected was based on the preference and clinical expertise of authors. Discussion: The inflammatory response consists of hormonal metabolic and immunological components and the extent correlates with the magnitude of the tissue injury. After trauma...... and uncomplicated surgery a delicate balance between pro- and anti-inflammatory mediators is observed.Trauma patients are, however, often exposed, not only to the trauma, but to several evens in the form of initial surgery and later final reconstructive surgery. In this case immune paralysis associated...

  14. Saturated fatty acids trigger TLR4-mediated inflammatory response.

    Science.gov (United States)

    Rocha, D M; Caldas, A P; Oliveira, L L; Bressan, J; Hermsdorff, H H

    2016-01-01

    Toll-like receptors (TLR) mediate infection-induced inflammation and sterile inflammation by endogenous molecules. Among the TLR family, TLR4 is the best understood. However, while its downstream signaling pathways have been well defined, not all ligands of TLR4 are currently known. Current evidence suggests that saturated fatty acids (SFA) act as non-microbial TLR4 agonists, and trigger its inflammatory response. Thus, our present review provides a new perspective on the potential mechanism by which SFAs could modulate TLR4-induced inflammatory responses: (1) SFAs can be recognized by CD14-TLR4-MD2 complex and trigger inflammatory pathways, similar to lipopolysaccharide (LPS). (2) SFAs lead to modification of gut microbiota with an overproduction of LPS after a high-fat intake, enhancing this natural TLR4 ligand. (3) In addition, this metabolic endotoxemia leads to an oxidative stress thereby producing atherogenic lipids - oxLDL and oxidized phospholipids - which trigger CD36-TLR4-TLR6 inflammatory response. (4) Also, the high SFA consumption increases the lipemia and the mmLDL and oxLDL formation through oxidative modifications of LDL. The mmLDL, unlike oxLDL, is involved in activation of the CD14-TLR4-MD2 inflammatory pathway. Those molecules can induce TLR4 inflammatory response by MyD88-dependent and/or MyD88-independent pathways that, in turn, promotes the expression of proinflammatory transcript factors such as factor nuclear kappa B (NF-κB), which plays a crucial role in the induction of inflammatory mediators (cytokines, chemokines, or costimulatory molecules) implicated in the development and progression of many chronic diseases.

  15. Pinoresinol from the fruits of Forsythia koreana inhibits inflammatory responses in LPS-activated microglia.

    Science.gov (United States)

    Jung, Hyo Won; Mahesh, Ramalingam; Lee, Jong Gu; Lee, Seung Ho; Kim, Young Shik; Park, Yong-Ki

    2010-08-23

    The activation of microglia plays an important role in a variety of brain disorders by the excessive production of inflammatory mediators such as nitric oxide (NO), prostaglandin E(2) (PGE(2)) and proinflammatory cytokines. We investigated here whether pinoresinol isolated from the fruits of Forsythia koreana Nakai inhibits the inflammatory responses in LPS-activated microglia. Pinoresinol inhibited the production of NO, PGE(2), TNF-alpha, IL-1beta and IL-6 in LPS-activated primary microglia. Also, pinoresinol attenuated mRNA and protein levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and proinflammatory cytokines in LPS-activation. However, most of these inhibitory effects of pinoresinol have been mediated by extracellular-signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) phosphorylation and the NF-kappaB dependent. The results suggest that pinoresinol attenuates inflammatory responses of microglia and could be potentially useful in modulation of inflammatory status in brain disorders.

  16. Genomic responses in mouse models poorly mimic human inflammatory diseases

    Science.gov (United States)

    Seok, Junhee; Warren, H. Shaw; Cuenca, Alex G.; Mindrinos, Michael N.; Baker, Henry V.; Xu, Weihong; Richards, Daniel R.; McDonald-Smith, Grace P.; Gao, Hong; Hennessy, Laura; Finnerty, Celeste C.; López, Cecilia M.; Honari, Shari; Moore, Ernest E.; Minei, Joseph P.; Cuschieri, Joseph; Bankey, Paul E.; Johnson, Jeffrey L.; Sperry, Jason; Nathens, Avery B.; Billiar, Timothy R.; West, Michael A.; Jeschke, Marc G.; Klein, Matthew B.; Gamelli, Richard L.; Gibran, Nicole S.; Brownstein, Bernard H.; Miller-Graziano, Carol; Calvano, Steve E.; Mason, Philip H.; Cobb, J. Perren; Rahme, Laurence G.; Lowry, Stephen F.; Maier, Ronald V.; Moldawer, Lyle L.; Herndon, David N.; Davis, Ronald W.; Xiao, Wenzhong; Tompkins, Ronald G.; Abouhamze, Amer; Balis, Ulysses G. J.; Camp, David G.; De, Asit K.; Harbrecht, Brian G.; Hayden, Douglas L.; Kaushal, Amit; O’Keefe, Grant E.; Kotz, Kenneth T.; Qian, Weijun; Schoenfeld, David A.; Shapiro, Michael B.; Silver, Geoffrey M.; Smith, Richard D.; Storey, John D.; Tibshirani, Robert; Toner, Mehmet; Wilhelmy, Julie; Wispelwey, Bram; Wong, Wing H

    2013-01-01

    A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. PMID:23401516

  17. Incidence of systemic inflammatory response syndrome after endovascular aortic repair

    DEFF Research Database (Denmark)

    De La Motte, L; Vogt, K; Jensen, Leif Panduro;

    2011-01-01

    AIM: The aim of this study was to estimate the incidence of the post-implantation syndrome/systemic inflammatory response syndrome (SIRS) after endovascular aortic repair. METHODS: All patients, undergoing elective primary endovascular repair of an asymptomatic infrarenal abdominal aortic aneurysm...

  18. The Pathogenesis of ACLF: The Inflammatory Response and Immune Function.

    Science.gov (United States)

    Moreau, Richard

    2016-05-01

    Although systemic inflammation is a hallmark of acute-on-chronic liver failure (ACLF), its role in the development of this syndrome is poorly understood. Here the author first summarizes the general principles of the inflammatory response. Inflammation can be triggered by exogenous or endogenous inducers. Important exogenous inducers include bacterial products such as pathogen-associated molecular patterns (PAMPs) and virulence factors. Pathogen-associated molecular patterns elicit inflammation through structural feature recognition (using innate pattern-recognition receptors [PRRs]), whereas virulence factors generally trigger inflammation via functional feature recognition. Endogenous inducers are called danger-associated molecular patterns (DAMPs) and include molecules released by necrotic cells and products of extracellular matrix breakdown. Danger-associated molecular patterns use different PRRs. The purpose of the inflammatory response may differ according to the type of stimulus: The aim of infection-induced inflammation is to decrease pathogen burden, whereas the DAMP-induced inflammation aims to promote tissue repair. An excessive inflammatory response can induce collateral tissue damage (a process called immunopathology). However immunopathology may not be the only mechanism of tissue damage; for example, organ failure can develop because of failed disease tolerance. In this review, the author also discusses how general principles of the inflammatory response can help us to understand the development of ACLF in different contexts: bacterial infection, severe alcoholic hepatitis, and cases in which there is no identifiable trigger.

  19. COMPARTMENTALIZATION OF THE INFLAMMATORY RESPONSE TO INHALED GRAIN DUST

    Science.gov (United States)

    Interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and the secreted form of the IL-1 receptor antagonist (sIL-1RA) are involved in the inflammatory response to inhaled grain dust. Previously, we found considerable production of these cytokines in the lower...

  20. Radiation-induced inflammatory markers of brain injury are modulated by PPARdelta activation in vitro and in vivo

    Science.gov (United States)

    Schnegg, Caroline Isabel

    As a result of improvements in cancer therapy and health care, the population of long-term cancer survivors is growing. For these approximately 12 million long-term cancer survivors, brain metastases are a significant risk. Fractionated partial or whole-brain irradiation (fWBI) is often required to treat both primary and metastatic brain cancer. Radiation-induced normal tissue injury, including progressive cognitive impairment, however, can significantly affect the well-being of the approximately 200,000 patients who receive these treatments each year. Recent reports indicate that radiation-induced brain injury is associated with chronic inflammatory and oxidative stress responses, as well as increased microglial activation in the brain. Anti-inflammatory drugs may, therefore, be a beneficial therapy to mitigate radiation-induced brain injury. We hypothesized that activation of peroxisomal proliferator activated receptor delta (PPARō) would prevent or ameliorate radiation-induced brain injury, including cognitive impairment, in part, by alleviating inflammatory responses in microglia. For our in vitro studies, we hypothesized that PPARō activation would prevent the radiation-induced inflammatory response in microglia following irradiation. Incubating BV-2 murine microglial cells with the (PPAR)ō agonist, L-165041, prevented the radiation-induced increase in: i) intracellular ROS generation, ii) Cox-2 and MCP-1 expression, and iii) IL-1β and TNF-α message levels. This occured, in part, through PPARō-mediated modulation of stress activated kinases and proinflammatory transcription factors. PPARō inhibited NF-κB via transrepression by physically interacting with the p65 subunit, and prevented activation of the PKCα/MEK1/2/ERK1/2/AP-1 pathway by inhibiting the radiation-induced increase in intracellular ROS generation. These data support the hypothesis that PPARō activation can modulate the radiation-induced oxidative stress and inflammatory responses in

  1. Colchicine-responsive protracted gouty arthritis with systemic inflammatory reactions.

    Science.gov (United States)

    Nonaka, Fumiaki; Migita, Kiyoshi; Haramura, Tomoko; Sumiyoshi, Remi; Kawakami, Atsushi; Eguchi, Katsumi

    2014-05-01

    Acute gouty arthritis is a severe but self-limiting arthritis caused by inflammatory responses to urate crystals. Oral colchicines are effective for initial stages or prophylaxis, but generally, colchicines are ineffective for established gouty arthritis. We describe an unusual case of gouty arthritis with systemic inflammatory reactions, including high fever and polymyalgia. Refractory polyarthritis and high fever were eradicated by colchicine treatment. Genetic analysis revealed a heterozygous mutation in exon 2 of the MEFV gene (E148Q). This case underscores the possibility that MEFV gene mutations may modify the phenotype of gouty arthritis.

  2. Obese mice exhibit an altered behavioural and inflammatory response to lipopolysaccharide

    Directory of Open Access Journals (Sweden)

    Catherine B. Lawrence

    2012-09-01

    Obesity is associated with an increase in the prevalence and severity of infections. Genetic animal models of obesity (ob/ob and db/db mice display altered centrally-mediated sickness behaviour in response to acute inflammatory stimuli such as lipopolysaccharide (LPS. However, the effect of diet-induced obesity (DIO on the anorectic and febrile response to LPS in mice is unknown. This study therefore determined how DIO and ob/ob mice respond to a systemic inflammatory challenge. C57BL/6 DIO and ob/ob mice, and their respective controls, were given an intraperitoneal (i.p. injection of LPS. Compared with controls, DIO and ob/ob mice exhibited an altered febrile response to LPS (100 μg/kg over 8 hours. LPS caused a greater and more prolonged anorexic effect in DIO compared with control mice and, in ob/ob mice, LPS induced a reduction in food intake and body weight earlier than it did in controls. These effects of LPS in obese mice were also seen after a fixed dose of LPS (5 μg. LPS (100 μg/kg induced Fos protein expression in several brain nuclei of control mice, with fewer Fos-positive cells observed in the brains of obese mice. An altered inflammatory response to LPS was also observed in obese mice compared with controls: changes in cytokine expression and release were detected in the plasma, spleen, liver and peritoneal macrophages in obese mice. In summary, DIO and ob/ob mice displayed an altered behavioural response and cytokine release to systemic inflammatory challenge. These findings could help explain why obese humans show increased sensitivity to infections.

  3. Platelets protect lung from injury induced by systemic inflammatory response

    Science.gov (United States)

    Luo, Shuhua; Wang, Yabo; An, Qi; Chen, Hao; Zhao, Junfei; Zhang, Jie; Meng, Wentong; Du, Lei

    2017-01-01

    Systemic inflammatory responses can severely injure lungs, prompting efforts to explore how to attenuate such injury. Here we explored whether platelets can help attenuate lung injury in mice resulting from extracorporeal circulation (ECC)-induced systemic inflammatory responses. Mice were subjected to ECC for 30 min, then treated with phosphate-buffered saline, platelets, the GPIIb/IIIa inhibitor Tirofiban, or the combination of platelets and Tirofiban. Blood and lung tissues were harvested 60 min later, and lung injury and inflammatory status were assessed. As expected, ECC caused systemic inflammation and pulmonary dysfunction, and platelet transfusion resulted in significantly milder lung injury and higher lung function. It also led to greater numbers of circulating platelet-leukocyte aggregates and greater platelet accumulation in the lung. Platelet transfusion was associated with higher production of transforming growth factor-β and as well as lower levels of tumour necrosis factor-α and neutrophil elastase in plasma and lung. None of these platelet effects was observed in the presence of Tirofiban. Our results suggest that, at least under certain conditions, platelets can protect lung from injury induced by systemic inflammatory responses. PMID:28155889

  4. Correlated Inflammatory Responses and Neurodegeneration in Peptide-Injected Animal Models of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    James G. McLarnon

    2014-01-01

    Full Text Available Animal models of Alzheimer’s disease (AD which emphasize activation of microglia may have particular utility in correlating proinflammatory activity with neurodegeneration. This paper reviews injection of amyloid-β (Aβ into rat brain as an alternative AD animal model to the use of transgenic animals. In particular, intrahippocampal injection of Aβ1-42 peptide demonstrates prominent microglial mobilization and activation accompanied by a significant loss of granule cell neurons. Furthermore, pharmacological inhibition of inflammatory reactivity is demonstrated by a broad spectrum of drugs with a common endpoint in conferring neuroprotection in peptide-injected animals. Peptide-injection models provide a focus on glial cell responses to direct peptide injection in rat brain and offer advantages in the study of the mechanisms underlying neuroinflammation in AD brain.

  5. DMPD: Cytokine signaling modules in inflammatory responses. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 18400190 Cytokine signaling modules in inflammatory responses. O'Shea JJ, Murray PJ...tory responses. PubmedID 18400190 Title Cytokine signaling modules in inflammatory responses. Authors O'Shea JJ, Murray

  6. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses

    Science.gov (United States)

    Baixauli, Francesc; Acín-Pérez, Rebeca; Villarroya-Beltrí, Carolina; Mazzeo, Carla; Nuñez-Andrade, Norman; Gabandé-Rodriguez, Enrique; Dolores Ledesma, Maria; Blázquez, Alberto; Martin, Miguel Angel; Falcón-Pérez, Juan Manuel; Redondo, Juan Miguel; Enríquez, Jose Antonio; Mittelbrunn, Maria

    2016-01-01

    Summary The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4+ T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration-deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward pro-inflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD+ levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify novel strategies for intervention in mitochondrial-related diseases. PMID:26299452

  7. Modulation of Hemostatic and Inflammatory Responses by Leptospira Spp.

    Science.gov (United States)

    Vieira, Mônica L.; Naudin, Clément; Mörgelin, Matthias; Romero, Eliete C.; Nascimento, Ana Lucia T. O.; Herwald, Heiko

    2016-01-01

    Leptospirosis is a worldwide spread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. In severe infections, hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. These complications often occur when the host response is controlled and/or modulated by the bacterial pathogen. In the present investigation, we aimed to analyze the modulation of the hemostatic and inflammatory host responses by the bacterial pathogen Leptospira. The effects of leptospires and their secreted products on stimulation of human intrinsic and extrinsic pathways of coagulation were investigated by means of altered clotting times, assembly and activation of contact system and induction of tissue factor. We show that both extrinsic and intrinsic coagulation cascades are modulated in response to Leptospira or leptospiral secreted proteins. We further find that the pro-inflammatory mediator bradykinin is released following contact activation at the bacterial surface and that pro-coagulant microvesicles are shed from monocytes in response to infection. Also, we show that human leptospirosis patients present higher levels of circulating pro-coagulant microvesicles than healthy individuals. Here we show that both pathways of the coagulation system are modulated by leptospires, possibly leading to altered hemostatic and inflammatory responses during the disease. Our results contribute to the understanding of the leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments for the severe manifestations of the disease. PMID:27167223

  8. Innate immune response to pulmonary contusion: Identification of cell-type specific inflammatory responses

    OpenAIRE

    Hoth, J. Jason; Wells, Jonathan D.; Yoza, Barbara K.; McCall, Charles E.

    2012-01-01

    Lung injury from pulmonary contusion is a common traumatic injury, predominantly seen after blunt chest trauma such as in vehicular accidents. The local and systemic inflammatory response to injury includes activation of innate immune receptors, elaboration of a variety inflammatory mediators, and recruitment of inflammatory cells to the injured lung. Using a mouse model of pulmonary contusion, we had previously shown that innate immune Toll like receptors 2 and 4 (TLR2 and TLR4) mediate the ...

  9. Affective and inflammatory responses among orchestra musicians in performance situation.

    Science.gov (United States)

    Pilger, Alexander; Haslacher, Helmuth; Ponocny-Seliger, Elisabeth; Perkmann, Thomas; Böhm, Karl; Budinsky, Alexandra; Girard, Angelika; Klien, Katharina; Jordakieva, Galateja; Pezawas, Lukas; Wagner, Oswald; Godnic-Cvar, Jasminka; Winker, Robert

    2014-03-01

    A number of studies have shown that mental challenge under controlled experimental conditions is associated with elevations in inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). However, relatively little work has been done on the effects of 'naturalistic' stressors on acute changes in inflammatory markers. The present study examined whether perceived arousal, valence and dominance in musicians are associated with pro-inflammatory and oxidative responses to a concert situation. Blood and salivary samples obtained from 48 members of a symphony orchestra on the day of rehearsal (i.e., control situation) and on the following day of premiere concert (i.e., test situation) were used to determine changes in salivary cortisol, pro-inflammatory markers (plasma myeloperoxidase, serum CRP, plasma IL-6), oxidative stress markers (paraoxonase1 activity and malondialdehyde), and homocysteine, a risk factor for vascular disease. Results of regression analyses showed a significant trend to increased myeloperoxidase (MPO) response in individuals with low valence score. Both affective states, valence and arousal, were identified as significant predictors of cortisol response during concert. In addition, control levels of plasma malondialdehyde were positively correlated with differences in IL-6 levels between premiere and rehearsal (r=.38, p=.012), pointing to higher oxidative stress in individuals with pronounced IL-6 response. Our results indicate that stress of public performance leads to increased concentrations of plasma MPO (20%), IL-6 (27%) and salivary cortisol (44%) in musicians. The decreasing effect of pleasantness on the MPO response was highly pronounced in non-smokers (r=-.60, p<.001), suggesting a significant role of emotional valence in stress-induced secretion of MPO. Additional studies are needed to assess the generalizability of these findings to other 'naturalistic' stress situations.

  10. The inflammatory response to vaccination is altered in the elderly.

    Science.gov (United States)

    El Yousfi, Mimoun; Mercier, Sabine; Breuillé, Denis; Denis, Philippe; Papet, Isabelle; Mirand, Philippe Patureau; Obled, Christiane

    2005-08-01

    To further explore whether immune function and acute phase response are altered during ageing, the response to a mild inflammatory stress (DT-Polio-Typhim vaccination) was studied in elderly and young subjects. Cytokine production (IFN-gamma, TNF-alpha, IL-6, IL-10) by whole blood cultures, circulating cytokines and acute phase proteins were analysed before and 2 days after vaccination. Prior to vaccination, only IFN-gamma production was lower in the elderly than in the young subjects due to a lower mononuclear cell number. In the same time, although in the normal range, several acute phase proteins were greater in elderly than in young subjects, suggesting a low-grade inflammatory state in the elderly. After vaccination, IFN-gamma production remained lower in the elderly than in the young, supporting an altered cell-mediated immunity with advancing age. TNF-alpha production was unaffected by either ageing or vaccination. IL-6 production was stimulated by vaccination in young subjects but not significantly in the elderly. IL-10 production was inhibited by vaccination in the elderly but not in the young. Acute phase proteins were less increased in elderly than in young subjects. Taken together, these results support a general lack of inflammatory response in the elderly exposed to an immune challenge and suggest that immune deficiency may concern both Th1 and Th2 responses. However, the interpretation must respect the limitation of small subjects number.

  11. Application of magnetic resonance spectroscopy in the differentiation of high-grade brain neoplasm and inflammatory brain lesions

    Energy Technology Data Exchange (ETDEWEB)

    Ferraz-Filho, Jose Roberto Lopes; Santana-Netto, Pedro Vieira; Sgnolf, Aline [FAMERP Medical School, Sao Jose do Rio Preto SP (Brazil). Image Dept.], e-mail: jrl.ferraz@terra.com.br; Rocha-Filho, Jose Alves; Mauad, Fernando [FAMERP Medical School, Sao Jose do Rio Preto SP (Brazil). Radiology Dept.; Sanches, Rafael Angelo [FAMERP Medical School, Sao Jose do Rio Preto SP (Brazil). Imaging Dept.

    2009-06-15

    This study aims at evaluating the application of magnetic resonance spectroscopy (MRS) in the differential diagnosis of brain tumors and inflammatory brain lesions. The examinations of 81 individuals, who performed brain MRS and were retrospectively analyzed. The patients with ages between 10 and 80 years old, were divided into two groups. Group A consisted of 42 individuals with diagnoses of cerebral toxoplasmosis and Group B was formed of 39 individuals with diagnosis of glial neoplasms. On analyzing the ROC curve, the discriminatory boundary for the Cho/Cr ratio between inflammatory lesions and tumors was 1.97 and for the NAA/Cr ratio it was 1.12. RMS is an important method useful in the distinction of inflammatory brain lesions and high-degree tumors when the Cho/Cr ratio is greater than 1.97 and the NAA/Cr ratio is less than 1.12. And so this method is important in the planning of treatment and monitoring of the therapeutic efficiency. (author)

  12. Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia.

    Science.gov (United States)

    Bozic, Iva; Savic, Danijela; Laketa, Danijela; Bjelobaba, Ivana; Milenkovic, Ivan; Pekovic, Sanja; Nedeljkovic, Nadezda; Lavrnja, Irena

    2015-01-01

    Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha α (TNF-α), interleukin-6 (IL-6), whereas it increased anti-inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the nucleus. Therefore, benfotiamine may

  13. The role of tissue factor in systemic inflammatory response syndrome.

    Science.gov (United States)

    Egorina, Elena M; Sovershaev, Mikhail A; Hansen, John-Bjarne

    2011-09-01

    Tissue factor (TF) is a major initiator of extrinsic pathway of blood coagulation. A dual role of TF in the extensive crosstalk between blood coagulation and inflammation has recently become apparent. The majority of the cases of systemic inflammatory response syndrome, disseminated intravascular coagulation, and sepsis are accompanied by hyperactivation of TF in circulating monocytes and damaged tissue. Systemic Gram-negative infection induces expression of TF by vascular cells. In addition to extrinsic coagulation pathway, TF induces proinflammatory signaling cascade originating from activation of protease-activated receptors. Because TF-activated proteolytic cascade is placed in a nexus between coagulation and inflammation, early modulation of TF activity presently becomes a tempting experimental therapeutic strategy in systemic inflammatory response syndrome patients.

  14. Inflammatory Responses to Salmonella Infections Are Serotype-Specific

    Directory of Open Access Journals (Sweden)

    Zhanna Ktsoyan

    2013-01-01

    Full Text Available The main purpose of this study was to investigate the profile of inflammatory response in patients with acute salmonellosis caused by two serotypes of Salmonella enterica, S. Enteritidis and S. Typhimurium, as well as in convalescent patients with previous acute disease caused by S. Enteritidis. Patients with acute disease showed significantly elevated levels of IL-1β, IL-17, IL-10, and calprotectin compared to healthy control subjects. In convalescent patients, these markers were also significantly elevated, with the exception of IL-1β. Multivariate statistical analyses with the use of these variables produced models with a good predictive accuracy resulting in excellent separation of the diseased and healthy cohorts studied. Overall, the results suggest that the profile of inflammatory response in this disease is determined, to a significant degree, by the serotype of Salmonella, and the profile of certain cytokines and calprotectin remains abnormal for a number of months following the acute disease stage.

  15. Inflammatory and Bone Remodeling Responses to the Cytolethal Distending Toxins

    OpenAIRE

    2014-01-01

    The cytolethal distending toxins (CDTs) are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs can also perturb the innate immune responses, by regulating inflammatory cytokine production and molecular mediators of bone remodeling in various cell types. These cellular and molecular events may in turn have an...

  16. Inflammatory and bone remodeling responses to the cytolethal distending toxins

    OpenAIRE

    2014-01-01

    The cytolethal distending toxins (CDTs) are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs can also perturb the innate immune responses, by regulating inflammatory cytokine production and molecular mediators of bone remodeling in various cell types. These cellular and molecular events may in turn have an e...

  17. Comorbidity between depression and inflammatory bowel disease explained by immune-inflammatory, oxidative, and nitrosative stress; tryptophan catabolite; and gut-brain pathways.

    Science.gov (United States)

    Martin-Subero, Marta; Anderson, George; Kanchanatawan, Buranee; Berk, Michael; Maes, Michael

    2016-04-01

    The nature of depression has recently been reconceptualized, being conceived as the clinical expression of activated immune-inflammatory, oxidative, and nitrosative stress (IO&NS) pathways, including tryptophan catabolite (TRYCAT), autoimmune, and gut-brain pathways. IO&NS pathways are similarly integral to the pathogenesis of inflammatory bowel disease (IBD). The increased depression prevalence in IBD associates with a lower quality of life and increased morbidity in IBD, highlighting the role of depression in modulating the pathophysiology of IBD.This review covers data within such a wider conceptualization that better explains the heightened co-occurrence of IBD and depression. Common IO&NS underpinning between both disorders is evidenced by increased pro-inflammatory cytokine levels, eg, interleukin-1 (IL-1) and tumor necrosis factor-α, IL-6 trans-signalling; Th-1- and Th-17-like responses; neopterin and soluble IL-2 receptor levels; positive acute phase reactants (haptoglobin and C-reactive protein); lowered levels of negative acute phase reactants (albumin, transferrin, zinc) and anti-inflammatory cytokines (IL-10 and transforming growth factor-β); increased O&NS with damage to lipids, proteinsm and DNA; increased production of nitric oxide (NO) and inducible NO synthase; lowered plasma tryptophan but increased TRYCAT levels; autoimmune responses; and increased bacterial translocation. As such, heightened IO&NS processes in depression overlap with the biological underpinnings of IBD, potentially explaining their increased co-occurrence. This supports the perspective that there is a spectrum of IO&NS disorders that includes depression, both as an emergent comorbidity and as a contributor to IO&NS processes. Such a frame of reference has treatment implications for IBD when "comorbid" with depression.

  18. How stem cells speak with host immune cells in inflammatory brain diseases.

    Science.gov (United States)

    Pluchino, Stefano; Cossetti, Chiara

    2013-09-01

    Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.

  19. Fetal cholinergic anti-inflammatory pathway and necrotizing enterocolitis: the brain-gut connection begins in utero

    Directory of Open Access Journals (Sweden)

    Luca eGarzoni

    2013-08-01

    Full Text Available Necrotizing enterocolitis (NEC is an acute neonatal inflammatory disease that affects the intestine and may result in necrosis, systemic sepsis and multisystem organ failure. NEC affects 5-10% of all infants with birth weight ≤ 1500 g or gestational age less than 30 weeks. Chorioamnionitis (CA is the main manifestation of pathological inflammation in the fetus and is strongly associated with NEC. CA affects 20% of full-term pregnancies and up to 60% of preterm pregnancies and, notably, is often an occult finding. Intrauterine exposure to inflammatory stimuli may switch innate immunity cells such as macrophages to a reactive phenotype (‘priming’. Confronted with renewed inflammatory stimuli during labour or postnatally, such sensitized cells can sustain a chronic or exaggerated production of proinflammatory cytokines associated with NEC (two-hit hypothesis. Via the cholinergic anti-inflammatory pathway, a neurally mediated innate anti-inflammatory mechanism, higher levels of vagal activity are associated with lower systemic levels of proinflammatory cytokines. This effect is mediated by the α7 subunit nicotinic acetylcholine receptor (α7nAChR on macrophages. The gut is the most extensive organ innervated by the vagus nerve; it is also the primary site of innate immunity in the newborn. Here we review the mechanisms of possible neuroimmunological brain-gut interactions involved in the induction and control of antenatal intestinal inflammatory response and priming. We propose a neuroimmunological framework to 1 study the long-term effects of perinatal intestinal response to infection and 2 to uncover new targets for preventive and therapeutic intervention.

  20. Systemic inflammatory responses during laparoscopic and open inguinal hernia repair: a randomised prospective study

    DEFF Research Database (Denmark)

    Jess, P; Schultz, Karen; Bendtzen, K;

    2000-01-01

    To see if the inflammatory responses during and after laparoscopic and open inguinal hernia repairs differed.......To see if the inflammatory responses during and after laparoscopic and open inguinal hernia repairs differed....

  1. Inflammatory Biomarkers as Differential Predictors of Antidepressant Response

    Directory of Open Access Journals (Sweden)

    Kenji Hashimoto

    2015-04-01

    Full Text Available Although antidepressants are generally effective in the treatment of major depressive disorder (MDD, it can still take weeks before patients feel the full antidepressant effects. Despite the efficacy of standard treatments, approximately two-thirds of patients with MDD fail to respond to pharmacotherapy. Therefore, the identification of blood biomarkers that can predict the treatment response to antidepressants would be highly useful in order to improve this situation. This article discusses inflammatory molecules as predictive biomarkers for antidepressant responses to several classes of antidepressants, including the N-methyl-d-aspartate (NMDA receptor antagonist ketamine.

  2. The relationship between inflammatory activity and brain atrophy in natalizumab treated patients

    Energy Technology Data Exchange (ETDEWEB)

    Magraner, M., E-mail: majomagbe@ono.com [Multiple Sclerosis Unit, Neurology Service, Hospital Universitari i Politecnic La Fe, Bulevar Sur s/n, 46026 Valencia (Spain); Coret, F., E-mail: coret_fra@gva.es [Multiple Sclerosis Unit, Neurology Service, Hospital Clinic de Valencia, Avda Blasco Ibanez 17, 46010 Valencia (Spain); Casanova, B., E-mail: Casanova_bon@gva.es [Multiple Sclerosis Unit, Neurology Service, Hospital Universitari i Politecnic La Fe, Bulevar Sur s/n, 46026 Valencia (Spain)

    2012-11-15

    Objective: To assess the evolution of brain atrophy and its relationship with inflammatory activity in RRMS patients treated with natalizumab. Methods: Eighteen RRMS patients were prospectively followed up for 18 months after starting natalizumab therapy. Patients were monitored monthly and assessed for signs of relapses, adverse events or disability increase. MRI scans were performed before starting natalizumab and every six months. Cross-sectional T2 lesion volume (T2LV) and the normalized brain volume (NBV) at baseline and 18 months MRI scans were calculated using the Steronauta{sup Registered-Sign} and SIENAx softwares, respectively. Longitudinal Percentage of Brain Volume Change (PBVC) was estimated with SIENA. Linkage between inflammatory activity and brain atrophy was studied. Results: Natalizumab reduced ARR by 67% and cumulative CEL by 87.5%. T2 lesion volume decreased from 1000 mm{sup 3}, to 960 mm{sup 3} (p = 0.006) and NBV decreased from 1.55 Multiplication-Sign 10{sup 5} mm{sup 3} to 1.42 Multiplication-Sign 10{sup 5} mm{sup 3} (p = 0.025). Global PBVC from baseline to 18 months was -2.5%, predominantly during the first six months (0-6 months PBVC -1.7%; 6-12 months PBVC -0.74%; 12-18 months PBVC -0.50%). The number of relapses before treatment was correlated to the PBVC during the first semester (Pearson's coefficient -0.520, p = 0.003), while the number of basal CEL or baseline T2LV did not correlate with brain atrophy rate. During follow-up, nine patients had clinical or radiological inflammatory activity. Their PBVC was significantly higher in the first semester (-2.3% to -1.1%, p = 0.002). Conclusions: Natalizumab reduced relapse rate and CEL in MRI. Brain atrophy predominated in the first semester and was related to previous inflammatory activity.

  3. The Inflammatory Response in Psoriasis: a Comprehensive Review.

    Science.gov (United States)

    Deng, Yaxiong; Chang, Christopher; Lu, Qianjin

    2016-06-01

    Psoriasis is a chronic inflammatory autoimmune disease characterized by an excessively aberrant hyperproliferation of keratinocytes. The pathogenesis of psoriasis is complex and the exact mechanism remains elusive. However, psoriasis is thought to result from a combination of genetic, epigenetic, and environmental influences. Recent studies have identified that epigenetic factors including dysregulated DNA methylation levels, abnormal histone modification and microRNAs expressions are involved in the development of psoriasis. The interplay of immune cells and cytokines is another critical factor in the pathogenesis of psoriasis. These factors or pathways include Th1/Th2 homeostasis, the Th17/Treg balance and the IL-23/Th17 axis. Th17 is believed particularly important in psoriasis due to its pro-inflammatory effects and its involvement in an integrated inflammatory loop with dendritic cells and keratinocytes, contributing to an overproduction of antimicrobial peptides, inflammatory cytokines, and chemokines that leads to amplification of the immune response. In addition, other pathways and signaling molecules have been found to be involved, including Th9, Th22, regulatory T cells, γδ T cells, CD8(+) T cells, and their related cytokines. Understanding the pathogenesis of psoriasis will allow us to develop increasingly efficient targeted treatment by blocking relevant inflammatory signaling pathways and molecules. There is no cure for psoriasis at the present time, and much of the treatment involves managing the symptoms. The biologics, while lacking the adverse effects associated with some of the traditional medications such as corticosteroids and methotrexate, have their own set of side effects, which may include reactivation of latent infections. Significant challenges remain in developing safe and efficacious novel targeted therapies that depend on a better understanding of the immunological dysfunction in psoriasis.

  4. Inflammatory response to strenuous muscular exercise in man

    Directory of Open Access Journals (Sweden)

    G. Camus

    1993-01-01

    Full Text Available Based on the humoral and cellular changes occurring during strenuous muscular work in humans, the concept of inflammatory response to exercise (IRE is developed. The main indices of IRE consist of signs of an acute phase response, leucocytosis and leucocyte activation, release of inflammatory mediators, tissue damage and cellular infiltrates, production of free radicals, activation of complement, and coagulation and fibrinolytic pathways. Depending on exercise intensity and duration, it seems likely that muscle and/or associated connective tissue damage, contact system activation due to shear stress on endothelium and endotoxaemia could be the triggering mechanisms of IRE. Although this phenomenon can be considered in most cases as a physiological process associated with tissue repair, exaggerated IRE could have physiopathological consequences. On the other hand, the influence of several factors such as age, sex, training, hormonal status, nutrition, anti-inflammatory drugs, and the extent to which IRE could be a potential risk for subjects undergoing intense physical training require further study.

  5. Berberine inhibits inflammatory activation of rat brain microglia

    Institute of Scientific and Technical Information of China (English)

    Kyong Nyon Nam; Jae-Hong Kim; Hoon-Ji Jung; Jung-Mi Park; Sang-Kwan Moon; Young-Suk Kim; Sun Yeou Kim; Eunjoo H.Lee

    2010-01-01

    Chronic activation of microglial cells endangers neuronal survival through the release of various proinflammatory and neurotoxic factors.Berberine,the effective ingredient of Coptidis Rhizoma and Cortex Phellodendri,has a wide range of pharmacological functions,including anti-inflammatory,anti-atherosclerotic and anti-cancer effects.The neuroprotective potential of berberine has previously been demonstrated.The present study aimed to examine whether berberine could repress microglial activation and can be considered a potential therapeutic candidate to target neurodegenerative diseases.Primary microglial cells and BV2 microglial cells were cultured and stimulated with bacterial lipopolysaccharide(LPS).Berberine chloride was treated prior to LPS or simultaneously with LPS stimulation.Results revealed that berberine was effective at inhibiting nitric oxide release from primary microglial cells when cells were exposed to the compound prior to LPS or simultaneously with LPS.It also reduced the LPS-stimulated production of tumor necrosis factor-α,interleukin-1β,prostaglandin E2,and intracellular reactive oxygen species and nuclear factor-kappa activation.Additionally,berberine reduced nitric oxide release from microglia stimulated with interferon-γ and amyloid β.These results suggest that berberine provides neuroprotection by reducing the production of various neurotoxic molecules from activated microglia.

  6. Regional neuroplastic brain changes in patients with chronic inflammatory and non-inflammatory visceral pain.

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    Jui-Yang Hong

    Full Text Available Regional cortical thickness alterations have been reported in many chronic inflammatory and painful conditions, including inflammatory bowel diseases (IBD and irritable bowel syndrome (IBS, even though the mechanisms underlying such neuroplastic changes remain poorly understood. In order to better understand the mechanisms contributing to grey matter changes, the current study sought to identify the differences in regional alterations in cortical thickness between healthy controls and two chronic visceral pain syndromes, with and without chronic gut inflammation. 41 healthy controls, 11 IBS subjects with diarrhea, and 16 subjects with ulcerative colitis (UC underwent high-resolution T1-weighted magnetization-prepared rapid acquisition gradient echo scans. Structural image preprocessing and cortical thickness analysis within the region of interests were performed by using the Laboratory of Neuroimaging Pipeline. Group differences were determined using the general linear model and linear contrast analysis. The two disease groups differed significantly in several cortical regions. UC subjects showed greater cortical thickness in anterior cingulate cortical subregions, and in primary somatosensory cortex compared with both IBS and healthy subjects. Compared with healthy subjects, UC subjects showed lower cortical thickness in orbitofrontal cortex and in mid and posterior insula, while IBS subjects showed lower cortical thickness in the anterior insula. Large effects of correlations between symptom duration and thickness in the orbitofrontal cortex and postcentral gyrus were only observed in UC subjects. The findings suggest that the mechanisms underlying the observed gray matter changes in UC subjects represent a consequence of peripheral inflammation, while in IBS subjects central mechanisms may play a primary role.

  7. Targeting the inflammatory response in healing myocardial infarcts.

    Science.gov (United States)

    Frangogiannis, Nikolaos G

    2006-01-01

    Healing of myocardial infarcts depends on an inflammatory cascade that ultimately results in clearance of dead cells and matrix debris and formation of a scar. Myocardial necrosis activates complement, Nuclear Factor (NF)-kappaB and Toll-like Receptor (TLR)-dependent pathways, and generates free radicals, triggering an inflammatory response. Chemokines and cytokines are markedly induced in the infarct and mediate recruitment and activation of neutrophils and mononuclear cells. Extravasation of platelets and plasma proteins, such as fibrinogen and fibronectin, results in formation of a clot, consisting of platelets embedded in a mesh of crosslinked fibrin. This provisional matrix provides a scaffold for migration of cells into the infarct. Monocytes differentiate into macrophages and secrete fibrogenic and angiogenic growth factors inducing formation of granulation tissue, containing myofibroblasts and neovessels. Repression of proinflammatory cytokine and chemokine synthesis, mediated in part through Transforming Growth Factor (TGF)-beta and Interleukin (IL)-10, is critical for resolution of the inflammatory infiltrate and transition to fibrous tissue deposition. Infarct myofibroblasts deposit extracellular matrix proteins and a collagen-based scar is formed. As the wound matures, fibroblasts undergo apoptosis and neovessels regress, resulting in formation of a scar with a low cellular content containing dense, cross-linked collagen. The pathologic and structural changes associated with infarct healing directly influence ventricular remodeling and affect prognosis in patients with myocardial infarction. Understanding the mechanisms involved in the regulation of the post-infarction inflammatory response, and the spatial and temporal parameters of wound healing is necessary in order to identify specific molecular targets for therapeutic intervention.

  8. Latent viral immune inflammatory response model for chronic multisymptom illness.

    Science.gov (United States)

    Maloney, Sean R; Jensen, Susan; Gil-Rivas, Virginia; Goolkasian, Paula

    2013-03-01

    A latent viral immune inflammatory response (LVIIR) model is presented which integrates factors that contribute to chronic multisymptom illness (CMI) in both the veteran and civilian populations. The LVIIR model for CMI results from an integration of clinical experience with a review of the literature in four distinct areas: (1) studies of idiopathic multisymptom illness in the veteran population including two decades of research on Gulf War I veterans with CMI, (2) new evidence supporting the existence of chronic inflammatory responses to latent viral antigens and the effect these responses may have on the nervous system, (3) recent discoveries concerning the role of vitamin D in maintaining normal innate and adaptive immunity including suppression of latent viruses and regulation of the immune inflammatory response, and (4) the detrimental effects of extreme chronic repetitive stress (ECRS) on the immune and nervous systems. The LVIIR model describes the pathophysiology of a pathway to CMI and presents a new direction for the clinical assessment of CMI that includes the use of neurological signs from a physical exam, objective laboratory data, and a new proposed latent viral antigen-antibody imaging technique for the peripheral and central nervous system. The LVIIR model predicts that CMI can be treated by a focus on reversal of immune system impairment, suppression of latent viruses and their antigens, and healing of nervous system tissue damaged by chronic inflammation associated with latent viral antigens and by ECRS. In addition, the LVIIR model suggests that maintaining optimal serum 25 OH vitamin D levels will maximize immune system suppression of latent viruses and their antigens and will minimize immune system inflammation. This model also emphasizes the importance of decreasing ECRS to improve immune system function and to minimize nervous system injury from excess serum glucocorticoid levels. The proposed model supports growing evidence that increasing

  9. Differential effects of exercise intensities in hippocampal BDNF, inflammatory cytokines and cell proliferation in rats during the postnatal brain development.

    Science.gov (United States)

    de Almeida, Alexandre Aparecido; Gomes da Silva, Sérgio; Fernandes, Jansen; Peixinho-Pena, Luiz Fernando; Scorza, Fulvio Alexandre; Cavalheiro, Esper Abrão; Arida, Ricardo Mario

    2013-10-11

    It has been established that low intensities of exercise produce beneficial effects for the brain, while high intensities can cause some neuronal damage (e.g. exacerbated inflammatory response and cell death). Although these effects are documented in the mature brain, the influence of exercise intensities in the developing brain has been poorly explored. To investigate the impact of exercise intensity in developing rats, we evaluated the hippocampal level of brain derived neurotrophic factor (BDNF), inflammatory cytokines (TNFα, IL6 and IL10) and the occurrence of hippocampal cell degeneration and proliferation at different stages of postnatal brain development of rats submitted to two physical exercise intensities. To this point, male rats were divided into different age groups: P21, P31, P41 and P51. Each age group was submitted to two exercise intensities (low and high) on a treadmill over 10 consecutive days, except the control rats. We verified that the density of proliferating cells was significantly higher in the dentate gyrus of rats submitted to low-intensity exercise from P21 to P30 compared with high-intensity exercise and control rats. A significant increase of proliferative cell density was found in rats submitted to high-intensity exercise from P31 to P40 when compared to low-intensity exercise and control rats. Elevated hippocampal levels of IL6 were detected in rats submitted to high-intensity exercise from P21 to P30 compared to control rats. From P41 to P50 period, higher levels of BDNF, TNFα and IL10 were found in the hippocampal formation of rats submitted to high-intensity exercise in relation to their control rats. Our data show that exercise-induced neuroplastic effects on BDNF levels and cellular proliferation in the hippocampal region are dependent on exercise intensity and developmental period. Thus, exercise intensity is an inflammation-inducing factor and exercise-induced inflammatory response during the postnatal brain development is

  10. Hemorrhagic shock shifts the serum cytokine profile from pro- to anti-inflammatory after experimental traumatic brain injury in mice.

    Science.gov (United States)

    Shein, Steven L; Shellington, David K; Exo, Jennifer L; Jackson, Travis C; Wisniewski, Stephen R; Jackson, Edwin K; Vagni, Vincent A; Bayır, Hülya; Clark, Robert S B; Dixon, C Edward; Janesko-Feldman, Keri L; Kochanek, Patrick M

    2014-08-15

    Secondary insults, such as hemorrhagic shock (HS), worsen outcome from traumatic brain injury (TBI). Both TBI and HS modulate levels of inflammatory mediators. We evaluated the addition of HS on the inflammatory response to TBI. Adult male C57BL6J mice were randomized into five groups (n=4 [naïve] or 8/group): naïve; sham; TBI (through mild-to-moderate controlled cortical impact [CCI] at 5 m/sec, 1-mm depth), HS; and CCI+HS. All non-naïve mice underwent identical monitoring and anesthesia. HS and CCI+HS underwent a 35-min period of pressure-controlled hemorrhage (target mean arterial pressure, 25-27 mm Hg) and a 90-min resuscitation with lactated Ringer's injection and autologous blood transfusion. Mice were sacrificed at 2 or 24 h after injury. Levels of 13 cytokines, six chemokines, and three growth factors were measured in serum and in five brain tissue regions. Serum levels of several proinflammatory mediators (eotaxin, interferon-inducible protein 10 [IP-10], keratinocyte chemoattractant [KC], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1alpha [MIP-1α], interleukin [IL]-5, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor [G-CSF]) were increased after CCI alone. Serum levels of fewer proinflammatory mediators (IL-5, IL-6, regulated upon activation, normal T-cell expressed, and secreted, and G-CSF) were increased after CCI+HS. Serum level of anti-inflammatory IL-10 was significantly increased after CCI+HS versus CCI alone. Brain tissue levels of eotaxin, IP-10, KC, MCP-1, MIP-1α, IL-6, and G-CSF were increased after both CCI and CCI+HS. There were no significant differences between levels after CCI alone and CCI+HS in any mediator. Addition of HS to experimental TBI led to a shift toward an anti-inflammatory serum profile--specifically, a marked increase in IL-10 levels. The brain cytokine and chemokine profile after TBI was minimally affected by the addition of HS.

  11. RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression.

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    Adam Labadorf

    Full Text Available Huntington's Disease (HD is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480 of the 28,087 confidently detected genes are differentially expressed (FDR<0.05 and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes, that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD.

  12. Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia.

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    Iva Bozic

    Full Text Available Microglial cells are resident immune cells of the central nervous system (CNS, recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS and NO; cyclooxygenase-2 (COX-2, heat-shock protein 70 (Hsp70, tumor necrosis factor alpha α (TNF-α, interleukin-6 (IL-6, whereas it increased anti-inflammatory interleukin-10 (IL-10 production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2, c-Jun N-terminal kinases (JNK and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB in the nucleus. Therefore

  13. Non inflammatory boronate based glucose-responsive insulin delivery systems.

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    Indrani Dasgupta

    Full Text Available Boronic acids, known to bind diols, were screened to identify non-inflammatory cross-linkers for the preparation of glucose sensitive and insulin releasing agglomerates of liposomes (Agglomerated Vesicle Technology-AVT. This was done in order to select a suitable replacement for the previously used cross-linker, ConcanavalinA (ConA, a lectin known to have both toxic and inflammatory effects in vivo. Lead-compounds were selected from screens that involved testing for inflammatory potential, cytotoxicity and glucose-binding. These were then conjugated to insulin-encapsulating nanoparticles and agglomerated via sugar-boronate ester linkages to form AVTs. In vitro, the particles demonstrated triggered release of insulin upon exposure to physiologically relevant concentrations of glucose (10 mmoles/L-40 mmoles/L. The agglomerates were also shown to be responsive to multiple spikes in glucose levels over several hours, releasing insulin at a rate defined by the concentration of the glucose trigger.

  14. The Transcriptome of the Fetal Inflammatory Response Syndrome

    Science.gov (United States)

    Madsen-Bouterse, Sally A.; Romero, Roberto; Tarca, Adi L.; Kusanovic, Juan Pedro.; Espinoza, Jimmy; Kim, Chong Jai; Kim, Jung-Sun; Edwin, Samuel S.; Gomez, Ricardo; Draghici, Sorin

    2012-01-01

    Problem The fetal inflammatory response syndrome (FIRS) is considered the counterpart of the systemic inflammatory response syndrome (SIRS), but similarities in their regulatory mechanisms are unclear. This study characterizes the fetal mRNA transcriptome of peripheral leukocytes to identify key biological processes and pathways involved in FIRS. Method of Study Umbilical cord blood from preterm neonates with FIRS (funisitis, plasma IL-6>11 pg/ml; n=10) and neonates with no evidence of inflammation (n=10) was collected at birth. Results Microarray analysis of leukocyte RNA revealed differential expression of 541 unique genes, changes confirmed by qRT-PCR for 41 or of 44 genes tested. Similar to SIRS and sepsis, ontological and pathway analyses yielded significant enrichment of biological processes including antigen processing and presentation, immune response, and processes critical to cellular metabolism. Results are comparable with microarray studies of endotoxin challenge models and pediatric sepsis, identifying 25 genes across all studies. Conclusions This study is the first to profile genome-wide expression in FIRS, which demonstrates a substantial degree of similarity with SIRS despite differences in fetal and adult immune systems. PMID:20059468

  15. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication

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    Gefei Wang

    2016-01-01

    Full Text Available Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i. but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy.

  16. Endotoxin-induced monocytic microparticles have contrasting effects on endothelial inflammatory responses.

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    Beryl Wen

    Full Text Available Septic shock is a severe disease state characterised by the body's life threatening response to infection. Complex interactions between endothelial cells and circulating monocytes are responsible for microvasculature dysfunction contributing to the pathogenesis of this syndrome. Here, we intended to determine whether microparticles derived from activated monocytes contribute towards inflammatory processes and notably vascular permeability. We found that endotoxin stimulation of human monocytes enhances the release of microparticles of varying phenotypes and mRNA contents. Elevated numbers of LPS-induced monocytic microparticles (mMP expressed CD54 and contained higher levels of transcripts for pro-inflammatory cytokines such as TNF, IL-6 and IL-8. Using a prothrombin time assay, a greater reduction in plasma coagulation time was observed with LPS-induced mMP than with non-stimulated mMP. Co-incubation of mMP with the human brain endothelial cell line hCMEC/D3 triggered their time-dependent uptake and significantly enhanced endothelial microparticle release. Unexpectedly, mMP also modified signalling pathways by diminishing pSrc (tyr416 expression and promoted endothelial monolayer tightness, as demonstrated by endothelial impedance and permeability assays. Altogether, these data strongly suggest that LPS-induced mMP have contrasting effects on the intercellular communication network and display a dual potential: enhanced pro-inflammatory and procoagulant properties, together with protective function of the endothelium.

  17. Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide

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    Santos-Galindo María

    2011-07-01

    Full Text Available Abstract Background Numerous neurological and psychiatric disorders show sex differences in incidence, age of onset, symptomatology or outcome. Astrocytes, one of the glial cell types of the brain, show sex differences in number, differentiation and function. Since astrocytes are involved in the response of neural tissue to injury and inflammation, these cells may participate in the generation of sex differences in the response of the brain to pathological insults. To explore this hypothesis, we have examined whether male and female astrocytes show a different response to an inflammatory challenge and whether perinatal testosterone influences this response. Methods Cortical astrocyte cultures were prepared from postnatal day 1 (one day after birth male or female CD1 mice pups. In addition, cortical astrocyte cultures were also prepared from female pups that were injected at birth with 100 μg of testosterone propionate or vehicle. Cultures were treated for 5 hours with medium containing lipopolysaccharide (LPS or with control medium. The mRNA levels of IL6, interferon-inducible protein 10 (IP10, TNFα, IL1β, Toll-like receptor 4 (TLR4, steroidogenic acute regulatory protein and translocator protein were assessed by quantitative real-time polymerase chain reaction. Statistical significance was assessed by unpaired t-test or by one-way analysis of variance followed by the Tukey post hoc test. Results The mRNA levels of IL6, TNFα and IL1β after LPS treatment were significantly higher in astrocytes derived from male or androgenized females compared to astrocytes derived from control or vehicle-injected females. In contrast, IP10 mRNA levels after LPS treatment were higher in astrocytes derived from control or vehicle-injected females than in those obtained from males or androgenized females. The different response of male and female astrocytes to LPS was due neither to differences in the basal expression of the inflammatory molecules nor to

  18. Effects of realgar on stress proteins, inflammatory mediators, and complement in brain tissue and serum of rats with inflammatory brain injury

    Institute of Scientific and Technical Information of China (English)

    Yishan Tang; Ningsheng Wang; Yinqing Zhang; Shaomei Ye; Weiping Ou

    2008-01-01

    BACKGROUND: The Chinese herbal compound realgar exerts detoxification effects as an adjuvant. It is suggested that realgar exerts detoxification via the following pathways: in the pathological state, realgar corrects the oxidative stress state by increasing stress levels, activating some endogenous protective factors and antagonizing the excessive release of inflammatory factors, as well as inhibiting complement activation.OBJECTIVE: To observe the changes in stress proteins, inflammatory mediators, and complement in the brain tissue and serum of rats with inflammatory brain injury, which have been treated with thc Chinese herbal compound Angong Niuhuang, and to compare the efficacy of Angong Niuhuang with that of realgar,to verify the mechanism of action of realgar.DESIGN, TIME AND SETTING: Randomized, controlled, cytological experiment, performed in the Institute of Clinical Pharmacology, Guangzhou University of Traditional Chinese Medicine in March 2006.MATERIALS: Thirty-six healthy, male, Sprague Dawley rats received 250 U/kg Bordetella pertussis via the common carotid artery within 15 seconds to induce inflammatory brain injury. Reagents and kits were as follows: Realgar and Angong Niuhuang powder (Foshan Second Pharmaceutical Factory, China), Bordetella pertussis diagnostic antigen (National Institute for the Control of Pharmaceutical and Biological Products,China), heat shock protein 70 (HSP70) enzyme-labeled immunosorbent assay (ELISA) kit (Stressgen, USA),tumor necrosis factor-α (TNF-α) ELISA kit (Biosource, USA), nitric oxide synthase (NOS) kit,Coomassie brilliant blue protein kit (Nanjing Jiancheng Bioengineering Co.,Ltd., China), and complements C3 and C4 (Shanghai Kehua Dongling Diagnositic Products Co.,Ltd., China),METHODS: Thirty-six rats were randomly and evenly divided into the following six groups: normal control,model, high-, middle-, and low-dose realgar-treated, and Angong Niuhuang-treated groups. At one hour prior to establishing the model

  19. Brain stem evoked response audiometry A Review

    OpenAIRE

    Balasubramanian Thiagarajan

    2015-01-01

    Brain stem evoked response audiometry (BERA) is a useful objective assessement of hearing. Major advantage of this procedure is its ability to test even infants in whom conventional audiometry may not be useful. This investigation can be used as a screening test for deafness in high risk infants. Early diagnosis and rehabilitation will reduce disability in these children. This article attempts to review the published literature on this subject. Methadology: Internet search using goog...

  20. The burn wound inflammatory response is influenced by midazolam.

    Science.gov (United States)

    Babcock, George F; Hernandez, Laura; Yadav, Ekta; Schwemberger, Sandy; Dugan, Amy

    2012-02-01

    Burn patients requiring hospitalization are often treated for anxiety with benzodiazepines (BDZs). Benzodiazepines are reported to influence immune system function. Immune system alterations are a major cause of burn-induced mortality. We wanted to determine whether the BDZ, midazolam given daily at an anxiolytic dose, had any influence on the burn injury-induced inflammatory response in the blood and wound. Mice received a 15% total body surface area flame burn and received either midazolam 1 mg/kg i.p. or saline 0.1 ml daily. Blood and skin wounds were harvested 24 h after injection on post-burn day 2, 3, 7, or 8. Mice treated with midazolam had significantly lower serum IL-1β (p=0.002), TNF-α (p=0.002), IL-6 (p=0.016), IL-10 (p=0.009), and TGF-β (p=0.004) than saline-treated mice, with little impact on serum chemokine levels. In the wound, TNF-α and IL-10 were the only cytokines significantly influenced by the drug, being lower (p=0.018) and higher (p=0.006), respectively. The chemokines in the wound influenced significantly by midazolam were MIP-1α, MIP-1β, and MIP-2 while MCP-1 and KC were not. There were more inflammatory cells at the burn wound margin in midazolam-treated mice on post-burn day 3. Although serum nitrate/nitrite was significantly increased by midazolam (p=0.03), both eNOS and iNOS mRNA expression in the wound were similar to the saline group. We found that midazolam given daily after burn injury significantly influenced the inflammatory response. The clinical implications of these findings on wound healing and shock following burn injury, especially larger burns, deserve further investigation.

  1. Modulation of Cholinergic Pathways and Inflammatory Mediators in Blast-Induced Traumatic Brain Injury

    Science.gov (United States)

    2013-01-01

    Neuroinflammation including cross-talk between central and peripheral immune systems is considered to be a primary event after blast exposure...cholinergic anti-inflammatory pathway has been proposed as a link in neuroimmunomodulation, especially during stress con- ditions [8–11]. Neuroinflammation is...BINT) elicits early complement activation and tumor necrosis factor alpha (TNFalpha) release in a rat brain, J. Neurol. Sci. 318 (2012) 146–154. [8

  2. Inhibition of inflammatory mediator release from microglia can treat ischemic/hypoxic brain injury★

    OpenAIRE

    Wang, Huaibo; Guo, Weitao; Liu, Hongliang; Zeng, Rong; Lu, Mingnan; Chen, Ziqiu; Xiao, Qixian

    2013-01-01

    Interleukin-1α and interleukin-1β aggravate neuronal injury by mediating the inflammatory reaction following ischemic/hypoxic brain injury. It remains unclear whether interleukin-1α and interleukin-1β are released by microglia or astrocytes. This study prepared hippocampal slices that were subsequently subjected to oxygen and glucose deprivation. Hematoxylin-eosin staining verified that neurons exhibited hypoxic changes. Results of enzyme-linked immunosorbent assay found that interleukin-1α a...

  3. Effect of ghrelin on inflammatory response in lung contusion.

    Science.gov (United States)

    Guven, Berrak; Gokce, Mertol; Saydam, Ozkan; Can, Murat; Bektas, Sibel; Yurtlu, Serhan

    2013-02-01

    The purpose of this study was to investigate the effects of ghrelin on inflammatory response and tissue damage following trauma-induced acute lung injury. Thirty male wistar albino rats (300-400 g) were randomly assigned into three groups: control group (n = 6), lung contusion plus saline (saline-treated, n = 12), and lung contusion plus ghrelin (ghrelin-treated, n = 12). Saline- or ghrelin-treated traumatic rats were sacrificed at two time points (24 and 72 hours) after lung contusion. Blood was collected for the analysis of serum adenosine deaminase (ADA). Tissue transforming growth factor-beta 1 (TGF-β1) and matrix metalloproteinase-2 (MMP-2) levels were measured by enzyme-linked immunosorbent assay and histopathological examination was performed on the lung tissue samples. Our results indicated that ghrelin significantly reduced morphologic damages. Serum ADA activities were significantly decreased after lung contusion and this decline started early with ghrelin treatment. TGF-β1 and MMP-2 levels in lung tissue were elevated at 72 hours after lung contusion and treatment with ghrelin significantly increased TGF-β1 level and reduced MMP-2 level. In conclusion, our study demonstrates that acute lung injury initiated proinflammatory responses and ghrelin administration showed an anti-inflammatory effect in lung contusion.

  4. Renal inflammatory response to urinary tract infection in rat neonates.

    Science.gov (United States)

    Zarepour, M; Moradpoor, H; Emamghorashi, F; Owji, S M; Roodaki, M; Khamoushi, M

    2015-09-01

    Urinary tract infection (UTI) is one of the most common bacterial infections. Maternal UTI is a risk factor for neonatal UTI. The aim of the present study was to determine the severity of renal inflammation in neonate rats born from mothers with induced UTI. Twelve pregnant rats (Sprague-Dawley) were included in study. The rats were divided into two groups (six rats in each group). In the first group, pyelonephritis was induced in the third trimester of pregnancy and the second group was used as a control group. After delivery, the neonates were divided into three groups based on days after birth (the 1 st, 3 rd and 7 th days after birth). In each group, two neonates of each mother were killed and a midline abdominal incision was made and both kidneys were aseptically removed. On the 7 th day, rat mothers were killed and their kidneys were removed. The preparations were evaluated with a bright field microscope for inflammatory response. Renal pathology showed inflammation in all UTI-induced mothers, but only two cases of neonates (2.1%) showed inflammation in the renal parenchyma. There was no relation between the positive renal culture and the pathological changes. We conclude that neonates with UTI born to UTI-induced mothers showed a lesser inflammatory response.

  5. Inflammatory Response in Preterm and Very Preterm Newborns with Sepsis

    Science.gov (United States)

    Segura-Cervantes, Enrique; Mancilla-Ramírez, Javier; González-Canudas, Jorge; Alba, Erika; Santillán-Ballesteros, René; Morales-Barquet, Deneb; Sandoval-Plata, Gabriela

    2016-01-01

    The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation. PMID:27293317

  6. Renal inflammatory response to urinary tract infection in rat neonates

    Directory of Open Access Journals (Sweden)

    M Zarepour

    2015-01-01

    Full Text Available Urinary tract infection (UTI is one of the most common bacterial infections. Maternal UTI is a risk factor for neonatal UTI. The aim of the present study was to determine the severity of renal inflammation in neonate rats born from mothers with induced UTI. Twelve pregnant rats (Sprague-Dawley were included in study. The rats were divided into two groups (six rats in each group. In the first group, pyelonephritis was induced in the third trimester of pregnancy and the second group was used as a control group. After delivery, the neonates were divided into three groups based on days after birth (the 1 st, 3 rd and 7 th days after birth. In each group, two neonates of each mother were killed and a midline abdominal incision was made and both kidneys were aseptically removed. On the 7 th day, rat mothers were killed and their kidneys were removed. The preparations were evaluated with a bright field microscope for inflammatory response. Renal pathology showed inflammation in all UTI-induced mothers, but only two cases of neonates (2.1% showed inflammation in the renal parenchyma. There was no relation between the positive renal culture and the pathological changes. We conclude that neonates with UTI born to UTI-induced mothers showed a lesser inflammatory response.

  7. Inflammatory and bone remodeling responses to the cytolethal distending toxins.

    Science.gov (United States)

    Belibasakis, Georgios N; Bostanci, Nagihan

    2014-04-04

    The cytolethal distending toxins (CDTs) are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs can also perturb the innate immune responses, by regulating inflammatory cytokine production and molecular mediators of bone remodeling in various cell types. These cellular and molecular events may in turn have an effect in enhancing local inflammation in diseases where CDT-producing bacteria are involved, such as Aggregatibacter actinomycetemcomitans, Haemophilus ducreyi, Campylobacter jejuni and Helicobacter hepaticus. One special example is the induction of pathological bone destruction in periodontitis. The opportunistic oral pathogen Aggregatibatcer actinoycemetemcomitans, which is involved in the aggressive form of the disease, can regulate the molecular mechanisms of bone remodeling in a manner that favors bone resorption, with the potential involvement of its CDT. The present review provides an overview of all known to-date inflammatory or bone remodeling responses of CDTs produced by various bacterial species, and discusses their potential contribution to the pathogenesis of the associated diseases.

  8. Inflammatory and Bone Remodeling Responses to the Cytolethal Distending Toxins

    Directory of Open Access Journals (Sweden)

    Georgios N. Belibasakis

    2014-04-01

    Full Text Available The cytolethal distending toxins (CDTs are a family of exotoxins produced by a wide range of Gram-negative bacteria. They are known for causing genotoxic stress to the cell, resulting in growth arrest and eventually apoptotic cell death. Nevertheless, there is evidence that CDTs can also perturb the innate immune responses, by regulating inflammatory cytokine production and molecular mediators of bone remodeling in various cell types. These cellular and molecular events may in turn have an effect in enhancing local inflammation in diseases where CDT-producing bacteria are involved, such as Aggregatibacter actinomycetemcomitans, Haemophilus ducreyi, Campylobacter jejuni and Helicobacter hepaticus. One special example is the induction of pathological bone destruction in periodontitis. The opportunistic oral pathogen Aggregatibatcer actinoycemetemcomitans, which is involved in the aggressive form of the disease, can regulate the molecular mechanisms of bone remodeling in a manner that favors bone resorption, with the potential involvement of its CDT. The present review provides an overview of all known to-date inflammatory or bone remodeling responses of CDTs produced by various bacterial species, and discusses their potential contribution to the pathogenesis of the associated diseases.

  9. Clinical significance of scoring system for systemic inflammatory response syndrome

    Institute of Scientific and Technical Information of China (English)

    HAN Jian; LIANG Hua-ping

    2006-01-01

    The concepts of systemic inflammatory response syndrome (SIRS) and scoring system were defined by the journal of Bone in 1992. SIRS was described as occurrence of two or more clinical criteria in four ones (fever or hypothermia, tachypnea, tachycardia, and leukocytosis).An early diagnosis and estimation of systemic inflammation in patients is helpful for treatment selection. This paper reviews the application of SIRS scoring system, which has been extensively validated for large groups of critical care patients with severe injury and critical surgical diseases.Recent studies have documented SIRS score as a significant predictive parameter of adverse outcome in critical care patients. Furthermore, some studies also give us a suggestion on how to reduce the overload systemic response.

  10. Iodinated contrast media alter immune responses in pro-inflammatory states.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2010-07-01

    Hypertonic saline causes a transient elevation of blood osmolality and has been shown to alter cellular inflammatory responses in pro-inflammatory states. Intravascular administration of iodine contrast media also causes a transient elevation of blood osmolarity.

  11. Perivascular Spaces--MRI Marker of Inflammatory Activity in the Brain?

    Science.gov (United States)

    Wuerfel, Jens; Haertle, Mareile; Waiczies, Helmar; Tysiak, Eva; Bechmann, Ingo; Wernecke, Klaus D.; Zipp, Frauke; Paul, Friedemann

    2008-01-01

    The Virchow-Robin spaces (VRS), perivascular compartments surrounding small blood vessels as they penetrate the brain parenchyma, are increasingly recognized for their role in leucocyte trafficking as well as for their potential to modulate immune responses. In the present study, we investigated VRS numbers and volumes in different brain regions…

  12. Innate immune response to pulmonary contusion: identification of cell type-specific inflammatory responses.

    Science.gov (United States)

    Hoth, J Jason; Wells, Jonathan D; Yoza, Barbara K; McCall, Charles E

    2012-04-01

    Lung injury from pulmonary contusion is a common traumatic injury, predominantly seen after blunt chest trauma, such as in vehicular accidents. The local and systemic inflammatory response to injury includes activation of innate immune receptors, elaboration of a variety of inflammatory mediators, and recruitment of inflammatory cells to the injured lung. Using a mouse model of pulmonary contusion, we had previously shown that innate immune Toll-like receptors 2 and 4 (TLR2 and TLR4) mediate the inflammatory response to lung injury. In this study, we used chimeric mice generated by adoptive bone marrow transfer between TLR2 or TLR4 and wild-type mice. We found that, in the lung, both bone marrow-derived and nonmyeloid cells contribute to TLR-dependent inflammatory responses after injury in a cell type-specific manner. We also show a novel TLR2-dependent injury mechanism that is associated with enhanced airway epithelial cell apoptosis and increased pulmonary FasL and Fas expression in the lungs from injured mice. Thus, in addition to cardiopulmonary physiological dysfunction, cell type-specific TLR and their differential response to injury may provide novel specific targets for management of patients with pulmonary contusion.

  13. The impact of intermittent umbilical cord occlusions on the inflammatory response in pre-term fetal sheep.

    Directory of Open Access Journals (Sweden)

    Andrew P Prout

    Full Text Available Fetal hypoxic episodes may occur antepartum with the potential to induce systemic and cerebral inflammatory responses thereby contributing to brain injury. We hypothesized that intermittent umbilical cord occlusions (UCOs of sufficient severity but without cumulative acidosis will lead to a fetal inflammatory response. Thirty-one chronically instrumented fetal sheep at ∼0.85 of gestation underwent four consecutive days of hourly UCOs from one to three minutes duration for six hours each day. Maternal and fetal blood samples were taken for blood gases/pH and plasma interleukin (IL-1β and IL-6 levels. Animals were euthanized at the end of experimental study with brain tissue processed for subsequent counting of microglia and mast cells. Intermittent UCOs resulted in transitory fetal hypoxemia with associated acidemia which progressively worsened the longer umbilical blood flow was occluded, but with no cumulative blood gas or pH changes over the four days of study. Fetal arterial IL-1β and IL-6 values showed no significant change regardless of the severity of the UCOs, nor was there any evident impact on the microglia and mast cell counts for any of the brain regions studied. Accordingly, intermittent UCOs of up to three minutes duration with severe, but limited fetal hypoxemia and no cumulative acidemia, do not result in either a systemic or brain inflammatory response in the pre-term ovine fetus. However, fetal IL-1B and IL-6 values were found to be well correlated with corresponding maternal values supporting the placenta as a primary source for these cytokines with related secretion into both circulations. Female fetuses were also found to have higher IL-1β levels than males, indicating that gender may impact on the fetal inflammatory response to various stimuli.

  14. [Intestinal-brain axis. Neuronal and immune-inflammatory mechanisms of brain and intestine pathology].

    Science.gov (United States)

    Bondarenko, V M; Riabichenko, E V

    2013-01-01

    Mutually directed connections between intestine and brain are implemented by endocrine, neural and immune systems and nonspecific natural immunity. Intestine micro flora as an active participant of intestine-brain axis not only influences intestine functions but also stimulates the development of CNS in perinatal period and interacts with higher nervous centers causing depression and cognitive disorders in pathology. A special role belongs to intestine microglia. Apart from mechanic (protective) and trophic functions for intestine neurons, glia implements neurotransmitter, immunologic, barrier and motoric functions in the intestine. An interconnection between intestine barrier function and hematoencephalic barrier regulation exists. Chronic endotoxinemia as a result of intestine barrier dysfunction forms sustained inflammation state in periventricular zone of the brain with consequent destabilization of hematoencephalic barriers and spread oF inflammation to other parts of the brain resulting in neurodegradation development.

  15. Cardiovascular and inflammatory response to cholecystokinin during endotoxemic shock.

    Science.gov (United States)

    Saia, Rafael Simone; Bertozi, Giuliana; Mestriner, Fabíola Leslie; Antunes-Rodrigues, José; Queiróz Cunha, Fernando; Cárnio, Evelin Capellari

    2013-01-01

    Cholecystokinin (CCK) was first described as a gastrointestinal hormone, but its receptors have been located in cardiac and vascular tissues, as well as in immune cells. Our aims were to investigate the role of CCK on lipopolysaccharide (LPS)-induced hypotension and its ability to modulate previously reported inflammatory mediators, therefore affecting cardiovascular function. To conduct these experiments, rats had their jugular vein cannulated for drug administration, and also, the femoral artery cannulated for mean arterial pressure (MAP) and heart rate records. Endotoxemia induced by LPS from Escherichia coli (1.5 mg/kg; i.v.) stimulated the release of CCK, a progressive drop in MAP, and increase in heart rate. Plasma tumor necrosis factor α (TNF-α), interleukin 10 (IL-10), nitrate, vasopressin, and lactate levels were elevated in the endotoxemic rats. The pretreatment with proglumide (nonselective CCK antagonist; 30 mg/kg; i.p.) aggravated the hypotension and also increased plasma TNF-α and lactate levels. On the other hand, CCK (0.4 μg/kg; i.v.) administered before LPS significantly restored MAP, reduced aortic and hepatic inducible nitric oxide synthase (iNOS) production, and elevated plasma vasopressin and IL-10 concentrations; it did not affect TNF-α. Physiological CCK concentration reduced nitrite and iNOS synthesis by peritoneal macrophages, possibly through a self-regulatory IL-10-dependent mechanism. Together, these data suggest a new role for the peptide CCK in modulating MAP, possibly controlling the inflammatory response, stimulating the anti-inflammatory cytokine, IL-10, and reducing vascular and macrophage iNOS-derived nitric oxide production. Based on these findings, CCK could be used as an adjuvant therapeutic agent to improve cardiovascular function.

  16. Interplay between the acute inflammatory response and heart rate variability in healthy human volunteers.

    Science.gov (United States)

    Kox, Matthijs; Ramakers, Bart P; Pompe, Jan C; van der Hoeven, Johannes G; Hoedemaekers, Cornelia W; Pickkers, Peter

    2011-08-01

    The autonomic nervous system and the inflammatory response are intimately linked. Heart rate variability (HRV) analysis is a widely used method to assess cardiac autonomic nervous system activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the acute inflammatory response to endotoxin. Second, we investigated whether the magnitude of the inflammatory response correlated with HRV alterations. Forty healthy volunteers received a single intravenous bolus of 2 ng/kg endotoxin (LPS, derived from Escherichia coli O:113). Of these, 12 healthy volunteers were administered LPS again 2 weeks later. Heart rate variability was determined at baseline (just before LPS administration) and hourly thereafter until 8 h after LPS administration. Plasma cytokine levels were determined at various time points. Baseline HRV indices did not correlate with the magnitude of the LPS-induced inflammatory response. Despite large alterations in HRV after LPS administration, the extent of the inflammatory response did not correlate with the magnitude of HRV changes. In subjects who were administered LPS twice, inflammatory cytokines were markedly attenuated after the second LPS administration, whereas LPS-induced HRV alterations were similar. Heart rate variability indices do not predict the acute inflammatory response in a standardized model of systemic inflammation. Although the acute inflammatory response results in HRV changes, no correlations with inflammatory cytokines were observed. Therefore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response.

  17. PPARgamma agonist curcumin reduces the amyloid-beta-stimulated inflammatory responses in primary astrocytes.

    Science.gov (United States)

    Wang, Hong-Mei; Zhao, Yan-Xin; Zhang, Shi; Liu, Gui-Dong; Kang, Wen-Yan; Tang, Hui-Dong; Ding, Jian-Qing; Chen, Sheng-Di

    2010-01-01

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Accumulating data indicate that astrocytes play an important role in the neuroinflammation related to the pathogenesis of AD. It has been shown that microglia and astrocytes are activated in AD brain and amyloid-beta (Abeta) can increase the expression of cyclooxygenase 2 (COX-2), interleukin-1, and interleukin-6. Suppressing the inflammatory response caused by activated astrocytes may help to inhibit the development of AD. Curcumin is a major constituent of the yellow curry spice turmeric and proved to be a potential anti-inflammatory drug in arthritis and colitis. There is a low age-adjusted prevalence of AD in India, a country where turmeric powder is commonly used as a culinary compound. Curcumin has been shown to suppress activated astroglia in amyloid-beta protein precursor transgenic mice. The real mechanism by which curcumin inhibits activated astroglia is poorly understood. Here we report that the expression of COX-2 and glial fibrillary acidic protein were enhanced and that of peroxisome proliferator-activated receptor gamma (PPARgamma) was decreased in Abeta(25-35)-treated astrocytes. In line with these results, nuclear factor-kappaB translocation was increased in the presence of Abeta. All these can be reversed by the pretreatment of curcumin. Furthermore, GW9662, a PPARgamma antagonist, can abolish the anti-inflammatory effect of curcumin. These results show that curcumin might act as a PPARgamma agonist to inhibit the inflammation in Abeta-treated astrocytes.

  18. Ozone promotes regeneration by regulating the inflammatory response in zebrafish.

    Science.gov (United States)

    Hao, Kenan; Li, Yanhao; Feng, Jianyu; Zhang, Wenqing; Zhang, Yiyue; Ma, Ning; Zeng, Qingle; Pang, Huajin; Wang, Chunyan; Xiao, Lijun; He, Xiaofeng

    2015-09-01

    Ozone is thought to advance wound healing by inhibiting inflammation, but the mechanism of this phenomenon has not been determined. Although the zebrafish is often used in regeneration experiments, there has been no report of zebrafish treated with ozonated water. We successfully established a zebrafish model of ozonated water treatment and demonstrate that ozonated water stimulates the regeneration of the zebrafish caudal fin, its mechanism, and time dependence. The growth rate of the caudal fin and the number of neutrophils migrating to the caudal fin wound after resection were higher in the experimental (ozonated) group than in the control group, preliminarily confirming that ozone-promoted regeneration is related to the stimulation of an early inflammatory response by ozone. Ozone modulated the expression of tumor necrosis factor-α (TNF-α) in two ways by regulating interleukin 10 (IL-10) expression. Therefore, ozone promotes tissue regeneration by regulating the inflammatory pathways. This effect of ozone in an experimental zebrafish model is demonstrated for the first time, confirming its promotion of wound healing and the mechanism of its effect in tissue regeneration. These results will open up new directions for ozone and regeneration research.

  19. Biomechanical changes in endothelial cells result from an inflammatory response

    Science.gov (United States)

    Vaitkus, Janina; Stroka, Kimberly; Aranda-Espinoza, Helim

    2012-02-01

    During periods of infection and disease, the immune system induces the release of TNF-α, an inflammatory cytokine, from a variety of cell types, such as macrophages. TNF-α, while circulating in the vasculature, binds to the apical surface of endothelial cells and causes a wide range of biological and mechanical changes to the endothelium. While the biological changes have been widely studied, the biomechanical aspects have been largely unexplored. Here, we investigated the biomechanical changes of the endothelium as a function of TNF-α treatment. First, we studied the traction forces applied by the endothelium, an effect that is much less studied than others. Through the use of traction force microscopy, we found that TNF-α causes an increase in traction forces applied by the endothelial cells as compared to non-treated cells. Then, we investigated cell morphology, cell mechanics, migration, and cytoskeletal dynamics. We found that in addition to increasing applied traction forces, TNF-α causes an increase in cell area and aspect ratio on average, as well as a shift in the organization of F-actin filaments within the cell. Combining these findings together, our results show that an inflammatory response heavily impacts the morphology, cell mechanics, migration, cytoskeletal dynamics, and applied traction forces of endothelial cells.

  20. Irbesartan reduces inflammatory response of central nervous system in a rat model of fluid percussion brain injury%厄贝沙坦减轻液压脑损伤大鼠神经系统的炎症反应

    Institute of Scientific and Technical Information of China (English)

    邢国祥; 魏敏; 修彬华; 马迎辉; 刘涛

    2016-01-01

    Objective To investigate the neuroprotective effect of the angiotensin Ⅱ receptor 1 (AT1) antagonist irbesartan on rat models with lateral fluid percussion brain injury (FPBI).Methods FPBI models were prepared using a modified fluid percussion injury method.Before and after modeling,irbesartan was given to the rats.The regional cerebral blood flow (rCBF) was monitored by laser Doppler flowmetry.Neurologic status was evaluated before and 1,3,5,7 days after FPBI surgery.Brains were removed for immunohistochemical evaluation of active microglias and macrophages.Results Compared to sham group,the rCBF and neurologic score of FPBI rats decreased significantly,while microglia and macrophage activation were confirmed.Treatment with iroesartan before FPBI surgery increased rCBF and improved neurological functions.In the peri-infarct cortex,irbesartan treatment attenuated the invasion of activated microglias and macrophages on day 7 after FPBI surgery.Conclusion Irbesartan can play a neuroprotective role through inhibiting microglia and macrophage activation in FPBI rats.%目的 研究血管紧张素Ⅱ受体1(AT1)抑制剂厄贝沙坦对侧位液压脑损伤模型大鼠神经系统炎症反应的影响.方法 利用改良的侧位液压损伤装置建立大鼠颅脑损伤(FPBI)模型,术前及术后给予厄贝沙坦治疗.用激光多普勒测定局部脑区血流(rCBF)的变化,术前及术后1、3、5、7d,利用神经功能评分评估大鼠神经功能损伤,免疫组织化学染色检测大鼠皮质小胶质细胞和巨噬细胞活化.结果 FPBI手术后损伤局部脑区rCBF明显下降,神经功能评分降低,损伤区周围脑组织小胶质细胞和巨噬细胞明显增多,厄贝沙坦治疗组大鼠rCBF显著高于单纯FPBI组,神经功能得到明显改善,损伤区周围脑组织小胶质细胞和巨噬细胞活化程度较轻.结论 厄贝沙坦预处理能够缓解大鼠脑损伤造成的神经功能障碍,减轻炎症反应,发挥神经保护作用.

  1. The Role of Protein Arginine Methyltransferases in Inflammatory Responses

    Directory of Open Access Journals (Sweden)

    Ji Hye Kim

    2016-01-01

    Full Text Available Protein arginine methyltransferases (PRMTs mediate the methylation of a number of protein substrates of arginine residues and serve critical functions in many cellular responses, including cancer development, progression, and aggressiveness, T-lymphocyte activation, and hepatic gluconeogenesis. There are nine members of the PRMT family, which are divided into 4 types (types I–IV. Although most PRMTs do not require posttranslational modification (PTM to be activated, fine-tuning modifications, such as interactions between cofactor proteins, subcellular compartmentalization, and regulation of RNA, via micro-RNAs, seem to be required. Inflammation is an essential defense reaction of the body to eliminate harmful stimuli, including damaged cells, irritants, or pathogens. However, chronic inflammation can eventually cause several types of diseases, including some cancers, atherosclerosis, rheumatoid arthritis, and periodontitis. Therefore, inflammation responses should be well modulated. In this review, we briefly discuss the role of PRMTs in the control of inflammation. More specifically, we review the roles of four PRMTs (CARM1, PRMT1, PRMT5, and PRMT6 in modulating inflammation responses, particularly in terms of modulating the transcriptional factors or cofactors related to inflammation. Based on the regulatory roles known so far, we propose that PRMTs should be considered one of the target molecule groups that modulate inflammatory responses.

  2. Regulation of inflammatory responses by IL-17F

    Science.gov (United States)

    Yang, Xuexian O.; Chang, Seon Hee; Park, Heon; Nurieva, Roza; Shah, Bhavin; Acero, Luis; Wang, Yi-Hong; Schluns, Kimberly S.; Broaddus, Russell R.; Zhu, Zhou; Dong, Chen

    2008-01-01

    Although interleukin (IL) 17 has been extensively characterized, the function of IL-17F, which has an expression pattern regulated similarly to IL-17, is poorly understood. We show that like IL-17, IL-17F regulates proinflammatory gene expression in vitro, and this requires IL-17 receptor A, tumor necrosis factor receptor–associated factor 6, and Act1. In vivo, overexpression of IL-17F in lung epithelium led to infiltration of lymphocytes and macrophages and mucus hyperplasia, similar to observations made in IL-17 transgenic mice. To further understand the function of IL-17F, we generated and analyzed mice deficient in IL-17F or IL-17. IL-17, but not IL-17F, was required for the initiation of experimental autoimmune encephalomyelitis. Mice deficient in IL-17F, but not IL-17, had defective airway neutrophilia in response to allergen challenge. Moreover, in an asthma model, although IL-17 deficiency reduced T helper type 2 responses, IL-17F–deficient mice displayed enhanced type 2 cytokine production and eosinophil function. In addition, IL-17F deficiency resulted in reduced colitis caused by dextran sulfate sodium, whereas IL-17 knockout mice developed more severe disease. Our results thus demonstrate that IL-17F is an important regulator of inflammatory responses that seems to function differently than IL-17 in immune responses and diseases. PMID:18411338

  3. Androgen deprivation modulates the inflammatory response induced by irradiation

    Directory of Open Access Journals (Sweden)

    Lin Paul-Yang

    2009-03-01

    Full Text Available Abstract Background The aim of this study was to determine whether radiation (RT-induced inflammatory responses and organ damage might be modulated by androgen deprivation therapies. Methods The mRNA and tissue sections obtained from the lungs, intestines and livers of irradiated mice with or without androgen deprivation were analyzed by real-time PCR and histological analysis. Activation of NF-kappa B was examined by measuring nuclear protein levels in the intestine and lung 24 h after irradiation. We also examined the levels of cyclooxygenase-2 (COX-2, TGF-β1 and p-AKT to elucidate the related pathway responsible to irradiation (RT -induced fibrosis. Results We found androgen deprivation by castration significantly augmented RT-induced inflammation, associated with the increase NF-κB activation and COX-2 expression. However, administration of flutamide had no obvious effect on the radiation-induced inflammation response in the lung and intestine. These different responses were probably due to the increase of RT-induced NF-κB activation and COX-2 expression by castration or lupron treatment. In addition, our data suggest that TGF-β1 and the induced epithelial-mesenchymal transition (EMT via the PI3K/Akt signaling pathway may contribute to RT-induced fibrosis. Conclusion When irradiation was given to patients with total androgen deprivation, the augmenting effects on the RT-induced inflammation and fibrosis should take into consideration for complications associated with radiotherapy.

  4. Impaired inflammatory response to glial cell death in genetically metallothionein-I- and -II-deficient mice

    DEFF Research Database (Denmark)

    Penkowa, M; Giralt, M; Moos, T

    1999-01-01

    Metallothionein I+II (MT-I+II) are acute-phase proteins which are upregulated during pathological conditions in the brain. To elucidate the neuropathological importance of MT-I+II, we have examined MT-I+II-deficient mice following ip injection with 6-aminonicotinamide (6-AN). 6-AN is antimetabolic...... and toxic for bone marrow cells and grey matter astrocytes. In MT+/+ mice, injection with 6-AN resulted in breakdown of the blood-brain barrier (BBB) and absence of GFAP-positive astrocytes in specific grey matter areas of the brain stem. Reactive astrocytosis encircled the damaged grey matter areas, which...... and histochemically detectable zinc increased in the brain stem after 6-AN similarly in MT+/+ and MT-/- mice. Bone marrow myeloid monocytes and macrophages were increased as a reaction to 6-AN only in MT+/+ mice. The results demonstrate that the capability of MT-/- mice to mount a normal inflammatory response...

  5. Brain Activity in Response to Visual Symmetry

    Directory of Open Access Journals (Sweden)

    Marco Bertamini

    2014-12-01

    Full Text Available A number of studies have explored visual symmetry processing by measuring event related potentials and neural oscillatory activity. There is a sustained posterior negativity (SPN related to the presence of symmetry. There is also functional magnetic resonance imaging (MRI activity in extrastriate visual areas and in the lateral occipital complex. We summarise the evidence by answering six questions. (1 Is there an automatic and sustained response to symmetry in visual areas? Answer: Yes, and this suggests automatic processing of symmetry. (2 Which brain areas are involved in symmetry perception? Answer: There is an extended network from extrastriate areas to higher areas. (3 Is reflection special? Answer: Reflection is the optimal stimulus for a more general regularity-sensitive network. (4 Is the response to symmetry independent of view angle? Answer: When people classify patterns as symmetrical or random, the response to symmetry is view-invariant. When people attend to other dimensions, the network responds to residual regularity in the image. (5 How are brain rhythms in the two hemispheres altered during symmetry perception? Answer: Symmetry processing (rather than presence produces more alpha desynchronization in the right posterior regions. Finally, (6 does symmetry processing produce positive affect? Answer: Not in the strongest sense, but behavioural measures reveal implicit positive evaluation of abstract symmetry.

  6. Inflammatory response in laparoscopic vs. open surgery for gastric cancer

    DEFF Research Database (Denmark)

    Okholm, Cecilie; Goetze, Jens Peter; Svendsen, Lars Bo

    2014-01-01

    lead to an increased susceptibility to complications and morbidity. The aim of this review was to investigate if laparoscopic surgery reduces the immunological response compared to open surgery in gastric cancer. METHODS: We conducted a literature search identifying relevant studies comparing......OBJECTIVE: Laparoscopic surgery may offer advantages compared to open surgery, such as earlier mobilization, less pain and lower post-surgical morbidity. Surgical stress is thought to be associated with the postoperative immunological changes in the body as an impaired immune function, which may...... laparoscopy or laparoscopic-assisted surgery with open gastric surgery. The main outcome was postoperative immunological status defined as surgical stress parameters, including inflammatory cytokines and blood parameters. RESULTS: We identified seven studies that addressed the immunological status in patients...

  7. TRAF-mediated regulation of immune and inflammatory responses

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The tumor necrosis factor (TNF) receptor-associated factor (TRAF) family consists of six mammalian members,and is shown to participate in signal transduction of a large number of receptor families including TNF receptor family (TNFR) and Toll-like receptors-interleukin-1 receptors (TLR-IL-1R) family.Upon receptor activation,TRAFs are directly or indirectly recruited to the intracellular domains of these receptors.They subsequently engage other signaling proteins to activate inhibitor of κB kinase (IKK) complex,TRAF family member-associated NF-κB activator (TANK)-binding kinase 1 (TBK1) and inducible I κB kinase (IKK-i) (also known as IKKε),ultimately leading to activation of transcription factors such as NF-κB and interferon-regulatory factor (IRF) to induce immune and inflammatory responses.

  8. Size-dependent long-term tissue response to biostable nanowires in the brain.

    Science.gov (United States)

    Gällentoft, Lina; Pettersson, Lina M E; Danielsen, Nils; Schouenborg, Jens; Prinz, Christelle N; Linsmeier, Cecilia Eriksson

    2015-02-01

    Nanostructured neural interfaces, comprising nanotubes or nanowires, have the potential to overcome the present hurdles of achieving stable communication with neuronal networks for long periods of time. This would have a strong impact on brain research. However, little information is available on the brain response to implanted high-aspect-ratio nanoparticles, which share morphological similarities with asbestos fibres. Here, we investigated the glial response and neuronal loss in the rat brain after implantation of biostable and structurally controlled nanowires of different lengths for a period up to one year post-surgery. Our results show that, as for lung and abdominal tissue, the brain is subject to a sustained, local inflammation when biostable and high-aspect-ratio nanoparticles of 5 μm or longer are present in the brain tissue. In addition, a significant loss of neurons was observed adjacent to the 10 μm nanowires after one year. Notably, the inflammatory response was restricted to a narrow zone around the nanowires and did not escalate between 12 weeks and one year. Furthermore, 2 μm nanowires did not cause significant inflammatory response nor significant loss of neurons nearby. The present results provide key information for the design of future neural implants based on nanomaterials.

  9. Regional brain shrinkage over two years: individual differences and effects of pro-inflammatory genetic polymorphisms.

    Science.gov (United States)

    Persson, N; Ghisletta, P; Dahle, C L; Bender, A R; Yang, Y; Yuan, P; Daugherty, A M; Raz, N

    2014-12-01

    We examined regional changes in brain volume in healthy adults (N=167, age 19-79years at baseline; N=90 at follow-up) over approximately two years. With latent change score models, we evaluated mean change and individual differences in rates of change in 10 anatomically-defined and manually-traced regions of interest (ROIs): lateral prefrontal cortex (LPFC), orbital frontal cortex (OF), prefrontal white matter (PFw), hippocampus (Hc), parahippocampal gyrus (PhG), caudate nucleus (Cd), putamen (Pt), insula (In), cerebellar hemispheres (CbH), and primary visual cortex (VC). Significant mean shrinkage was observed in the Hc, CbH, In, OF, and PhG, and individual differences in change were noted in all regions, except the OF. Pro-inflammatory genetic variants modified shrinkage in PhG and CbH. Carriers of two T alleles of interleukin-1β (IL-1β C-511T, rs16944) and a T allele of methylenetetrahydrofolate reductase (MTHFR C677T, rs1801133) polymorphisms showed increased PhG shrinkage. No effects of a pro-inflammatory polymorphism for C-reactive protein (CRP-286C>A>T, rs3091244) or apolipoprotein (APOE) ε4 allele were noted. These results replicate the pattern of brain shrinkage observed in previous studies, with a notable exception of the LPFC, thus casting doubt on the unique importance of prefrontal cortex in aging. Larger baseline volumes of CbH and In were associated with increased shrinkage, in conflict with the brain reserve hypothesis. Contrary to previous reports, we observed no significant linear effects of age and hypertension on regional brain shrinkage. Our findings warrant further investigation of the effects of neuroinflammation on structural brain change throughout the lifespan.

  10. Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies.

    Directory of Open Access Journals (Sweden)

    Gaia Codolo

    Full Text Available Parkinson's disease (PD is one of the most common neurodegenerative diseases. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Another feature is represented by the formation in these cells of inclusions called Lewy bodies (LB, principally constituted by fibrillar α-synuclein (αSyn. This protein is considered a key element in the aetiology of a group of neurodegenerative disorders termed synucleinopathies, which include PD, but the cellular and molecular mechanisms involved are not completely clear. It is established that the inflammatory process plays a crucial role in the pathogenesis and/or progression of PD; moreover, it is known that aggregated αSyn, released by neurons, activates microglia cells to produce pro-inflammatory mediators, such as IL-1β. IL-1β is one of the strongest pro-inflammatory cytokines; it is produced as an inactive mediator, and its maturation and activation requires inflammasome activation. In particular, the NLRP3 inflammasome is activated by a wide variety of stimuli, among which are crystallized and particulate material. In this work, we investigated the possibility that IL-1β production, induced by fibrillar αSyn, is involved the inflammasome activation. We demonstrated the competence of monomeric and fibrillar αSyn to induce synthesis of IL-1β, through TLR2 interaction; we found that the secretion of the mature cytokine was a peculiarity of the fibrillated protein. Moreover, we observed that the secretion of IL-1β involves NLRP3 inflammasome activation. The latter relies on the phagocytosis of fibrillar αSyn, followed by increased ROS production and cathepsin B release into the cytosol. Taken together, our data support the notion that fibrillar αSyn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD.

  11. IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines.

    Science.gov (United States)

    Li, Xinyuan; Mai, Jietang; Virtue, Anthony; Yin, Ying; Gong, Ren; Sha, Xiaojin; Gutchigian, Stefanie; Frisch, Andrew; Hodge, Imani; Jiang, Xiaohua; Wang, Hong; Yang, Xiao-Feng

    2012-01-01

    It remains unknown whether newly identified anti-inflammatory/immunosuppressive cytokine interleukin-35 (IL-35) is different from other anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β in terms of inhibition of inflammation initiation and suppression of full-blown inflammation. Using experimental database mining and statistical analysis methods we developed, we examined the tissue expression profiles and regulatory mechanisms of IL-35 in comparison to other anti-inflammatory cytokines. Our results suggest that in contrast to TGF-β, IL-35 is not constitutively expressed in human tissues but it is inducible in response to inflammatory stimuli. We also provide structural evidence that AU-rich element (ARE) binding proteins and microRNAs target IL-35 subunit transcripts, by which IL-35 may achieve non-constitutive expression status. Furthermore, we propose a new system to categorize anti-inflammatory cytokines into two groups: (1) the house-keeping cytokines, such as TGF-β, inhibit the initiation of inflammation whereas (2) the responsive cytokines including IL-35 suppress inflammation in full-blown stage. Our in-depth analyses of molecular events that regulate the production of IL-35 as well as the new categorization system of anti-inflammatory cytokines are important for the design of new strategies of immune therapies.

  12. Effect of Dietary Conjugated Linoleic Acid Supplementation on Early Inflammatory Responses during Cutaneous Wound Healing

    Directory of Open Access Journals (Sweden)

    Na-Young Park

    2010-01-01

    Full Text Available Inflammatory response is considered the most important period that regulates the entire healing process. Conjugated linoleic acid (CLA, a class of linoleic acid positional and geometric isomers, is well known for its antioxidant and anti-inflammatory properties. We hypothesized that dietary CLA supplementation accelerates cutaneous wound healing by regulating antioxidant and anti-inflammatory functions. To investigate wound closure rates and inflammatory responses, we used a full-thickness excisional wound model after 2-week treatments with control, 0.5%, or 1% CLA-supplemented diet. Mice fed dietary CLA supplementation had reduced levels of oxidative stress and inflammatory markers. Moreover, the wound closure rate was improved significantly in mice fed a 1% CLA-supplemented diet during early stage of wound healing (inflammatory stage. We conclude that dietary CLA supplementation enhances the early stage of cutaneous wound healing as a result of modulating oxidative stress and inflammatory responses.

  13. Maresin 1 Mitigates Inflammatory Response and Protects Mice from Sepsis

    Directory of Open Access Journals (Sweden)

    Ruidong Li

    2016-01-01

    Full Text Available Sepsis, frequently caused by infection of bacteria, is considered as an uncontrollable systematic inflammation response syndrome (SIRS. Maresin 1 (Mar1 is a new proresolving mediator with potent anti-inflammatory effect in several animal models. However, its effect in sepsis is still not investigated. To address this question, we developed sepsis model in BALB/c mice by cecal ligation and puncture (CLP with or without Mar1 treatment. Our data showed that Mar1 markedly improved survival rate and decreased the levels of proinflammatory cytokines in CLP mice such as interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and interleukin-1β (IL-1β. Furthermore, Mar1 reduced serum level of lipopolysaccharide (LPS and enhanced the bacteria clearance in mice sepsis model. Moreover, Mar1 attenuated lung injury and decreased level of alanine transaminase (ALT, aspartate transaminase (AST, creatinine (Cre, and blood urea nitrogen (BUN in serum in mice after CLP surgery. Treatment with Mar1 inhibited activation of nuclear factor kappa B (NF-κb pathway. In conclusion, Mar1 exhibited protective effect in sepsis by reducing LPS, bacteria burden in serum, inhibiting inflammation response, and improving vital organ function. The possible mechanism is partly involved in inhibition of NF-κb activation.

  14. Subclinical inflammatory response after accelerated corneal cross-linking

    Institute of Scientific and Technical Information of China (English)

    Hassan Hashemi; Nahid Ashraf; Ebrahim Jafarzadehpur; Alireza Hedayatfar; Soheila Asgari

    2016-01-01

    Background: To evaluate the inlfammatory response after accelerated collagen cross-linking (CXL) in eyes with keratoconus. Methods: Consecutive eyes with keratoconus undergoing CXL surgery were included in this non-randomized interventional study. Aqueous lfare was measured pre- and post-operatively with a laser lfare photometer at 1 week, 1, 3 and 6 months after CXL. Results: Sixty eyes of 60 patients were entered into the study. Before CXL, the mean lfare value was 4.5 photons per millisecond (ph/ms). The lfare values observed at week 1 (7.1 ph/ms; P=0.008), month 1 (6.5 ph/ms; P=0.04), month 3 (6.7 ph/ms; P=0.004) and month 6 (6.7 ph/ms; P=0.004) were signiifcantly higher compared to baseline. Flare values were not signiifcantly different from week 1 up to 6 months after CXL (P=0.930). No statistically significant correlation was detected between the amount of inlfammation and keratometric indices. Conclusions: Accelerated CXL in patients with keratoconus may cause a subclinical inflammatory response which is evident as slight but rather long-lasting rise of aqueous lfare.

  15. Synthesis and evaluation of the anti-inflammatory effects of niflumic acid lipophilic prodrugs in brain edema.

    Science.gov (United States)

    el Kihel, L; Bourass, J; Richomme, P; Petit, J Y; Letourneux, Y

    1996-11-01

    Five new lipophilic prodrugs of the non-steroidal anti-inflammatory drug, niflumic acid (Nifluril, CAS 4394-00-7), were synthetized and evaluated on the experimental brain edema (injection of phospholipase A2). The effect of these drugs in comparison with dexamethasone which elicits a marked effect on clinical and experimental brain edema was evaluated. Niflumic acid was vectorised by cholesterol, hexadecanol and by three 1,3-diacylglycerols. The anti-inflammatory activity of these compounds on experimental brain edema was evaluated by determination of the prostaglandin E2 (PGE2) brain tissue concentration. Niflumic acid reduced the prostaglandin E2 production more significantly than dexamethasone. Niflumic acid prodrug forms (1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyl] glycerol and 1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyloxybuta noyl] glycerol also showed a marked anti-inflammatory activity at low concentrations.

  16. Is leptin related to systemic inflammatory response in acute pancreatitis?

    Institute of Scientific and Technical Information of China (English)

    Andrés Duarte-Rojo; Ana Lezama-Barreda; Mar(i)a Teresa Ram(i)rez-lglesias; Mario Peláez Luna; Guillermo Robles-Diaz

    2006-01-01

    AIM: To evaluate the relationship between leptin and systemic inflammation in acute pancreatitis.METHODS: Consecutive patients with acute pancreatitis were included. Body mass index and serum samples were obtained at admission. Leptin, TNF-α, IL-6, -8and -10 levels were determined by ELISA. Severity was defined according to Atlanta criteria.RESULTS: Fifty-two (29 females) patients were studied.Overall body mass index was similar between mild and severe cases, although women with severe pancreatitis had lower body mass index (P = 0.04) and men showed higher body mass index (P = 0.05). No difference was found in leptin levels regarding the severity of pancreatitis, but higher levels tended to appear in male patients with increased body mass index and severe pancreatitis (P = 0.1). A multivariate analysis showed no association between leptin levels and severity. The strongest cytokine associated with severity was IL-6.Correlations of leptin with another cytokines only showed a trend for IL-8 (P = 0.058).CONCLUSION: High body mass index was associated with severity only in males, which may be related to android fat distribution. Serum leptin seems not to play a role on the systemic inflammatory response in acute pancreatitis and its association with severe outcome in males might represent a marker of increased adiposity.

  17. Circulating Mitochondrial DAMPs Cause Inflammatory Responses to Injury

    Science.gov (United States)

    Zhang, Qin; Raoof, Mustafa; Chen, Yu; Sumi, Yuka; Sursal, Tolga; Junger, Wolfgang; Brohi, Karim; Itagaki, Kiyoshi; Hauser, Carl J.

    2009-01-01

    Injury causes a systemic inflammatory response syndrome (SIRS) clinically much like sepsis 1. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors 2. Similarly, cellular injury can release endogenous damage-associated molecular patterns (DAMPs) that activate innate immunity 3. Mitochondria are evolutionary endosymbionts that were derived from bacteria 4 and so might bear bacterial molecular motifs. We show here that injury releases mitochondrial DAMPs (MTD) into the circulation with functionally important immune consequences. MTD include formyl peptides and mitochondrial DNA. These activate human neutrophils (PMN) through formyl peptide receptor-1 and TLR9 respectively. MTD promote PMN Ca2+ flux and phosphorylation of MAP kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTD can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These can then signal through identical innate immune pathways to create a sepsis-like state. The release of such mitochondrial ‘enemies within’ by cellular injury is a key link between trauma, inflammation and SIRS. PMID:20203610

  18. Role of Fiber Length on Phagocytosis & Inflammatory Response

    Science.gov (United States)

    Turkevich, Leonid; Stark, Carahline; Champion, Julie

    2014-03-01

    Asbestos fibers have long been associated with lung cancer death. The inability of immune cells (e.g. macrophages) to effectively remove asbestos leads to chronic inflammation and disease. This study examines the role of fiber length on toxicity at the cellular level using model glass fibers. A major challenge is obtaining single diameter fibers but differing in length. Samples of 1 micron diameter fibers with different length distributions were prepared: short fibers (less than 15 microns) by aggressive crushing, and long fibers (longer than 15 microns) by successive sedimentation. Time-lapse video microscopy monitored the interaction of MH-S murine alveolar macrophages with the fibers: short fibers were easily internalized by the macrophages, but long fibers resisted internalization over many hours. Production of TNF- α (tumor necrosis factor alpha), a general inflammatory secreted cytokine, and Cox-2 (cyclo-oxygenase-2), an enzyme that produces radicals, each exhibited a dose-dependence that was greater for long than for short fibers. These results corroborate the importance of fiber length in both physical and biochemical cell response and support epidemiological observations of higher toxicity for longer fibers.

  19. Experimental obstructive cholestasis: the wound-like inflammatory liver response

    Directory of Open Access Journals (Sweden)

    Aller María-Angeles

    2008-11-01

    Full Text Available Abstract Obstructive cholestasis causes hepatic cirrhosis and portal hypertension. The pathophysiological mechanisms involved in the development of liver disease are multiple and linked. We propose grouping these mechanisms according to the three phenotypes mainly expressed in the interstitial space in order to integrate them. Experimental extrahepatic cholestasis is the model most frequently used to study obstructive cholestasis. The early liver interstitial alterations described in these experimental models would produce an ischemia/reperfusion phenotype with oxidative and nitrosative stress. Then, the hyperexpression of a leukocytic phenotype, in which Kupffer cells and neutrophils participate, would induce enzymatic stress. And finally, an angiogenic phenotype, responsible for peribiliary plexus development with sinusoidal arterialization, occurs. In addition, an intense cholangiocyte proliferation, which acquires neuroendocrine abilities, stands out. This histopathological finding is also associated with fibrosis. It is proposed that the sequence of these inflammatory phenotypes, perhaps with a trophic meaning, ultimately produces a benign tumoral biliary process – although it poses severe hepatocytic insufficiency. Moreover, the persistence of this benign tumor disease would induce a higher degree of dedifferentiation and autonomy and, therefore, its malign degeneration.

  20. Tourniquet-induced systemic inflammatory response in extremity surgery.

    LENUS (Irish Health Repository)

    Wakai, A

    2012-02-03

    BACKGROUND: Tourniquet-induced reperfusion injury in animals produces significant systemic inflammatory effects. This study investigated whether a biologic response occurs in a clinically relevant model of tourniquet-induced reperfusion injury. METHODS: Patients undergoing elective knee arthroscopy were prospectively randomized into controls (no tourniquet) and subjects (tourniquet-controlled). The effects of tourniquet-induced reperfusion on monocyte activation state, neutrophil activation state, and transendothelial migration (TEM) were studied. Changes in the cytokines implicated in reperfusion injury, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-10 were also determined. RESULTS: After 15 minutes of reperfusion, neutrophil and monocyte activation were significantly increased. Pretreatment of neutrophils with pooled subject (ischemia-primed) plasma significantly increased TEM. In contrast, TEM was not significantly altered by ischemia-primed plasma pretreatment of the endothelial monolayer. Significant elevation of tumor necrosis factor-alpha and IL-1beta were observed in subjects compared with controls after 15 minutes of reperfusion. There was no significant difference in serum IL-10 levels between the groups at all the time points studied. CONCLUSION: These results indicate a transient neutrophil and monocyte activation after tourniquet-ischemia that translates into enhanced neutrophil transendothelial migration with potential for tissue injury.

  1. Anti-inflammatory effect of Taraxacum officinale leaves on lipopolysaccharide-induced inflammatory responses in RAW 264.7 cells.

    Science.gov (United States)

    Koh, Yoon-Jeoung; Cha, Dong-Soo; Ko, Je-Sang; Park, Hyun-Jin; Choi, Hee-Don

    2010-08-01

    To investigate the efficacy and the mechanism of the anti-inflammatory effect of Taraxacum officinale leaves (TOLs), the effect of a methanol extract and its fractions recovered from TOLs on lipopolysaccharide (LPS)-induced responses was studied in the mouse macrophage cell line, RAW 264.7. Cells were pretreated with various concentrations of the methanol extract and its fractions and subsequently incubated with LPS (1 microg/mL). The levels of nitric oxide (NO), prostaglandin (PG) E(2), and pro-inflammatory cytokines including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined using enzyme-linked immunosorbent assays. Expressions of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 and activation of mitogen-activated protein (MAP) kinases were analyzed using western blotting. The methanol extract and its fractions inhibited LPS-induced production of NO, pro-inflammatory cytokines, and PGE(2) in a dose-dependent manner. The chloroform fraction significantly suppressed production of NO, PGE(2), and two pro-inflammatory cytokines (TNF-alpha and IL-1beta) in a dose-dependent manner with 50% inhibitory concentration values of 66.51, 90.96, 114.76, and 171.06 microg/mL, respectively. The ethyl acetate fraction also inhibited production of the inflammatory molecules. The chloroform and ethyl acetate fractions reduced LPS-induced expressions of iNOS and COX-2 and activation of MAP kinases in a dose-dependent manner. Among the fractions of the methanol extract, the chloroform and ethyl acetate fractions exhibited the most effective anti-inflammatory activities. These results show that the anti-inflammatory effects of TOLs are probably due to down-regulation of NO, PGE(2), and pro-inflammatory cytokines and reduced expressions of iNOS and COX-2 via inactivation of the MAP kinase signal pathway.

  2. Systemic inflammatory response to exhaustive exercise in patients with chronic obstructive pulmonary disease.

    NARCIS (Netherlands)

    Helvoort, H.A.C. van; Pol, M.H.J. van de; Heijdra, Y.F.; Dekhuijzen, P.N.R.

    2005-01-01

    Systemic inflammation may be present in patients with chronic obstructive pulmonary disease (COPD). Exercise is known to elicit an inflammatory response. We hypothesized that the systemic inflammatory response to exercise might be exaggerated in COPD patients compared to healthy subjects. Sixteen CO

  3. Endocannabinoids and inflammatory response in periodontal ligament cells.

    Directory of Open Access Journals (Sweden)

    Burcu Özdemir

    Full Text Available Endocannabinoids are associated with multiple regulatory functions in several tissues. The main endocannabinoids, anandamide (AEA and 2-arachidonylglycerol (2-AG, have been detected in the gingival crevicular fluid of periodontitis patients, but the association between periodontal disease or human periodontal ligament cells (hPdLCs and endocannabinoids still remain unclear. The aim of the present study was to examine the effects of AEA and 2-AG on the proliferation/viability and cytokine/chemokine production of hPdLCs in the presence/absence of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS. The proliferation/viability of hPdLCs was measured using 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT-assay. Interleukin-6 (IL-6, interleukin-8 (IL-8, and monocyte chemotactic protein-1 (MCP-1 levels were examined at gene expression and protein level by real-time PCR and ELISA, respectively. AEA and 2-AG did not reveal any significant effects on proliferation/viability of hPdLCs in the absence of P. gingivalis LPS. However, hPdLCs viability was significantly increased by 10-20 µM AEA in the presence of P. gingivalis LPS (1 µg/ml. In the absence of P. gingivalis LPS, AEA and 2-AG did not exhibit any significant effect on the expression of IL-8 and MCP-1 expression in hPdLCs, whereas IL-6 expression was slightly enhanced by 10 µM 2-AG and not affected by AEA. In P.gingivalis LPS stimulated hPdLCs, 10 µM AEA down-regulated gene-expression and protein production of IL-6, IL-8, and MCP-1. In contrast, 10 µM 2-AG had an opposite effect and induced a significant up-regulation of gene and protein expression of IL-6 and IL-8 (P<0.05 as well as gene-expression of MCP-1 in P. gingivalis LPS stimulated hPdLCs. Our data suggest that AEA appears to have an anti-inflammatory and immune suppressive effect on hPdLCs' host response to P.gingivalis LPS, whereas 2-AG appears to promote detrimental inflammatory processes. In conclusion

  4. Endocannabinoids and inflammatory response in periodontal ligament cells.

    Science.gov (United States)

    Özdemir, Burcu; Shi, Bin; Bantleon, Hans Peter; Moritz, Andreas; Rausch-Fan, Xiaohui; Andrukhov, Oleh

    2014-01-01

    Endocannabinoids are associated with multiple regulatory functions in several tissues. The main endocannabinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG), have been detected in the gingival crevicular fluid of periodontitis patients, but the association between periodontal disease or human periodontal ligament cells (hPdLCs) and endocannabinoids still remain unclear. The aim of the present study was to examine the effects of AEA and 2-AG on the proliferation/viability and cytokine/chemokine production of hPdLCs in the presence/absence of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS). The proliferation/viability of hPdLCs was measured using 3,4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT)-assay. Interleukin-6 (IL-6), interleukin-8 (IL-8), and monocyte chemotactic protein-1 (MCP-1) levels were examined at gene expression and protein level by real-time PCR and ELISA, respectively. AEA and 2-AG did not reveal any significant effects on proliferation/viability of hPdLCs in the absence of P. gingivalis LPS. However, hPdLCs viability was significantly increased by 10-20 µM AEA in the presence of P. gingivalis LPS (1 µg/ml). In the absence of P. gingivalis LPS, AEA and 2-AG did not exhibit any significant effect on the expression of IL-8 and MCP-1 expression in hPdLCs, whereas IL-6 expression was slightly enhanced by 10 µM 2-AG and not affected by AEA. In P.gingivalis LPS stimulated hPdLCs, 10 µM AEA down-regulated gene-expression and protein production of IL-6, IL-8, and MCP-1. In contrast, 10 µM 2-AG had an opposite effect and induced a significant up-regulation of gene and protein expression of IL-6 and IL-8 (P<0.05) as well as gene-expression of MCP-1 in P. gingivalis LPS stimulated hPdLCs. Our data suggest that AEA appears to have an anti-inflammatory and immune suppressive effect on hPdLCs' host response to P.gingivalis LPS, whereas 2-AG appears to promote detrimental inflammatory processes. In conclusion, AEA and 2

  5. CD40/CD40L Dyad in the Inflammatory and Immune Responses in the Central Nervous System

    Institute of Scientific and Technical Information of China (English)

    Keqiang Chen; Jian Huang; Wanghua Gong; Lingzhi Zhang; Peichu Yu; Ji Ming Wang

    2006-01-01

    CD40 and its cognate ligand (CD40L) are a pair of regulators of pro-inflammatory and immune responses. In the central nervous system (CNS), CD40 is expressed on a variety of cells, including vascular endothelial cells, smooth muscle cells, astrocytes and microglia (the brain macrophages, being the most sensitive cell type to respond to CD40 ligand). Interaction between CD40 on microglia and CD40L presented by infiltrating T lymphocytes and other resident CNS cells triggers a series of intracellular signaling events that promote the production of a wide array of cytokines, chemokines and neurotoxins. Thus, both molecules serve as amplifiers of pro-inflammatory and immune responses in the CNS and constitute important molecular targets for therapeutic intervention of diseases.

  6. Dextromethorphan provides neuroprotection via anti-inflammatory and anti-excitotoxicity effects in the cortex following traumatic brain injury.

    Science.gov (United States)

    Pu, Benfang; Xue, Yonghua; Wang, Qingming; Hua, Chunhui; Li, Xinyuan

    2015-09-01

    Traumatic brain injury (TBI) is caused by primary and secondary injury mechanisms. TBI induces a certain amount of inflammatory responses and glutamate excitotoxicity that are believed to participate in the pathogenesis of secondary injury. The non‑narcotic anti‑tussive drug dextromethorphan (DM) has been reported to have a high safety profile in humans and its neuroprotective against a variety of disorders, including cerebral ischemia, epilepsy and acute brain injury. However, few studies have explored the underlying mechanisms of the neuroprotective effects of DM in animals in the setting of TBI. The aim of the present study was to investigate the neuroprotective effects of DM on TBI and to determine the underlying mechanisms. Rats were subjected to a controlled cortical impact (CCI) injury and randomly divided into three groups: Sham‑operated, TBI and DM treatment groups. The DM treatment group was administered DM (30 mg/kg of body weight, intraperitoneally) immediately after injury. It was identified that DM treatment following TBI significantly reduced brain edema and neurological deficits, as well as increased neuronal survival. These effects correlated with a decrease of tumor necrosis factor α, interleukin‑1β (IL‑1β) and IL‑6 protein expression and an increase of glutamate/aspartate transporter and glutamate transporter‑1 in the cortex of the brain. These results provided in vivo evidence that DM exerts neuroprotective effects via reducing inflammation and excitotoxicity induced following TBI. The present study has shed light on the potential use of DM as a neuroprotective agent in the treatment of cerebral injuries.

  7. Monitoring the Response of Hyperbilirubinemia in the Mouse Brain by In Vivo Bioluminescence Imaging.

    Science.gov (United States)

    Manni, Isabella; Di Rocco, Giuliana; Fusco, Salvatore; Leone, Lucia; Barbati, Saviana Antonella; Carapella, Carmine Maria; Grassi, Claudio; Piaggio, Giulia; Toietta, Gabriele

    2016-12-28

    Increased levels of unconjugated bilirubin are neurotoxic, but the mechanism leading to neurological damage has not been completely elucidated. Innovative strategies of investigation are needed to more precisely define this pathological process. By longitudinal in vivo bioluminescence imaging, we noninvasively visualized the brain response to hyperbilirubinemia in the MITO-Luc mouse, in which light emission is restricted to the regions of active cell proliferation. We assessed that acute hyperbilirubinemia promotes bioluminescence in the brain region, indicating an increment in the cell proliferation rate. Immunohistochemical detection in brain sections of cells positive for both luciferase and the microglial marker allograft inflammatory factor 1 suggests proliferation of microglial cells. In addition, we demonstrated that brain induction of bioluminescence was altered by pharmacological displacement of bilirubin from its albumin binding sites and by modulation of the blood-brain barrier permeability, all pivotal factors in the development of bilirubin-induced neurologic dysfunction. We also determined that treatment with minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, or administration of bevacizumab, an anti-vascular endothelial growth factor antibody, blunts bilirubin-induced bioluminescence. Overall the study supports the use of the MITO-Luc mouse as a valuable tool for the rapid response monitoring of drugs aiming at preventing acute bilirubin-induced neurological dysfunction.

  8. Effects of blood products on inflammatory response in endothelial cells in vitro.

    Directory of Open Access Journals (Sweden)

    Martin Urner

    Full Text Available BACKGROUND: Transfusing blood products may induce inflammatory reactions within the vascular compartment potentially leading to a systemic inflammatory response. Experiments were designed to assess the inflammatory potential of different blood products in an endothelial cell-based in vitro model and to compare baseline levels of potentially activating substances in transfusion products. METHODS: The inflammatory response from pre-activated (endotoxin-stimulated and non-activated endothelial cells as well as neutrophil endothelial transmigration in response to packed red blood cells (PRBC, platelet concentrates (PC and fresh frozen plasma (FFP was determined. Baseline inflammatory mediator and lipid concentrations in blood products were evaluated. RESULTS: Following incubation with all blood products, an increased inflammatory mediator release from endothelial cells was observed. Platelet concentrates, and to a lesser extent also FFP, caused the most pronounced response, which was accentuated in already pre-stimulated endothelial cells. Inflammatory response of endothelial cells as well as blood product-induced migration of neutrophils through the endothelium was in good agreement with the lipid content of the according blood product. CONCLUSION: Within the group of different blood transfusion products both PC and FFP have a high inflammatory potential with regard to activation of endothelial cells. Inflammation upon blood product exposure is strongly accentuated when endothelial cells are pre-injured. High lipid contents in the respective blood products goes along with an accentuated inflammatory reaction from endothelial cells.

  9. Intramuscular nerve damage in lacerated skeletal muscles may direct the inflammatory cytokine response during recovery.

    Science.gov (United States)

    Pereira, Barry P; Tan, Bee Leng; Han, Hwan Chour; Zou, Yu; Aung, Khin Zarchi; Leong, David T

    2012-07-01

    The expression of inflammatory cytokines and growth factors in surgically repaired lacerated muscles over a 12-week recovery phase was investigated. We hypothesized that these expression levels are influenced by both neural and muscular damage within lacerated muscles. Microarrays were confirmed with reverse transcription-polymerase chain reaction assays and histology of biopsies at the lesion of three simulated lacerated muscle models in 130 adult rats. The lacerated medial gastrocnemius with the main intramuscular nerve branch either cut (DN), crushed but leaving an intact nerve sheath (RN); or preserved intact (PN) were compared. At 4 weeks, DN had a higher number of interleukins up-regulated. DN and RN also had a set of Bmp genes significantly expressed between 2 and 8 weeks (P ≤ 0.05). By 12 weeks, DN had a poorer and slower myogenic recovery and greater fibrosis formation correlating with an up-regulation of the Tgf-β gene family. DN also showed poorer re-innervation with higher mRNA expression levels of nerve growth factor (Ngf) and brain-derived neurotrophin growth factor (Bdnf) over RN and PN. This study demonstrates that the inflammatory response over 12 weeks in lacerated muscles may be directed by the type of intramuscular nerve damage, which can influence the recovery at the lesion site. Inflammatory-related genes associated to the type of intramuscular nerve damage include Gas-6, Artemin, Fgf10, Gdf8, Cntf, Lif, and Igf-2. qPCR also found up-regulation of Bdnf (1-week), neurotrophin-3 (2w), Lif (4w), and Ngf (4w, 8w) mRNA expressions in DN, making them possible candidates for therapeutic treatment to arrest the poor recovery in muscle lacerations (250).

  10. Naoxintong dose effects on inflammatory factor expression in the rat brain following focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Xiangjian Zhang; Li Xü; Zuoran Chen; Shuchao Hu; Liying Zhang; Haiyan Li; Ruichun Liu

    2008-01-01

    well as the high-dose, moderate-dose, and low-dose Naoxintong groups at 24 hours, which reached a peak at 48 hours. At 6, 24, 48, 72 hours, and 7 days, brain water content was greater in the ischemic hemisphere of rats from the saline, as well as the high-dose, moderate-dose, and low-dose Naoxintong groups, compared with the sham operation group (P < 0.05). At 24 and 48 hours, brain water content was reduced in the high-dose and moderate-dose Naoxintong groups, compared to the saline and low-dose Naoxintong groups (P < 0.05). In the saline, as well as high-dose, moderate-dose, and low-dose Naoxintong groups, neuronal edema was observed at 6 hours surrounding the ischemic sites. Inflammatory cells appeared at 24 hours, reached a peak at 48 hours, and gradually diminished. A small amount of glial cell proliferation and neuronal degeneration were observed in the hippocampus at 72 hours following infarction. Microglial proliferation and aggregation were detected at 7 days after infarction. Expression of nuclear factor-κB, interleukin-6, tumor necrosis factor- α, and complement 3 was significantly less in the high-dose, moderate-dose, and low-dose Naoxintong groups, compared to the sham operation group (P < 0.05). Expression of the above-mentioned inflammatory cytokines was lower in rat brain tissues of the high-dose Naoxintong group, compared to the low-dose Naoxintong group (P < 0.05).CONCLUSION: High-dose Naoxintong and moderate-dose Naoxintong significantly alleviated rat brain edema and decreased expression of nuclear factor- κB, interleukin-6, tumor necrosis factor- α, and complement 3 in brain tissues. The protective effect of high-dose Naoxintong was most significant.

  11. Effects of Acute Lithium Treatment on Brain Levels of Inflammatory Mediators in Poststroke Rats

    Directory of Open Access Journals (Sweden)

    Matthew Boyko

    2015-01-01

    Full Text Available Stroke is a leading cause of mortality and morbidity worldwide. Few therapeutic options with proven efficacy are available for the treatment of this disabling disease. Lithium is the gold standard treatment for bipolar disorder. Moreover, lithium has been shown to exhibit neuroprotective effects and therapeutic efficacy as a treatment of other neurological disorders. This study was undertaken to examine the effects of lithium on brain inflammatory mediators levels, fever, and mortality in postischemic stroke rats. Ischemic stroke was induced by occlusion of the mid cerebral artery (MCAO. Pretreatment with a single dose of lithium at 2 hours before MCAO induction significantly reduced the elevation in interleukin- (IL- 6 and prostaglandin E2 levels in brain of post-MCAO rats, as compared to vehicle-treated animals. On the other hand, lithium did not affect the elevation in IL-1α, IL-10, IL-12, and tumor necrosis factor-α levels in brain of post-MCAO rats. Moreover, pretreatment with lithium did not alter post-MCAO fever and mortality. These results suggest that acute pretreatment with a single dose of lithium did not markedly affect post-MCAO morbidity and mortality in rats.

  12. Galectin-3 released in response to traumatic brain injury acts as an alarmin orchestrating brain immune response and promoting neurodegeneration

    Science.gov (United States)

    Yip, Ping Kei; Carrillo-Jimenez, Alejandro; King, Paul; Vilalta, Anna; Nomura, Koji; Chau, Chi Cheng; Egerton, Alexander Michael Scott; Liu, Zhuo-Hao; Shetty, Ashray Jayaram; Tremoleda, Jordi L.; Davies, Meirion; Deierborg, Tomas; Priestley, John V.; Brown, Guy Charles; Michael-Titus, Adina Teodora; Venero, Jose Luis; Burguillos, Miguel Angel

    2017-01-01

    Traumatic brain injury (TBI) is currently a major cause of morbidity and poor quality of life in Western society, with an estimate of 2.5 million people affected per year in Europe, indicating the need for advances in TBI treatment. Within the first 24 h after TBI, several inflammatory response factors become upregulated, including the lectin galectin-3. In this study, using a controlled cortical impact (CCI) model of head injury, we show a large increase in the expression of galectin-3 in microglia and also an increase in the released form of galectin-3 in the cerebrospinal fluid (CSF) 24 h after head injury. We report that galectin-3 can bind to TLR-4, and that administration of a neutralizing antibody against galectin-3 decreases the expression of IL-1β, IL-6, TNFα and NOS2 and promotes neuroprotection in the cortical and hippocampal cell populations after head injury. Long-term analysis demonstrated a significant neuroprotection in the cortical region in the galectin-3 knockout animals in response to TBI. These results suggest that following head trauma, released galectin-3 may act as an alarmin, binding, among other proteins, to TLR-4 and promoting inflammation and neuronal loss. Taking all together, galectin-3 emerges as a clinically relevant target for TBI therapy. PMID:28128358

  13. Lactic acid delays the inflammatory response of human monocytes

    Energy Technology Data Exchange (ETDEWEB)

    Peter, Katrin, E-mail: katrin.peter@ukr.de [Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg (Germany); Rehli, Michael, E-mail: michael.rehli@ukr.de [Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg (Germany); RCI Regensburg Center for Interventional Immunology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg (Germany); Singer, Katrin, E-mail: katrin.singer@ukr.de [Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg (Germany); Renner-Sattler, Kathrin, E-mail: kathrin.renner-sattler@ukr.de [Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg (Germany); Kreutz, Marina, E-mail: marina.kreutz@ukr.de [Department of Internal Medicine III, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg (Germany); RCI Regensburg Center for Interventional Immunology, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg (Germany)

    2015-02-13

    Lactic acid (LA) accumulates under inflammatory conditions, e.g. in wounds or tumors, and influences local immune cell functions. We previously noted inhibitory effects of LA on glycolysis and TNF secretion of human LPS-stimulated monocytes. Here, we globally analyze the influence of LA on gene expression during monocyte activation. To separate LA-specific from lactate- or pH-effects, monocytes were treated for one or four hours with LPS in the presence of physiological concentrations of LA, sodium lactate (NaL) or acidic pH. Analyses of global gene expression profiles revealed striking effects of LA during the early stimulation phase. Up-regulation of most LPS-induced genes was significantly delayed in the presence of LA, while this inhibitory effect was attenuated in acidified samples and not detected after incubation with NaL. LA targets included genes encoding for important monocyte effector proteins like cytokines (e.g. TNF and IL-23) or chemokines (e.g. CCL2 and CCL7). LA effects were validated for several targets by quantitative RT-PCR and/or ELISA. Further analysis of LPS-signaling pathways revealed that LA delayed the phosphorylation of protein kinase B (AKT) as well as the degradation of IκBα. Consistently, the LPS-induced nuclear accumulation of NFκB was also diminished in response to LA. These results indicate that the broad effect of LA on gene expression and function of human monocytes is at least partially caused by its interference with immediate signal transduction events after activation. This mechanism might contribute to monocyte suppression in the tumor environment. - Highlights: • Lactic acid broadly delays LPS-induced gene expression in human monocytes. • Expression of important monocyte effector molecules is affected by lactic acid. • Interference of lactic acid with TLR signaling causes the delayed gene expression. • The profound effect of lactic acid might contribute to immune suppression in tumors.

  14. Inflammatory response in patients undergoing uterine artery embolization as compared to patients undergoing conventional hysterectomy

    DEFF Research Database (Denmark)

    Brøchner, A C; Mygil, B; Elle, B;

    2009-01-01

    : To investigate whether uterine artery embolization generates a reduced inflammatory response as compared with conventional hysterectomy. MATERIAL AND METHODS: 40 women, 20 in each group, entered this prospective, non-randomized study. The two groups were comparable concerning age, comorbidity, and body......-mass index (BMI). RESULTS: We found a significant difference between the inflammatory responses in women undergoing embolization compared with the inflammatory response in women having an abdominal hysterectomy. Women undergoing embolization were subjected to a much smaller inflammatory burden, their total...... morphine consumption was lower, and their return to work was faster than women subjected to conventional hysterectomy. CONCLUSION: Uterine artery embolization generates a reduced inflammatory response compared with conventional hysterectomy....

  15. Diffusion Based Modeling of Human Brain Response to External Stimuli

    CERN Document Server

    Namazi, Hamidreza

    2012-01-01

    Human brain response is the overall ability of the brain in analyzing internal and external stimuli in the form of transferred energy to the mind/brain phase-space and thus, making the proper decisions. During the last decade scientists discovered about this phenomenon and proposed some models based on computational, biological, or neuropsychological methods. Despite some advances in studies related to this area of the brain research there was less effort which have been done on the mathematical modeling of the human brain response to external stimuli. This research is devoted to the modeling of human EEG signal, as an alert state of overall human brain activity monitoring, due to receiving external stimuli, based on fractional diffusion equation. The results of this modeling show very good agreement with the real human EEG signal and thus, this model can be used as a strong representative of the human brain activity.

  16. S1PR1 expression correlates with inflammatory responses to Newcastle disease virus infection.

    Science.gov (United States)

    Li, Yaling; Xie, Peng; Sun, Minhua; Xiang, Bin; Kang, Yinfeng; Gao, Pei; Zhu, Wenxian; Ning, Zhangyong; Ren, Tao

    2016-01-01

    Newcastle disease virus (NDV) is the causative agent of Newcastle disease, which is characterized by inflammatory pathological changes in the organs of chickens. The inflammatory response to this disease has not been well characterized. Previous reports showed that the sphingosine-1-phosphate-1 receptor (S1PR1), a G protein-coupled receptor, is important to the activation of inflammatory responses. To understand better the viral pathogenesis and host inflammatory response, we analyzed S1PR1 expression during NDV infection. We observed a direct correlation between chicken embryo fibroblast (CEF) cellular inflammatory responses and S1PR1 expression. Virulent NDV-infected CEF cells also had elevated levels of pro-inflammatory cytokines (IL-1β, IL-6 and IL-18). When S1PR1 was inhibited by using the specific antagonist W146, pro-inflammatory cytokine production declined. Overexpression of S1PR1 resulted in increased virus-induced IL-1β production. S1PR1 expression levels did not impact significantly NDV replication. These findings highlight the important role of S1PR1 in inflammatory responses in NDV infection.

  17. Dihydropyrimidinase-like 3 regulates the inflammatory response of activated microglia.

    Science.gov (United States)

    Manivannan, J; Tay, S S W; Ling, E-A; Dheen, S T

    2013-12-03

    Microglia, the resident immune cells of the CNS, are known to respond to injuries, infection and inflammation in the CNS by producing proinflammatory cytokines and phagocytosing cell debris and pathogens. In this study, we investigated the expression pattern and role of dihydropyrimidinase-like 3 (Dpysl3), a member of collapsin response mediator protein family, on the inflammatory reaction of microglia. Microarray analysis comparing the global gene expression profile of ameboid and ramified microglia has shown that Dpysl3 is mainly expressed in ameboid microglia in the 5-day postnatal rat brain. Immunohistochemical analysis revealed that Dpysl3 was intensely expressed in ameboid microglial cells in the rat brain till postnatal 7th day and then gradually diminished in ramified microglia of 2 weeks postnatal rat brain. Further, in vitro analysis confirmed that Dpysl3 expression was induced in activated BV-2 microglia treated with lipopolysaccharide (LPS). It is well documented that microglial activation by LPS increased the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity in BV-2 microglia. However, siRNA-mediated knockdown of Dpysl3 prevented the LPS-induced expression of iNOS and cytokines including interleukin-1 beta, and tumor necrosis factor-alpha as well as nuclear translocation of NF-κB in microglia. Remarkably, knockdown of Dpysl3 inhibited the migration of activated microglia coupled with deranged actin filament configuration (as revealed by F-actin cytoskeleton expression) in lamellipodia projecting from the cells. Knockdown of Dpysl3 also inhibited the phagocytic ability of activated microglia. These findings suggest that knockdown of Dpysl3 can inhibit activation, migration and phagocytic capability of microglia and consequently reduce neuroinflammation.

  18. 4T1 Murine Mammary Carcinoma Cells Enhance Macrophage-Mediated Innate Inflammatory Responses

    OpenAIRE

    Laurence Madera; Anna Greenshields; Power Coombs, Melanie R.; Hoskin, David W.

    2015-01-01

    Tumor progression and the immune response are intricately linked. While it is known that cancers alter macrophage inflammatory responses to promote tumor progression, little is known regarding how cancers affect macrophage-dependent innate host defense. In this study, murine bone-marrow-derived macrophages (BMDM) were exposed to murine carcinoma-conditioned media prior to assessment of the macrophage inflammatory response. BMDMs exposed to 4T1 mammary carcinoma-conditioned medium demonstrated...

  19. Enriched environment decreases microglia and brain macrophages inflammatory phenotypes through adiponectin-dependent mechanisms: Relevance to depressive-like behavior.

    Science.gov (United States)

    Chabry, Joëlle; Nicolas, Sarah; Cazareth, Julie; Murris, Emilie; Guyon, Alice; Glaichenhaus, Nicolas; Heurteaux, Catherine; Petit-Paitel, Agnès

    2015-11-01

    Regulation of neuroinflammation by glial cells plays a major role in the pathophysiology of major depression. While astrocyte involvement has been well described, the role of microglia is still elusive. Recently, we have shown that Adiponectin (ApN) plays a crucial role in the anxiolytic/antidepressant neurogenesis-independent effects of enriched environment (EE) in mice; however its mechanisms of action within the brain remain unknown. Here, we show that in a murine model of depression induced by chronic corticosterone administration, the hippocampus and the hypothalamus display increased levels of inflammatory cytokines mRNA, which is reversed by EE housing. By combining flow cytometry, cell sorting and q-PCR, we show that microglia from depressive-like mice adopt a pro-inflammatory phenotype characterized by higher expression levels of IL-1β, IL-6, TNF-α and IκB-α mRNAs. EE housing blocks pro-inflammatory cytokine gene induction and promotes arginase 1 mRNA expression in brain-sorted microglia, indicating that EE favors an anti-inflammatory activation state. We show that microglia and brain-macrophages from corticosterone-treated mice adopt differential expression profiles for CCR2, MHC class II and IL-4recα surface markers depending on whether the mice are kept in standard environment or EE. Interestingly, the effects of EE were abolished when cells are isolated from ApN knock-out mouse brains. When injected intra-cerebroventricularly, ApN, whose level is specifically increased in cerebrospinal fluid of depressive mice raised in EE, rescues microglia phenotype, reduces pro-inflammatory cytokine production by microglia and blocks depressive-like behavior in corticosterone-treated mice. Our data suggest that EE-induced ApN increase within the brain regulates microglia and brain macrophages phenotype and activation state, thus reducing neuroinflammation and depressive-like behaviors in mice.

  20. Principal component analysis of the cytokine and chemokine response to human traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Adel Helmy

    Full Text Available There is a growing realisation that neuro-inflammation plays a fundamental role in the pathology of Traumatic Brain Injury (TBI. This has led to the search for biomarkers that reflect these underlying inflammatory processes using techniques such as cerebral microdialysis. The interpretation of such biomarker data has been limited by the statistical methods used. When analysing data of this sort the multiple putative interactions between mediators need to be considered as well as the timing of production and high degree of statistical co-variance in levels of these mediators. Here we present a cytokine and chemokine dataset from human brain following human traumatic brain injury and use principal component analysis and partial least squares discriminant analysis to demonstrate the pattern of production following TBI, distinct phases of the humoral inflammatory response and the differing patterns of response in brain and in peripheral blood. This technique has the added advantage of making no assumptions about the Relative Recovery (RR of microdialysis derived parameters. Taken together these techniques can be used in complex microdialysis datasets to summarise the data succinctly and generate hypotheses for future study.

  1. Neuroendocrine modulation of the inflammatory response in common carp: adrenaline regulates leukocyte profile and activity

    NARCIS (Netherlands)

    Kepka, M.; Verburg-van Kemenade, B.M.L.; Chadzinska, M.K.

    2013-01-01

    Inflammatory responses have to be carefully controlled, as high concentrations and/or prolonged action of inflammation-related molecules (e.g. reactive oxygen species, nitric oxide and pro-inflammatory cytokines) can be detrimental to host tissue and organs. One of the potential regulators of the in

  2. A new role for T cells in dampening innate inflammatory responses

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The inflammatory response is an attempt by a host to protect itself against injurious stimuli and initiate the tissue healing process [1,2]. Although the production of both pro-and anti-inflammatory mediators which occurs mainly within tissues is a systemic process,

  3. The inflammatory response in cardiac surgery: an overview of the pathophysiology and clinical implications.

    Science.gov (United States)

    Corral-Velez, Vicente; Lopez-Delgado, Juan C; Betancur-Zambrano, Nelson L; Lopez-Suñe, Neus; Rojas-Lora, Mariel; Torrado, Herminia; Ballus, Josep

    2015-01-01

    During cardiac surgery different factors, such as the aortic clamp, the extracorporeal circulation and the surgical injury itself, produce complex inflammatory responses which can lead to varying degrees of ischemia-reperfusion injury and/or systemic inflammatory response. This may have clinical implications due to hemodynamic changes related with an enlarged vasodilatory response. Thus, maintaining adequate levels of blood pressure during and after cardiac surgery represents a challenge for physicians when inflammatory response appears. The use of noradrenaline to raise arterial pressure is the most current pharmacological approach in the operating room and ICU. However, it is not always effective and other drugs, such as methylene blue, have to be used among others in specific cases as rescue therapy. The aim of our research is to review briefly the pathophysiology and clinical implications in the treatment of the inflammatory response in cardiac surgery, together with the mechanisms involved in those treatments.

  4. Electrical resistance increases at the tissue-electrode interface as an early response to nucleus accumbens deep brain stimulation.

    Science.gov (United States)

    Kale, Rajas P; Kouzani, Abbas Z; Berk, Julian; Walder, Ken; Berk, Michael; Tye, Susannah J; Kale, Rajas P; Kouzani, Abbas Z; Berk, Julian; Walder, Ken; Berk, Michael; Tye, Susannah J; Berk, Julian; Berk, Michael; Tye, Susannah J; Kouzani, Abbas Z; Kale, Rajas P; Walder, Ken

    2016-08-01

    The therapeutic actions of deep brain stimulation are not fully understood. The early inflammatory response of electrode implantation is associated with symptom relief without electrical stimulation, but is negated by anti-inflammatory drugs. Early excitotoxic necrosis and subsequent glial scarring modulate the conductivity of the tissue-electrode interface, which can provide some detail into the inflammatory response of individual patients. The feasibility of this was demonstrated by measuring resistance values across a bipolar electrode which was unilaterally implanted into the nucleus accumbens of a rat while receiving continuous deep brain stimulation with a portable back-mounted device using clinical parameters (130Hz, 200μA, 90μs) for 3 days. Daily resistance values rose significantly (pstimulation.

  5. Myeloperoxidase modulates lung epithelial responses to pro-inflammatory agents

    NARCIS (Netherlands)

    Haegens, A.; Vernooy, J. H. J.; Heeringa, P.; Mossman, B. T.; Wouters, E. F. M.

    2008-01-01

    During extensive inflammation, neutrophils undergo secondary necrosis causing myeloperoxidase (MPO) release that may damage resident lung cells. Recent observations suggest that MPO has pro-inflammatory properties, independent of its enzymatic activity. The aims of the present study were to characte

  6. Imaging of an inflammatory injury in the newborn rat brain with photoacoustic tomography.

    Directory of Open Access Journals (Sweden)

    Edgar Guevara

    Full Text Available BACKGROUND: The precise assessment of cerebral saturation changes during an inflammatory injury in the developing brain, such as seen in periventricular leukomalacia, is not well defined. This study investigated the impact of inflammation on locoregional cerebral oxygen saturation in a newborn rodent model using photoacoustic imaging. METHODS: 1 mg/kg of lipopolysaccharide(LPS diluted in saline or saline alone was injected under ultrasound guidance directly in the corpus callosum of P3 rat pups. Coronal photoacoustic images were carried out 24 h after LPS exposure. Locoregional oxygen saturation (SO2 and resting state connectivity were assessed in the cortex and the corpus callosum. Microvasculature was then evaluated on cryosection slices by lectin histochemistry. RESULTS: Significant reduction of SO2 was found in the corpus callosum; reduced SO2 was also found in the cortex ipsilateral to the injection site. Seed-based functional connectivity analysis showed that bilateral connectivity was not affected by LPS exposure. Changes in locoregional oxygen saturation were accompanied by a significant reduction in the average length of microvessels in the left cortex but no differences were observed in the corpus callosum. CONCLUSION: Inflammation in the developing brain induces marked reduction of locoregional oxygen saturation, predominantly in the white matter not explained by microvascular degeneration. The ability to examine regional saturation offers a new way to monitor injury and understand physiological disturbance non-invasively.

  7. Dissemination of Orientia tsutsugamushi and inflammatory responses in a murine model of scrub typhus.

    Directory of Open Access Journals (Sweden)

    Christian A Keller

    2014-08-01

    Full Text Available Central aspects in the pathogenesis of scrub typhus, an infection caused by Orientia (O. tsutsugamushi, have remained obscure. Its organ and cellular tropism are poorly understood. The purpose of this study was to analyze the kinetics of bacterial dissemination and associated inflammatory responses in infected tissues in an experimental scrub typhus mouse model, following infection with the human pathogenic strain Karp. We provide a thorough analysis of O. tsutsugamushi infection in inbred Balb/c mice using footpad inoculation, which is close to the natural way of infection. By a novel, highly sensitive qPCR targeting the multi copy traD genes, we quantitatively monitored the spread of O. tsutsugamushi Karp from the skin inoculation site via the regional lymph node to the internal target organs. The highest bacterial loads were measured in the lung. Using confocal imaging, we also detected O. tsutsugamushi at the single cell level in the lung and found a predominant macrophage rather than endothelial localization. Immunohistochemical analysis of infiltrates in lung and brain revealed differently composed lesions with specific localizations: iNOS-expressing macrophages were frequent in infiltrative parenchymal noduli, but uncommon in perivascular lesions within these organs. Quantitative analysis of the macrophage response by immunohistochemistry in liver, heart, lung and brain demonstrated an early onset of macrophage activation in the liver. Serum levels of interferon (IFN-γ were increased during the acute infection, and we showed that IFN-γ contributed to iNOS-dependent bacterial growth control. Our data show that upon inoculation to the skin, O. tsutsugamushi spreads systemically to a large number of organs and gives rise to organ-specific inflammation patterns. The findings suggest an essential role for the lung in the pathogenesis of scrub typhus. The model will allow detailed studies on host-pathogen interaction and provide further

  8. Managing the Inflammatory Response after Cardiopulmonary Bypass : Review of the Studies in Animal Models

    NARCIS (Netherlands)

    Liguori, Gabriel Romero; Kanas, Alexandre Fligelman; Moreira, Luiz Felipe Pinho

    2014-01-01

    OBJECTIVE: To review studies performed in animal models that evaluated therapeutic interventions to inflammatory response and microcirculatory changes after cardiopulmonary bypass. METHODS: It was used the search strategy ("Cardiopulmonary Bypass" (MeSH)) and ("Microcirculation" (MeSH) or "Inflammat

  9. Neuroprotection and enhanced neurogenesis by extract from the tropical plant Knema laurina after inflammatory damage in living brain tissue.

    Science.gov (United States)

    Häke, Ines; Schönenberger, Silvia; Neumann, Jens; Franke, Katrin; Paulsen-Merker, Katrin; Reymann, Klaus; Ismail, Ghazally; Bin Din, Laily; Said, Ikram M; Latiff, A; Wessjohann, Ludger; Zipp, Frauke; Ullrich, Oliver

    2009-01-03

    Inflammatory reactions in the CNS, resulting from a loss of control and involving a network of non-neuronal and neuronal cells, are major contributors to the onset and progress of several major neurodegenerative diseases. Therapeutic strategies should therefore keep or restore the well-controlled and finely-tuned balance of immune reactions, and protect neurons from inflammatory damage. In our study, we selected plants of the Malaysian rain forest by an ethnobotanic survey, and investigated them in cell-based-assay-systems and in living brain tissue cultures in order to identify anti-inflammatory and neuroprotective effects. We found that alcoholic extracts from the tropical plant Knema laurina (Black wild nutmeg) exhibited highly anti-inflammatory and neuroprotective effects in cell culture experiments, reduced NO- and IL-6-release from activated microglia cells dose-dependently, and protected living brain tissue from microglia-mediated inflammatory damage at a concentration of 30 microg/ml. On the intracellular level, the extract inhibited ERK-1/2-phosphorylation, IkB-phosphorylation and subsequently NF-kB-translocation in microglia cells. K. laurina belongs to the family of Myristicaceae, which have been used for centuries for treatment of digestive and inflammatory diseases and is also a major food plant of the Giant Hornbill. Moreover, extract from K. laurina promotes also neurogenesis in living brain tissue after oxygen-glucose deprivation. In conclusion, extract from K. laurina not only controls and limits inflammatory reaction after primary neuronal damage, it promotes moreover neurogenesis if given hours until days after stroke-like injury.

  10. Brain Responses Differ to Faces of Mothers and Fathers

    Science.gov (United States)

    Arsalidou, Marie; Barbeau, Emmanuel J.; Bayless, Sarah J.; Taylor, Margot J.

    2010-01-01

    We encounter many faces each day but relatively few are personally familiar. Once faces are familiar, they evoke semantic and social information known about the person. Neuroimaging studies demonstrate differential brain activity to familiar and non-familiar faces; however, brain responses related to personally familiar faces have been more rarely…

  11. Functional MRI of food-induced brain responses

    NARCIS (Netherlands)

    Smeets, P.A.M.

    2006-01-01

    The ultimate goal of this research was to find central biomarkers of satiety, i.e., physiological measures in the brain that relate to subjectively rated appetite, actual food intake, or both. This thesis describes the changes in brain activity in response to food stimuli as measured by functional M

  12. Acute-Phase Inflammatory Response in Idiopathic Sudden Deafness: Pathogenic Implications

    OpenAIRE

    López-González, Miguel A.; Antonio Abrante; Carmen López-Lorente; Antonio Gómez; Emilio Domínguez; Francisco Esteban

    2012-01-01

    The acute-phase inflammatory response in the peripheral bloodstream can be an expression of transient cerebral ischaemia in idiopathic sudden deafness. For this, a neurological and otorhinolaryngological examination of each patient, performing tests on audiometry, and tympanometry, haemogram, and cranial magnetic resonance were performed. The acute-phase inflammatory response manifests as an increased neutrophil/lymphocyte ratio that is detected 48–72 hours after the appearance of sudden deaf...

  13. Citral reduces nociceptive and inflammatory response in rodents

    Directory of Open Access Journals (Sweden)

    Lucindo J. Quintans-Júnior

    2011-06-01

    Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

  14. Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM)-Mediated Protection of Ischemic Brain.

    Science.gov (United States)

    Lin, Chi-Hsin; Wang, Chen-Hsuan; Hsu, Shih-Lan; Liao, Li-Ya; Lin, Ting-An; Hsueh, Chi-Mei

    2016-01-01

    The protective value of neuron-derived conditioned medium (NCM) in cerebral ischemia and the underlying mechanism(s) responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD) for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO) animal model, we discovered that ischemia/reperfusion (I/R)-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFβ1, NT-3 and GDNF) and p-ERK dependent manner. Brain injection with TGFβ1, NT3, GDNF and ERK agonist (DADS) alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1β release from GOSD-treated microglia and limit the infiltration of IL-β-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti-oxidant and potentially anti-glutamate activities (NCM-induced IL-1β can inhibit the glutamate-mediated neurotoxicity) and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFβ1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation.

  15. The Systemic Inflammatory Response in Patients with Appendicitis: a Progressive Phenomenon.

    Science.gov (United States)

    Beltrán, Marcelo A

    2015-12-01

    The systemic inflammatory response has been described in patients with appendicitis. However, its progression from onset of symptoms to diagnosis has not been characterized. The specific purpose of this study was to describe and characterize the systemic inflammatory response to appendicitis. A descriptive cross-sectional study was conducted. One hundred eighty-three patients were studied, divided into four groups from onset of symptoms to diagnosis. The primary outcome measure was to determine the systemic inflammatory response to appendicitis according to the established groups of time intervals. The secondary outcome measure was the analysis of C-reactive protein for the same purpose. The variables of the systemic inflammatory response, according to diagnostic intervals, showed non-significant differences in white blood cell count. The temperature rose constantly after 48 h, reaching its peak after 72 h (p = 0.001), and the respiratory rate rose after 73 h (p inflammatory response criteria (p inflammatory response to appendicitis is progressive, being more marked along the timeline from onset of symptoms to diagnosis.

  16. Benevolent sexism alters executive brain responses.

    Science.gov (United States)

    Dardenne, Benoit; Dumont, Muriel; Sarlet, Marie; Phillips, Christophe; Balteau, Evelyne; Degueldre, Christian; Luxen, André; Salmon, Eric; Maquet, Pierre; Collette, Fabienne

    2013-07-10

    Benevolence is widespread in our societies. It is defined as considering a subordinate group nicely but condescendingly, that is, with charity. Deleterious consequences for the target have been reported in the literature. In this experiment, we used functional MRI (fMRI) to identify whether being the target of (sexist) benevolence induces changes in brain activity associated with a working memory task. Participants were confronted by benevolent, hostile, or neutral comments before and while performing a reading span test in an fMRI environment. fMRI data showed that brain regions associated previously with intrusive thought suppression (bilateral, dorsolateral, prefrontal, and anterior cingulate cortex) reacted specifically to benevolent sexism compared with hostile sexism and neutral conditions during the performance of the task. These findings indicate that, despite being subjectively positive, benevolence modifies task-related brain networks by recruiting supplementary areas likely to impede optimal cognitive performance.

  17. Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats.

    Science.gov (United States)

    Zhang, Tingting; Su, Jingyuan; Guo, Bingyu; Wang, Kaiwen; Li, Xiaoming; Liang, Guobiao

    2015-09-01

    Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro-inflammatory cytokines and chemokines. Disruption of blood-brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-κB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-κB and their downstream pro-inflammatory cytokines in the cortex and by up-regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption.

  18. Age-related differences in the response of the brain to dietary melatonin.

    Science.gov (United States)

    Campbell, Arezoo; Sharman, Edward; Bondy, Stephen C

    2014-02-01

    The aged brain is prone to excessive levels of immune activity, not initiated by an acute response to an extrinsic agent. While dietary melatonin is reported to attenuate the extent of expression of proinflammatory genes, little is known about the extent to which these changes can be translated into altered levels of corresponding proteins. The baseline levels of the proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-1 alpha, were greater in older (~29 months old) compared to younger (~7 months old) mouse brains. Acute (3 h) exposure to lipopolysaccharide (LPS) induced activation of nuclear factor kappa B (NF-κB), but not inflammatory cytokines in the brain. The serum level of TNF-α was increased after LPS injection, indicating a systemic immune response to the bacterial cell wall component. Dietary melatonin (40 ppm for 9.3 weeks) did not prevent LPS-induced changes in younger animals but caused an increased systemic TNF-α response in older mice. Melatonin did reduce markers of carbonyl formation in brain proteins of young animals and nitrosylative damage to peptide-bound amino acid residues, in the brains of older animals. Acute LPS challenge did not significantly affect these oxidative markers. Thus, despite lack of clear evidence of attenuation of the NF-κB-cytokine inflammatory trajectory within the CNS by melatonin, this agent did show a protective effect against free radical-initiated injury to amino acid residues within proteins. The results illustrate that previously reported changes in gene expression following melatonin treatment need not be closely paralleled by corresponding changes in protein content.

  19. Expression of pro-inflammatory and anti-inflammatory cytokines in brain of atherosclerotic rats and effects of Ginkgo biloba extract

    Institute of Scientific and Technical Information of China (English)

    Ya-bin JIAO; Yao-cheng RUI; Tie-jun LI; Peng-yuan YANG; Yan QIU

    2005-01-01

    Aim: To study the protein and mRNA expressions of pro-inflammatory and antiinflammatory cytokines in the brain of rats with atherosclerosis (AS) and the effects of Ginkgo biloba extract (GbE) on expressions of cytokines.Methods:The experimental model of AS in rats were established by intraperitioneal injection of vitamin D3 with high fat/cholesterol diet.GbE 100 mg/kg was administered to rats by ig.After 8 weeks, the expressions of IL- 1β, TNF-α, IL-10, and IL-10R in the brain tissues of AS rats were detected by enzyme-linked immunosorbant assay,immunohistochemistry, Western blotting, and reverse transcriptase polymerase chain reaction.Results: The protein and mRNA expressions of IL-1 β, TNF-α, and IL-10 in the brains were markedly higher in AS groups than that in control groups (6.11±0.15, 1.55±0.14, 0.54±0.04 ng/g wet weight vs 0.80±0.14, 0.33±0.09, and 0.33±0.02 ng/g wet weight, respectively).The protein and mRNA expressions of IL-1β and TNF-α in the brains were markedly lower in GbE groups (3.82±0.54, 0.95±0.08 ng/g wet weight) than that in AS groups, the protein and mRNA expressions of IL-10 and IL-10R in the brains were markedly higher in GbE groups (0.85±0.06 ng/g wet weight) than that in AS groups.Conclusion: GbE inhibited production of pro-inflammatory cytokines IL-1 β and TNF-α, but upregulated the production of anti-inflammatory cytokines, IL-10 and IL-1 0R in brain,which might be related with its anti-AS actions.

  20. VARIABILITY OF LEUKOCYTE COUNT AS AN INFLAMMATORY RESPONSE AMONG HYPERTENSIVES

    Directory of Open Access Journals (Sweden)

    Brinda

    2015-12-01

    Full Text Available INTRODUCTION Hypertension, a globally prevailing non communicable disease has been linked to various pathophysiological mechanisms. The new spotlight is on the inflammatory mechanism, which has been embarked on this study by utilising the White blood cell counts as the predominant marker. The pathogenesis behind this concept is the endothelial alteration which occurs in hypertension, causing increased oxidative stress and release of inflammatory mediators and further causing damage to the vascular walls and may result in sustained hypertension. OBJECTIVE To substantiate the difference in leukocyte count among the hypertensives and normotensives, to assess the variation in the leukocyte count among varied grades of hypertension. METHODS 80 subjects and 40 controls of both sex and age between 20-60 years were taken. Subjects with other chronic medical disorders, pregnancy, menstruation phase, history of infections in past 3 months, obesity, smokers and regular alcoholics were excluded. Three recordings of blood pressure were measured with a standard mercury sphygmomanometer. The differential leukocyte count was estimated with an automated counter. RESULTS Statistical analysis was done using independent sample t-test and one-way ANOVA. Total Leukocyte count (Mean = 8397.50 ± 1666.57 was raised significantly among the hypertensives, with P value <0.001. Comparison was done on the total count with the varied hypertensive years, which was suggestive of increase in total count among the pre hypertensives (systolic pressure and there was linear increase in total count with diastolic pressure though not statistically significant. CONCLUSION The elevation of white blood cell count is suggestive of underlying inflammatory mechanism among the hypertensives. The onset of inflammation could be at the onset of hypertension, as there is rise in total leukocyte count among the pre hypertensives which could also lead to sustained hypertension.

  1. Nutrition before and during Surgery and the Inflammatory Response of the Heart: A Randomized Controlled Trial.

    Science.gov (United States)

    Visser, Marlieke; Niessen, Hans W M; Kok, Wouter E M; Cocchieri, Riccardo; Wisselink, Willem; van Leeuwen, Paul A M; de Mol, Bas A J M

    2015-01-01

    Major surgery induces a long fasting time and provokes an inflammatory response which increases the risk of infections. Nutrition given before and during surgery can avoid fasting and has been shown to increase the arginine/asymmetric dimetlhylarginine ratio, a marker of nitric oxide availability, in cardiac tissue and increased concentrations of branched chain amino acids in blood plasma. However, the effect of this new nutritional strategy on organ inflammatory response is unknown. Therefore, we studied the effect of nutrition before and during cardiac surgery on myocardial inflammatory response. In this trial, 32 patients were randomised between enteral, parenteral, and no nutrition supplementation (control) from 2 days before, during, up to 2 days after coronary artery bypass grafting. Both solutions included proteins or amino acids, glucose, vitamins, and minerals. Myocardial atrial tissue was sampled before and after revascularization and was analysed immunohistochemically, subdivided into cardiomyocytic, fatty, and fibrotic areas. Inflammatory cells, especially leukocytes, were present in cardiac tissue in all study groups. No significant differences were found in the myocardial inflammatory response between the enteral, parenteral, and control groups. In conclusion, nutrition given before and during surgery neither stimulates nor diminishes the myocardial inflammatory response in patients undergoing coronary artery bypass grafting. The trial was registered in Netherlands Trial Register (NTR): NTR2183.

  2. Brain responses to food and weight loss.

    Science.gov (United States)

    Behary, Preeshila; Miras, Alexander D

    2014-09-01

    In this symposium report, we examine how functional neuroimaging has revolutionized the study of human eating behaviour. In the last 20 years, functional magnetic resonance and positron emission tomography techniques have enabled researchers to understand how the human brain regions that control homeostatic and hedonic eating respond to food in physiological and pathological states. Hypothalamic, brainstem, limbic and cortical brain areas form part of a well-co-ordinated brain system that responds to central and peripheral neuronal, hormonal and nutrient signals. Even in physiological conditions, it promotes the consumption of energy-dense food, because this is advantageous in evolutionary terms. Its function is dysregulated in the context of obesity so as to promote weight gain and resist weight loss. Pharmacological and bariatric surgical interventions might be more successful than lifestyle interventions in inducing weight loss and maintenance because, unlike dieting, they reduce not only hunger but also the reward value of food through their actions in homeostatic and hedonic brain regions. Functional neuroimaging is a research tool that cannot be used in isolation; its findings become meaningful and useful only when combined with data from direct measures of eating behaviour. The neuroimaging technology is continuously improving and is expected to contribute further to the in-depth understanding of the obesity phenotype and accelerate the development of more effective and safer treatments for the condition.

  3. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide.

    Science.gov (United States)

    Frank, Matthew G; Miguel, Zurine D; Watkins, Linda R; Maier, Steven F

    2010-01-01

    Acute and chronic stress has been found to sensitize or prime the neuroinflammatory response to both peripheral and central immunologic challenges. Several studies suggest that stress-induced sensitization of neuroinflammatory processes may be mediated by the glucocorticoid (GC) response to stress. GCs, under some conditions, exhibit pro-inflammatory properties, however whether GCs are sufficient to prime neuroinflammatory responses has not been systematically investigated. In the present investigation, we tested whether acute administration of exogenous GCs would be sufficient to reproduce the stress-induced sensitization of neuroinflammatory responses under a number of different timing relationships between GC administration and immune challenge (lipopolysaccharide; LPS). We demonstrate here that GCs potentiate both the peripheral (liver) and central (hippocampus) pro-inflammatory response (e.g. TNFalpha, IL-1beta, IL-6) to a peripheral immune challenge (LPS) if GCs are administered prior (2 and 24h) to challenge. Prior exposure (24h) to GCs also potentiated the pro-inflammatory response of hippocampal microglia to LPS ex vivo. In contrast, when GCs are administered after (1h) a peripheral immune challenge, GCs suppress the pro-inflammatory response to LPS in both liver and hippocampus. GCs also up-regulated microglial activation markers including Toll-like Receptor 2. The present data suggest that the temporal relationship between GC treatment and immune challenge may be an important factor determining whether GCs exhibit pro- or anti-inflammatory properties.

  4. MicroRNA-155 in exosomes secreted from helicobacter pylori infection macrophages immunomodulates inflammatory response

    Science.gov (United States)

    Wang, Jianjun; Deng, Zhiyong; Wang, Zeyou; Wu, Jianhong; Gu, Tao; Jiang, Yibiao; Li, Guangxin

    2016-01-01

    Exosomes containing microRNA-155 act as molecule carriers during immune cell-cell communication and play an important role in the inflammatory response of H. pylori infection macrophages. Previous reports have found that miR-155 was over-expressed in H. pylori infection macrophages, but the significance of which is still unknown. In this study, we analyzed the impact of miR-155 loaded in exosomes derived from macrophages to the inflammatory response of H. pylori infection macrophages and possible mechanisms. We found that miR-155 promoted the expression of inflammatory cytokines including TNF-a, IL-6, IL-23, but also increased the expression of CD40, CD63, CD81, and MCH-I. Meanwhile, inflammatory signal pathways proteins, such as MyD88, NF-κB in H. pylori infection macrophages were down-regulated due to the over-expression of miR-155. Experiments in vitro or in vivo revealed that miR-155 promoted macrophages to inhibit or kill H. pylori by regulating the inflammatory response of cells to prevent the gastritis caused by H. pylori infection. These findings contribute to the understanding of miR-155 contained in exosomes in inflammatory responses of H. pylori infection macrophages. PMID:27725852

  5. Topical insulin application improves healing by regulating the wound inflammatory response.

    Science.gov (United States)

    Chen, Xuelian; Liu, Yan; Zhang, Xiong

    2012-01-01

    Inflammation, the initiating stage of wound healing, is characterized by increased endothelial permeability, infiltration of inflammatory cells, and secretion of numerous growth factors and chemokines. By controlling wound contamination and infection, as well as inducing the repairing process, inflammatory response plays an irreplaceable role during wound healing. We utilized a variety of approaches to observe the effect of insulin on wound inflammatory response, specifically the effect of insulin on the function of wound macrophages. We also investigated whether insulin-regulated inflammatory response contributed to insulin-induced healing. Mice excisional wounds treated with insulin showed advanced infiltration and resolution of macrophages, which correlated with the expression of monocyte chemotactic protein-1, a potent chemotactic factor for macrophages. Blockage of monocyte chemotactic protein-1 resulted in reduced macrophages infiltration and impaired wound healing despite the presence of insulin. In vitro studies showed insulin-facilitated monocytes/macrophages chemotaxis, pinocytosis/phagocytosis, and secretion of inflammatory mediators as well. Our study strongly suggests that insulin is a potent healing accelerant. Regulating wound inflammatory response, especially the quantity and function of macrophages, is one of the mechanisms explaining insulin-induced accelerated wound healing.

  6. Inhibition of inflammatory mediator release from microglia can treat ischemic/hypoxic brain injury

    Institute of Scientific and Technical Information of China (English)

    Huaibo Wang; Weitao Guo; Hongliang Liu; Rong Zeng; Mingnan Lu; Ziqiu Chen; Qixian Xiao

    2013-01-01

    Interleukin-1α and interleukin-1β aggravate neuronal injury by mediating the inflammatory reaction following ischemic/hypoxic brain injury. It remains unclear whether interleukin-1α and interleukin-1β are released by microglia or astrocytes. This study prepared hippocampal slices that were subsequently subjected to oxygen and glucose deprivation. Hematoxylin-eosin staining verified that neurons exhibited hypoxic changes. Results of enzyme-linked immunosorbent assay found that interleukin-1α and interleukin-1β participated in this hypoxic process. Moreover, when hypoxic injury occurred in the hippocampus, the release of interleukin-1α and interleukin-1β was mediated by the P2X4 receptor and P2X7 receptor. Immunofluorescence staining revealed that during ischemia/hypoxia, the P2X4 receptor, P2X7 receptor, interleukin-1α and interleukin-1β expression was detectable in rat hippocampal microglia, but only P2X4 receptor and P2X7 receptor expression was detected in astrocytes. Results suggested that the P2X4 receptor and P2X7 receptor, respectively, mediated interleukin-1α and interleukin-1β released by microglia, resulting in hippocampal ischemic/hypoxic injury. Astrocytes were activated, but did not synthesize or release interleukin-1α and interleukin-1β.

  7. The laminin response in inflammatory bowel disease: protection or malignancy?

    Directory of Open Access Journals (Sweden)

    Caroline Spenlé

    Full Text Available Laminins (LM, basement membrane molecules and mediators of epithelial-stromal communication, are crucial in tissue homeostasis. Inflammatory Bowel Diseases (IBD are multifactorial pathologies where the microenvironment and in particular LM play an important yet poorly understood role in tissue maintenance, and in cancer progression which represents an inherent risk of IBD. Here we showed first that in human IBD colonic samples and in murine colitis the LMα1 and LMα5 chains are specifically and ectopically overexpressed with a concomitant nuclear p53 accumulation. Linked to this observation, we provided a mechanism showing that p53 induces LMα1 expression at the promoter level by ChIP analysis and this was confirmed by knockdown in cell transfection experiments. To mimic the human disease, we induced colitis and colitis-associated cancer by chemical treatment (DSS combined or not with a carcinogen (AOM in transgenic mice overexpressing LMα1 or LMα5 specifically in the intestine. We demonstrated that high LMα1 or LMα5 expression decreased susceptibility towards experimentally DSS-induced colon inflammation as assessed by histological scoring and decrease of pro-inflammatory cytokines. Yet in a pro-oncogenic context, we showed that LM would favor tumorigenesis as revealed by enhanced tumor lesion formation in both LM transgenic mice. Altogether, our results showed that nuclear p53 and associated overexpression of LMα1 and LMα5 protect tissue from inflammation. But in a mutation setting, the same LM molecules favor progression of IBD into colitis-associated cancer. Our transgenic mice represent attractive new models to acquire knowledge about the paradoxical effect of LM that mediate either tissue reparation or cancer according to the microenvironment. In the early phases of IBD, reinforcing basement membrane stability/organization could be a promising therapeutic approach.

  8. Weight cycling enhances adipose tissue inflammatory responses in male mice.

    Directory of Open Access Journals (Sweden)

    Sandra Barbosa-da-Silva

    Full Text Available BACKGROUND: Obesity is associated with low-grade chronic inflammation attributed to dysregulated production, release of cytokines and adipokines and to dysregulated glucose-insulin homeostasis and dyslipidemia. Nutritional interventions such as dieting are often accompanied by repeated bouts of weight loss and regain, a phenomenon known as weight cycling (WC. METHODS: In this work we studied the effects of WC on the feed efficiency, blood lipids, carbohydrate metabolism, adiposity and inflammatory markers in C57BL/6 male mice that WC two or three consecutive times by alternation of a high-fat (HF diet with standard chow (SC. RESULTS: The body mass (BM grew up in each cycle of HF feeding, and decreased after each cycle of SC feeding. The alterations observed in the animals feeding HF diet in the oral glucose tolerance test, in blood lipids, and in serum and adipose tissue expression of adipokines were not recuperated after WC. Moreover, the longer the HF feeding was (two, four and six months, more severe the adiposity was. After three consecutive WC, less marked was the BM reduction during SC feeding, while more severe was the BM increase during HF feeding. CONCLUSION: In conclusion, the results of the present study showed that both the HF diet and WC are relevant to BM evolution and fat pad remodeling in mice, with repercussion in blood lipids, homeostasis of glucose-insulin and adipokine levels. The simple reduction of the BM during a WC is not able to recover the high levels of adipokines in the serum and adipose tissue as well as the pro-inflammatory cytokines enhanced during a cycle of HF diet. These findings are significant because a milieu with altered adipokines in association with WC potentially aggravates the chronic inflammation attributed to dysregulated production and release of adipokines in mice.

  9. Sirt2 suppresses inflammatory responses in collagen-induced arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Jiangtao [Department of Orthopaedics, Qilu Hospital, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China); Department of Orthopaedics, Yantaishan Hospital, 91 Jiefang Road, Yantai, Shandong 264001 (China); Sun, Bing; Jiang, Chuanqiang; Hong, Huanyu [Department of Orthopaedics, Yantaishan Hospital, 91 Jiefang Road, Yantai, Shandong 264001 (China); Zheng, Yanping, E-mail: yanpingzheng@yahoo.com [Department of Orthopaedics, Qilu Hospital, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong 250012 (China)

    2013-11-29

    Highlights: •Sirt2 expression decreases in collagen-induced arthritis (CIA). •Sirt2 knockout aggravates severity of arthritis in mice with CIA. •Sirt2 knockout increases levels of pro-inflammatory factors in the serum. •Sirt2 deacetylates p65 and inhibits pro-inflammatory factors expression. •Sirt2 rescue abates severity of arthritis in mice with CIA. -- Abstract: Arthritis is a common autoimmune disease that is associated with progressive disability, systemic complications and early death. However, the underling mechanisms of arthritis are still unclear. Sirtuins are a NAD{sup +}-dependent class III deacetylase family, and regulate cellular stress, inflammation, genomic stability, carcinogenesis, and energy metabolism. Among the sirtuin family members, Sirt1 and Sirt6 are critically involved in the development of arthritis. It remains unknown whether other sirtuin family members participate in arthritis. Here in this study, we demonstrate that Sirt2 inhibits collagen-induced arthritis (CIA) using in vivo and in vitro evidence. The protein and mRNA levels of Sirt2 significantly decreased in joint tissues of mice with CIA. When immunized with collagen, Sirt2-KO mice showed aggravated severity of arthritis based on clinical scores, hind paw thickness, and radiological and molecular findings. Mechanically, Sirt2 deacetylated p65 subunit of nuclear factor-kappa B (NF-κB) at lysine 310, resulting in reduced expression of NF-κB-dependent genes, including interleukin 1β (IL-1β), IL-6, monocyte chemoattractant protein 1(MCP-1), RANTES, matrix metalloproteinase 9 (MMP-9) and MMP-13. Importantly, our rescue experiment showed that Sirt2 re-expression abated the severity of arthritis in Sirt2-KO mice. Those findings strongly indicate Sirt2 as a considerably inhibitor of the development of arthritis.

  10. Spontaneous one-lung ventilation increases the lung inflammatory response : an experimental pilot study

    OpenAIRE

    Machado, Humberto S; Sá, Paula; Nunes, Catarina S; Couceiro, António; Silva, Álvaro Moreira da; Águas, Artur

    2014-01-01

    Study objective: The purpose of this study was to investigate if spontaneous one-lung ventilation would induce any type of inflammatory lung response when compared to spontaneous two-lung ventilation and its intensity, by quantification of inflammatory cells in lung histology at the end of the procedure. Design: In vivo prospective randomised animal study Setting: University research laboratory Subjects: New Zealand rabbits Interventions: Rabbits (n=20) were randomly assigned to 4 groups (n=5...

  11. 20 Years On: Is It Time to Redefine the Systemic Inflammatory Response to Cardiothoracic Surgery?

    OpenAIRE

    Landis, R. Clive

    2015-01-01

    The “systemic inflammatory response” has never been defined from a cardiothoracic surgery perspective, but borrowed its definition from the critical care field at a landmark 1992 definition conference on sepsis. It is unclear why the diagnostic criteria for the Systemic Inflammatory Response Syndrome (SIRS) were adopted in isolation, ignoring other potentially more useful definitions for Severe Septic Shock or Secondary Multiple Organ Dysfunction Syndrome. The 1992 SIRS definition for sepsis ...

  12. Infectious Complications and Immune/Inflammatory Response in Cardiogenic Shock Patients: A Prospective Observational Study

    Science.gov (United States)

    Parenica, Jiri; Jarkovsky, Jiri; Malaska, Jan; Mebazaa, Alexandre; Gottwaldova, Jana; Helanova, Katerina; Litzman, Jiri; Dastych, Milan; Tomandl, Josef; Spinar, Jindrich; Dostalova, Ludmila; Lokaj, Petr; Tomandlova, Marie; Pavkova, Monika Goldergova; Sevcik, Pavel; Legrand, Matthieu

    2017-01-01

    ABSTRACT Introduction: Patients with cardiogenic shock (CS) are at a high risk of developing infectious complications; however, their early detection is difficult, mainly due to a frequently occurring noninfectious inflammatory response, which accompanies an extensive myocardial infarction (MI) or a postcardiac arrest syndrome. The goal of our prospective study was to describe infectious complications in CS and the immune/inflammatory response based on a serial measurement of several blood-based inflammatory biomarkers. Methods: Eighty patients with CS were evaluated and their infections were monitored. Inflammatory markers (C-reactive protein, procalcitonin, pentraxin 3, presepsin) were measured seven times per week. The control groups consisted of 11 patients with ST segment elevation myocardial infarction without CS and without infection, and 22 patients in septic shock. Results: Infection was diagnosed in 46.3% of patients with CS; 16 patients developed an infection within 48 h. Respiratory infection was most common, occurring in 33 out of 37 patients. Infection was a significant or even the main reason of death only in 3.8% of all patients with CS, and we did not find statistically significant difference in 3-month mortality between group of patients with CS with and without infection. There was no statistically significant prolongation of the duration of mechanical ventilation associated with infection. Strong inflammatory response is often in patients with CS due to MI, but we found no significant difference in the course of the inflammatory response expressed by evaluated biomarkers in patients with CS with and without infection. We found a strong relationship between the elevated inflammatory markers (sampled at 12 h) and the 3-month mortality: the area under the curve of receiver operating characteristic ranged between 0.683 and 0.875. Conclusion: The prevalence of infection in patients with CS was 46.3%, and respiratory tract infections were the most

  13. Role of inflammatory cytokines in the response of solid cancers to photodynamic therapy

    Science.gov (United States)

    Korbelik, Mladen; Sun, Jinghai; Cecic, Ivana; Dougherty, Graeme J.

    2001-04-01

    Photodynamic therapy (PDT) elicits a strong acute inflammatory response that has both local and systemic (acute phase response) attributes. The insult mediated by PDT-induced oxidative stress at the targeted site triggers a complex multifactorial response engaging host defence mechanisms associated with the inflammatory process to participate in the eradication of the treated tumor. Inflammatory cytokines are important mediators of critical events in this process as they regulate the activity of inflammatory, endothelial and other cells. The initial stimulus for enhanced production and release of cytokines likely originates from several types of events, such as activated transcription factors and complement deposition. The PDT-induced complement activation appears to be directly linked to the enhanced expression of various cytokines, including chemokines such as KC (in mouse models), and classic inflammatory cytokines such as IL-1β, TNF-α , IL-6 and IL-10. A variety of interventions that modulate the activity of particular cytokines performed in conjunction with PDT were shown to influence the therapy outcome. The treatments such as using blocking antibodies and local or systemic cytokine delivery may either reduce or dramatically improve the curative effect of PDT. The inflammatory and related cytokines that at present appear particularly interesting and merit further investigation for use as adjuvants to PDT are IL-3, IL-8, IL-15, TNF-α, IFN-γ, G-CSF and GM-CSF.

  14. Potential use of salivary markers for longitudinal monitoring of inflammatory immune responses to vaccination

    NARCIS (Netherlands)

    Lim, Pei Wen; Garssen, Johan; Sandalova, Elena

    2016-01-01

    Vaccination, designed to trigger a protective immune response against infection, is a trigger for mild inflammatory responses. Vaccination studies can address the question of inflammation initiation, levels, and resolution as well as its regulation for respective studied pathogens. Such studies larg

  15. Repressor and activator protein accelerates hepatic ischemia reperfusion injury by promoting neutrophil inflammatory response.

    Science.gov (United States)

    Li, Chang Xian; Lo, Chung Mau; Lian, Qizhou; Ng, Kevin Tak-Pan; Liu, Xiao Bing; Ma, Yuen Yuen; Qi, Xiang; Yeung, Oscar Wai Ho; Tergaonkar, Vinay; Yang, Xin Xiang; Liu, Hui; Liu, Jiang; Shao, Yan; Man, Kwan

    2016-05-10

    Repressor and activator protein (Rap1) directly regulates nuclear factor-κB (NF-κB) dependent signaling, which contributes to hepatic IRI. We here intended to investigate the effect of Rap1 in hepatic ischemia reperfusion injury (IRI) and to explore the underlying mechanisms. The association of Rap1 expression with hepatic inflammatory response were investigated in both human and rat liver transplantation. The effect of Rap1 in hepatic IRI was studied in Rap1 knockout mice IRI model in vivo and primary cells in vitro. Our results showed that over expression of Rap1 was associated with severe liver graft inflammatory response, especially in living donor liver transplantation. The results were also validated in rat liver transplantation model. In mice hepatic IRI model, the knockout of Rap1 reduced hepatic damage and hepatic inflammatory response. In primary cells, the knockout of Rap1 suppressed neutrophils migration activity and adhesion in response to liver sinusoidal endothelial cells through down-regulating neutrophils F-Actin expression and CXCL2/CXCR2 pathway. In addition, the knockout of Rap1 also decreased production of pro-inflammatory cytokines/chemokines in primary neutrophils and neutrophils-induced hepatocyte damage. In conclusion, Rap1 may induce hepatic IRI through promoting neutrophils inflammatory response. Rap1 may be the potential therapeutic target of attenuating hepatic IRI.

  16. Hsp70 inducer, 17-allylamino-demethoxygeldanamycin, provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury

    Science.gov (United States)

    Gu, Youquan; Chen, Jun; Wang, Tianhong; Zhou, Chaoning; Liu, Zhaodong; Ma, Lanhua

    2016-01-01

    Traumatic brain injury (TBI) is the predominant cause of mortality in young adults and children living in China. TBI induces inflammatory responses; in addition, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 are important pro-inflammatory cytokines. Considering the observation that Hsp-70 overexpression can exert neuroprotection, identifying a drug that is able to induce the upregulation of Hsp70 has the potential to be a promising therapy for the treatment of neurological diseases. Thus, the present study assessed the clinical effectiveness of an anticancer drug and Hsp70 activator, 17-allylamino-demethoxygeldanamycin (17-AAG), to evaluate its potential as a treatment for patients with TBI. The aim of present study was to determine the neuroprotective effects of 17-AAG following trauma and to investigate the underlying mechanisms of action. To establish rat models, rats were subjected to a controlled cortical impact injury and randomly divided into vehicle or 17-AAG groups. In the 17-AAG group, rats were administered with an intraperitoneal injection of 17-AAG (80 mg/kg) immediately following the establishment of TBI. The motor function was measured using Neurologic Severity Score, and neuronal death was evaluated using immunofluorescence. The expression levels of GLT-1, Bcl-2 and Hsp-70 were detected by western blot analysis and the expression levels of inflammatory cytokines were quantified using ELISA. The present study determined that 17-AAG significantly reduced brain edema and motor neurological deficits (P<0.05), in addition to increasing neuronal survival. The aforementioned findings are associated with a downregulation of the expression levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. Conversely, no significant changes of glutamate transporter-1 expression were observed. The present results suggest that 17-AAG treatment may provide a neuroprotective effect by reducing inflammation following TBI.

  17. Qingkailing Suppresses the Activation of BV2 Microglial Cells by Inhibiting Hypoxia/Reoxygenation-Induced Inflammatory Responses

    Directory of Open Access Journals (Sweden)

    Lulu Mana

    2014-01-01

    Full Text Available Qingkailing (QKL is a well-known composite extract used in traditional Chinese medicine. This extract has been extensively administered to treat the acute phase of cerebrovascular disease. Our previous experiments confirmed that QKL exerts an inhibitory effect on cerebral ischemia-induced inflammatory responses. However, whether QKL suppresses the activation of microglia, the primary resident immune cells in the brain, has yet to be determined. In this study, BV2 microglial cells were used to validate the protective effects of QKL treatment following ischemia-reperfusion injury simulated via hypoxia/reoxygenation in vitro. Under these conditions, high expression levels of ROS, COX-2, iNOS, and p-p38 protein were detected. Following ischemia/reperfusion injury, QKL significantly increased the activity of BV2 cells to approximately the basal level by modulating microglial activation via inhibition of inflammatory factors, including TNF-α, COX-2, iNOS, and p-p38. However, QKL treatment also displayed dose-dependent differences in its inhibitory effects on p38 phosphorylation and inflammatory factor expression.

  18. Value of MR spectroscopy in infectious and inflammatory brain diseases; Wertigkeit der MR-Spektroskopie bei infektioesen und entzuendlichen Hirnerkrankungen

    Energy Technology Data Exchange (ETDEWEB)

    Papanagiotou, P.; Schmidt, K.I.; Alexandrou, M.; Koerner, H.; Reith, W. [Universitaetsklinikum des Saarlandes, Klinik fuer Diagnostische und Interventionelle Neuroradiologie, Homburg/Saar (Germany)

    2010-09-15

    Proton magnetic resonance spectroscopy (MRS) is a non-invasive method for measuring cerebral metabolite concentrations in various pathologic conditions. This review discusses the MRS findings in the most common infectious and inflammatory brain diseases. (orig.) [German] Die Magnetresonanzspektroskopie (MRS) ist eine nichtinvasive Methode, die die Messung der Konzentration zerebraler Metaboliten erlaubt. Die Wertigkeit der MRS bei den wichtigsten infektioesen und entzuendlichen Hirnerkrankungen werden in diesem Review diskutiert. (orig.)

  19. Minocycline effects on cerebral edema: relations with inflammatory and oxidative stress markers following traumatic brain injury in mice.

    Science.gov (United States)

    Homsi, Shadi; Federico, Fabiola; Croci, Nicole; Palmier, Bruno; Plotkine, Michel; Marchand-Leroux, Catherine; Jafarian-Tehrani, Mehrnaz

    2009-09-29

    One of the severe complications following traumatic brain injury (TBI) is cerebral edema and its effective treatment is of great interest to prevent further brain damage. This study investigated the effects of minocycline, known for its anti-inflammatory properties, on cerebral edema and its respective inflammatory markers by comparing different dose regimens, on oxidative stress and on neurological dysfunction following TBI. The weight drop model was used to induce TBI in mice. The brain water content was measured to evaluate cerebral edema. Inflammatory markers were detected by ELISA (IL-1beta), zymography and Western blot (MMP-9). The oxidative stress marker (glutathione levels) and neurological function were measured by Griffith technique and string test, respectively. Minocycline was administered i.p. once (5 min), twice (5 min and 3 h) or triple (5 min, 3 h and 9 h) following TBI. The first dose of minocycline only varied (45 or 90 mg/kg), whereas the following doses were all at 45 mg/kg. The single and double administrations of minocycline reduced the increase of inflammatory markers at 6 h post-TBI. Minocycline also reduced cerebral edema at this time point, only after double administration and at the high dose regimen, although with no effect on the TBI-induced oxidized glutathione increase. The anti-edematous effect of minocycline persisted up to 24 h, upon a triple administration, and accompanied by a neurological recovery. In conclusion, we reported an anti-edematous effect of minocycline after TBI in mice according to a specific treatment regimen. These findings emphasize that the beneficial effects of minocycline depend on the treatment regimen following a brain injury.

  20. Arctigenin Treatment Protects against Brain Damage through an Anti-Inflammatory and Anti-Apoptotic Mechanism after Needle Insertion

    OpenAIRE

    2016-01-01

    Convection enhanced delivery (CED) infuses drugs directly into brain tissue. Needle insertion is required and results in a stab wound injury (SWI). Subsequent secondary injury involves the release of inflammatory and apoptotic cytokines, which have dramatic consequences on the integrity of damaged tissue, leading to the evolution of a pericontusional-damaged area minutes to days after in the initial injury. The present study investigated the capacity for arctigenin (ARC) to prevent secondary ...

  1. Impact of nutrition on immune function and the inflammatory response

    Science.gov (United States)

    The review utilizes data on three micronutrients (vitamin A, zinc and iron), anthropometrically defined undernutrition (stunting, wasting and underweight) and obesity to evaluate the effect on immune function, recovery of immune function in response to nutritional interventions, related health outco...

  2. Soluble Mediators in Platelet Concentrates Modulate Dendritic Cell Inflammatory Responses in an Experimental Model of Transfusion.

    Science.gov (United States)

    Perros, Alexis J; Christensen, Anne-Marie; Flower, Robert L; Dean, Melinda M

    2015-10-01

    The transfusion of platelet concentrates (PCs) is widely used to treat thrombocytopenia and severe trauma. Ex vivo storage of PCs is associated with a storage lesion characterized by partial platelet activation and the release of soluble mediators, such as soluble CD40 ligand (sCD40L), RANTES, and interleukin (IL)-8. An in vitro whole blood culture transfusion model was employed to assess whether mediators present in PC supernatants (PC-SNs) modulated dendritic cell (DC)-specific inflammatory responses (intracellular staining) and the overall inflammatory response (cytometric bead array). Lipopolysaccharide (LPS) was included in parallel cultures to model the impact of PC-SNs on cell responses following toll-like receptor-mediated pathogen recognition. The impact of both the PC dose (10%, 25%) and ex vivo storage period was investigated [day 2 (D2), day 5 (D5), day 7 (D7)]. PC-SNs alone had minimal impact on DC-specific inflammatory responses and the overall inflammatory response. However, in the presence of LPS, exposure to PC-SNs resulted in a significant dose-associated suppression of the production of DC IL-12, IL-6, IL-1α, tumor necrosis factor-α (TNF-α), and macrophage inflammatory protein (MIP)-1β and storage-associated suppression of the production of DC IL-10, TNF-α, and IL-8. For the overall inflammatory response, IL-6, TNF-α, MIP-1α, MIP-1β, and inflammatory protein (IP)-10 were significantly suppressed and IL-8, IL-10, and IL-1β significantly increased following exposure to PC-SNs in the presence of LPS. These data suggest that soluble mediators present in PCs significantly suppress DC function and modulate the overall inflammatory response, particularly in the presence of an infectious stimulus. Given the central role of DCs in the initiation and regulation of the immune response, these results suggest that modulation of the DC inflammatory profile is a probable mechanism contributing to transfusion-related complications.

  3. Rosmarinus officinalis extract suppresses Propionibacterium acnes-induced inflammatory responses.

    Science.gov (United States)

    Tsai, Tsung-Hsien; Chuang, Lu-Te; Lien, Tsung-Jung; Liing, Yau-Rong; Chen, Wei-Yu; Tsai, Po-Jung

    2013-04-01

    Propionibacterium acnes is a key pathogen involved in the progression of acne inflammation. The development of a new agent possessing antimicrobial and anti-inflammatory activity against P. acnes is therefore of interest. In this study, we investigated the inhibitory effect of rosemary (Rosmarinus officinalis) extract on P. acnes-induced inflammation in vitro and in vivo. The results showed that ethanolic rosemary extract (ERE) significantly suppressed the secretion and mRNA expression of proinflammatory cytokines, including interleukin (IL)-8, IL-1β, and tumor necrosis factor-α in P. acnes-stimulated monocytic THP-1 cells. In an in vivo mouse model, concomitant intradermal injection of ERE attenuated the P. acnes-induced ear swelling and granulomatous inflammation. Since ERE suppressed the P. acnes-induced nuclear factor kappa-B (NF-κB) activation and mRNA expression of Toll-like receptor (TLR) 2, the suppressive effect of ERE might be due, at least partially, to diminished NF-κB activation and TLR2-mediated signaling pathways. Furthermore, three major constituents of ERE, carnosol, carnosic acid, and rosmarinic acid, exerted different immumodulatory activities in vitro. In brief, rosmarinic acid significantly suppressed IL-8 production, while the other two compounds inhibited IL-1β production. Further study is needed to explore the role of bioactive compounds of rosemary in mitigation of P. acnes-induced inflammation.

  4. Involvement of glycosphingolipid-enriched lipid rafts in inflammatory responses.

    Science.gov (United States)

    Iwabuchi, Kazuhisa

    2015-01-01

    Glycosphingolipids (GSLs) are membrane components consisting of hydrophobic ceramide and hydrophilic sugar moieties. GSLs cluster with cholesterol in cell membranes to form GSL-enriched lipid rafts. Biochemical analyses have demonstrated that GSL-enriched lipid rafts contain several kinds of transducer molecules, including Src family kinases. Among the GSLs, lactosylceramide (LacCer, CDw17) can bind to various microorganisms, is highly expressed on the plasma membranes of human phagocytes, and forms lipid rafts containing the Src family tyrosine kinase Lyn. LacCer-enriched lipid rafts mediate immunological and inflammatory reactions, including superoxide generation, chemotaxis, and non-opsonic phagocytosis. Therefore, LacCer-enriched membrane microdomains are thought to function as pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) expressed on microorganisms. LacCer also serves as a signal transduction molecule for functions mediated by CD11b/CD18-integrin (αM/β2-integrin, CR3, Mac-1), as well as being associated with several key cellular processes. LacCer recruits PCKα/ε and phospholipase A2 to stimulate PECAM-1 expression in human monocytes and their adhesion to endothelial cells, as well as regulating β1-integrin clustering and endocytosis on cell surfaces. This review describes the organizational and inflammation-related functions of LacCer-enriched lipid rafts.

  5. Wound trauma mediated inflammatory signaling attenuates a tissue regenerative response in MRL/MpJ mice

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    Elster Eric A

    2010-05-01

    Full Text Available Abstract Background Severe trauma can induce pathophysiological responses that have marked inflammatory components. The development of systemic inflammation following severe thermal injury has been implicated in immune dysfunction, delayed wound healing, multi-system organ failure and increased mortality. Methods In this study, we examined the impact of thermal injury-induced systemic inflammation on the healing response of a secondary wound in the MRL/MpJ mouse model, which was anatomically remote from the primary site of trauma, a wound that typically undergoes scarless healing in this specific strain. Ear-hole wounds in MRL/MpJ mice have previously displayed accelerated healing and tissue regeneration in the absence of a secondary insult. Results Severe thermal injury in addition to distal ear-hole wounds induced marked local and systemic inflammatory responses in the lungs and significantly augmented the expression of inflammatory mediators in the ear tissue. By day 14, 61% of the ear-hole wounds from thermally injured mice demonstrated extensive inflammation with marked inflammatory cell infiltration, extensive ulceration, and various level of necrosis to the point where a large percentage (38% had to be euthanized early during the study due to extensive necrosis, inflammation and ear deformation. By day 35, ear-hole wounds in mice not subjected to thermal injury were completely closed, while the ear-hole wounds in thermally injured mice exhibited less inflammation and necrosis and only closed partially (62%. Thermal injury resulted in marked increases in serum levels of IL-6, TNFα, KC (CXCL1, and MIP-2α (CXCL2. Interestingly, attenuated early ear wound healing in the thermally injured mouse resulted in incomplete tissue regeneration in addition to a marked inflammatory response, as evidenced by the histological appearance of the wound and increased transcription of potent inflammatory mediators. Conclusion These findings suggest that the

  6. Systemic inflammatory response syndrome (SIRS): where did it come from and is it still relevant today?

    Science.gov (United States)

    Balk, Robert A

    2014-01-01

    The concept of a systemic inflammatory response syndrome (SIRS) to describe the complex pathophysiologic response to an insult such as infection, trauma, burns, pancreatitis, or a variety of other injuries came from a 1991 consensus conference charged with the task of developing an easy-to-apply set of clinical parameters to aid in the early identification of potential candidates to enter into clinical trials to evaluate new treatments for sepsis. There was recognition that a diverse group of injuries produced a common inflammatory response in the host and provided attractive targets for new anti-inflammatory molecules designed to prevent further propagation and/or provide specific treatment. Effective application of these new anti-inflammatory strategies necessitated identification of early clinical markers that could be assessed in real-time and were likely to define a population of patients that would have a beneficial response to the targeted intervention. It was felt that early clinical manifestations might be more readily available to clinicians than more sophisticated and specific assays for inflammatory substances that were systemically released by the network of injurious inflammatory events. Therefore, the early definition of a systemic inflammatory response syndrome (SIRS) was built upon a foundation of basic clinical and laboratory abnormalities that were readily available in almost all clinical settings. With further refinement, it was hoped, that this definition would have a high degree of sensitivity, coupled with a reasonable degree of specificity. This manuscript reviews the derivation, application, utilization, potential benefits, and speculation regarding the future of the SIRS definition.

  7. Inflammation-like glial response in lead-exposed immature rat brain.

    Science.gov (United States)

    Struzynska, Lidia; Dabrowska-Bouta, Beata; Koza, Katarzyna; Sulkowski, Grzegorz

    2007-01-01

    Numerous studies on lead (Pb) neurotoxicity have indicated this metal to be a dangerous toxin, particularly during developmental stages of higher organisms. Astrocytes are responsible for sequestration of this metal in brain tissue. Activation of astroglia may often lead to loss of the buffering function and contribute to pathological processes. This phenomenon is accompanied by death of neuronal cells and may be connected with inflammatory events arising from the production of a wide range of cytokines and chemokines. The effects of prolonged exposure to Pb upon glial activation are examined in immature rats to investigate this potential proinflammatory effect. When analyzed at the protein level, glial activation is observed after Pb exposure, as reflected by the increased level of glial fibrillary acidic protein and S-100beta proteins in all parts of the brain examined. These changes are associated with elevation of proinflammatory cytokines. Production of interleukin (IL)-1beta and tumor necrosis factor-alpha is observed in hippocampus, and production of IL-6 is seen in forebrain. The expression of fractalkine is observed in both hippocampus and forebrain but inconsiderably in the cerebellum. In parallel with cytokine expression, signs of synaptic damage in hippocampus are seen after Pb exposure, as indicated by decreased levels of the axonal markers synapsin I and synaptophysin. Obtained results indicate chronic glial activation with coexisting inflammatory and neurodegenerative features as a new mechanism of Pb neurotoxicity in immature rat brain.

  8. Metabolic factors-triggered inflammatory response drives antidepressant effects of exercise in CUMS rats.

    Science.gov (United States)

    Liu, Weina; Wang, Hongmei; Wang, Yangkai; Li, Haipeng; Ji, Liu

    2015-08-30

    Chronic stress is a potential contributing factor for depression, accompanying with metabolic and inflammatory response. Exercise is considered as a treatment for depression, but mechanisms underlying its beneficial effects still remain unknown. The objectives of present study were to confirm that metabolic factors-triggered inflammatory response mediates the antidepressant actions of exercise in chronic unpredictable mild stress (CUMS) rats. It has been found that CUMS stimulated expression of ghrelin and its receptor Ghsr, but inhibited expression of leptin and its receptor LepRb. Ghrelin, via binding to Ghsr, induced phosphorylation of GSK-3β on Tyr216 and decreased phosphorylation on Ser9, thus increasing GSK-3β activity. Conversely, ghrelin binding to Ghsr decreased STAT3 activity, through decreasing phosphorylation of STAT3 on Tyr705 and increasing Ser727 phosphorylation. Negatively correlated with ghrelin, leptin binding to LepRb had opposite effects on the activity of GSK-3β and STAT3 via phosphorylation. In addition, decreased leptin level initiated NLRP3 activity via LepRb. Furthermore, GSK-3β inhibited STAT3 activation, thus promoting the expression of NLRP3. Meanwhile, swim improved metabolic and inflammatory response both in CUMS and control rats. Our findings suggest that exercise not only ameliorates metabolic disturbance and inflammatory response in depression, but also contributes to metabolic and inflammatory function in normal conditions.

  9. An Update on the Inflammatory Response after Endovascular Repair for Abdominal Aortic Aneurysm

    Directory of Open Access Journals (Sweden)

    Eleni Arnaoutoglou

    2015-01-01

    Full Text Available Postimplantation syndrome (PIS is the clinical and biochemical expression of an inflammatory response following endovascular repair of an aortic aneurysm (EVAR. The goal of this review is to provide an update on the inflammatory response after endovascular repair of abdominal aortic aneurysm, discussing its causes and effects on the clinical outcome of the patient. PIS concerns nearly one-third of patients after EVAR. It is generally a benign condition, although in some patients it may negatively affect outcome. The different definitions and conclusions drawn from several studies reveal that PIS needs to be redefined with standardized diagnostic criteria. The type of the endograft’s material seems to play a role in the inflammatory response. Future studies should focus on a better understanding of the underlying pathophysiology, predictors, and risk factors as well as determining whether effective preventive strategies are necessary.

  10. Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues.

    Science.gov (United States)

    Fry, Donald E

    2012-01-01

    Human sepsis is thought to be systemic inflammatory response syndrome (SIRS) that is activated by invasive infection. The multiple organ dysfunction syndrome (MODS) is the identified failure of critical organ function in patients that have sustained SIRS. Because SIRS and MODS are consequences of the excessive activation of inflammation, extensive research and numerous clinical trials have pursued treatments that would modify the inflammatory response. This presentation reviews the normal local mechanisms of inflammation and provides a theoretical framework for the transition of the inflammatory process to a systemic level. Clinical trials with biomodulators to block or inhibit inflammation have generally failed to improve the outcomes in patients with severe sepsis, septic shock, and MODS. The role of counter-inflammatory signaling and the newer concept of the cholinergic anti-inflammatory pathway are being investigated, and newer hypotheses are focusing upon the balancing of proinflammatory and counter-inflammatory mechanisms as important directions for newer therapies. It is concluded that failure to define novel and effective treatments reflects fundamental gaps in our understanding of inflammation and its regulation.

  11. Systemic Inflammatory Effects of Traumatic Brain Injury, Femur Fracture, and Shock: An Experimental Murine Polytrauma Model

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    C. Probst

    2012-01-01

    Full Text Available Objective. Despite broad research in neurotrauma and shock, little is known on systemic inflammatory effects of the clinically most relevant combined polytrauma. Experimental investigation in an animal model may provide relevant insight for therapeutic strategies. We describe the effects of a combined injury with respect to lymphocyte population and cytokine activation. Methods. 45 male C57BL/6J mice (mean weight 27 g were anesthetized with ketamine/xylazine. Animals were subjected to a weight drop closed traumatic brain injury (WD-TBI, a femoral fracture and hemorrhagic shock (FX-SH. Animals were subdivided into WD-TBI, FX-SH and combined trauma (CO-TX groups. Subjects were sacrificed at 96 h. Blood was analysed for cytokines and by flow cytometry for lymphocyte populations. Results. Mortality was 8%, 13% and 47% for FX-SH, WD-TBI and CO-TX groups (P<0.05. TNFα (11/13/139 for FX-SH/WD-TBI/CO-TX; P<0.05, CCL2 (78/96/227; P<0.05 and IL-6 (16/48/281; P=0.05 showed significant increases in the CO-TX group. Lymphocyte populations results for FX-SH, WD-TBI and CO-TX were: CD-4 (31/21/22; P= n.s., CD-8 (7/28/34, P<0.05, CD-4-CD-8 (11/12/18; P= n.s., CD-56 (36/7/8; P<0.05. Conclusion. This study shows that a combination of closed TBI and femur-fracture/ shock results in an increase of the humoral inflammation. More attention to combined injury models in inflammation research is indicated.

  12. Fish and mammalian phagocytes differentially regulate pro-inflammatory and homeostatic responses in vivo.

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    Aja M Rieger

    Full Text Available Phagocytosis is a cellular mechanism that is important to the early induction of antimicrobial responses and the regulation of adaptive immunity. At an inflammatory site, phagocytes serve as central regulators for both pro-inflammatory and homeostatic anti-inflammatory processes. However, it remains unclear if this is a recent evolutionary development or whether the capacity to balance between these two seemingly contradictory processes is a feature already displayed in lower vertebrates. In this study, we used murine (C57BL/6 and teleost fish (C. auratus in vitro and in vivo models to assess the evolutionary conservation of this dichotomy at a site of inflammation. At the level of the macrophage, we found that teleost fish already displayed divergent pro-inflammatory and homeostatic responses following internalization of zymosan or apoptotic bodies, respectively, and that these were consistent with those of mice. However, fish and mice displayed significant differences in vivo with regards to the level of responsiveness to zymosan and apoptotic bodies, the identity of infiltrating leukocytes, their rate of infiltration, and the kinetics and strength of resulting antimicrobial responses. Unlike macrophages, significant differences were identified between teleost and murine neutrophilic responses. We report for the first time that activated murine, but not teleost neutrophils, possess the capacity to internalize apoptotic bodies. This internalization translates into reduction of neutrophil ROS production. This may play an important part in the recently identified anti-inflammatory activity that mammalian neutrophils display during the resolution phase of inflammation. Our observations are consistent with continued honing of inflammatory control mechanisms from fish to mammals, and provide added insights into the evolutionary path that has resulted in the integrated, multilayered responses that are characteristic of higher vertebrates.

  13. The inflammatory response in COPD : in mice and men

    NARCIS (Netherlands)

    Brandsma, Corry Anke

    2008-01-01

    The aim of this thesis was to investigate both the early and late effects of cigarette smoke and nitrogen dioxide (NO2) exposure and the potential dampening effects of heme oxygenase-1 (HO-1) in animal models for COPD. Additionally, we investigated the role of the specific immune response in the inf

  14. Regulation of Toll-like receptors-dependent inflammatory response 

    Directory of Open Access Journals (Sweden)

    Ewa Kowalczyk

    2013-03-01

    Full Text Available Toll-like receptors (TLRs are a pivotal part of our innate immune response. They recognize a wide variety of pathogens and instigate an immune response, thus facilitating the removal of the disease-causing agent. Due to the intense nature of this response its strict control is of keyimportance, as a prolonged inflammatory signal leads to carcinogenesis and autoimmune disorders. The signaling cascade initiated by the activated TLR is complex and consists of multiple stages. It involves a variety of adaptor proteins, protein kinases and effector transcription factors. The number of stages in this process enables many possible checkpoints and ways of regulation. Signal modulation involves differentiated expression of TLRs, splicing variants of their adaptorproteins, enzymes modifying proteins engaged in the cascade and many more. This review focuses on endogenous factors responsible for controlling the TLR-dependent inflammatory response as well as on pharmacological therapies designed for regulating the innate immune response.  

  15. LXW7 ameliorates focal cerebral ischemia injury and attenuates inflammatory responses in activated microglia in rats

    Energy Technology Data Exchange (ETDEWEB)

    Fang, T.; Zhou, D.; Lu, L.; Tong, X.; Wu, J.; Yi, L. [Department of Neurology, Shenzhen Hospital, Peking University, Shenzhen (China)

    2016-08-01

    Inflammation plays a pivotal role in ischemic stroke, when activated microglia release excessive pro-inflammatory mediators. The inhibition of integrin αvβ3 improves outcomes in rat focal cerebral ischemia models. However, the mechanisms by which microglia are neuroprotective remain unclear. This study evaluated whether post-ischemic treatment with another integrin αvβ3 inhibitor, the cyclic arginine-glycine-aspartic acid (RGD) peptide-cGRGDdvc (LXW7), alleviates cerebral ischemic injury. The anti-inflammatory effect of LXW7 in activated microglia within rat focal cerebral ischemia models was examined. A total of 108 Sprague-Dawley rats (250–280 g) were subjected to middle cerebral artery occlusion (MCAO). After 2 h, the rats were given an intravenous injection of LXW7 (100 μg/kg) or phosphate-buffered saline (PBS). Neurological scores, infarct volumes, brain water content (BWC) and histology alterations were determined. The expressions of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], and Iba1-positive activated microglia, within peri-ischemic brain tissue, were assessed with ELISA, western blot and immunofluorescence staining. Infarct volumes and BWC were significantly lower in LXW7-treated rats compared to those in the MCAO + PBS (control) group. The LXW7 treatment lowered the expression of pro-inflammatory cytokines. There was a reduction of Iba1-positive activated microglia, and the TNF-α and IL-1β expressions were attenuated. However, there was no difference in the Zea Longa scores between the ischemia and LXW7 groups. The results suggest that LXW7 protected against focal cerebral ischemia and attenuated inflammation in activated microglia. LXW7 may be neuroprotective during acute MCAO-induced brain damage and microglia-related neurodegenerative diseases.

  16. Global genetic variations predict brain response to faces.

    Science.gov (United States)

    Dickie, Erin W; Tahmasebi, Amir; French, Leon; Kovacevic, Natasa; Banaschewski, Tobias; Barker, Gareth J; Bokde, Arun; Büchel, Christian; Conrod, Patricia; Flor, Herta; Garavan, Hugh; Gallinat, Juergen; Gowland, Penny; Heinz, Andreas; Ittermann, Bernd; Lawrence, Claire; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Nichols, Thomas; Lathrop, Mark; Loth, Eva; Pausova, Zdenka; Rietschel, Marcela; Smolka, Michal N; Ströhle, Andreas; Toro, Roberto; Schumann, Gunter; Paus, Tomáš

    2014-08-01

    Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼ 500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML), we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI) in a community-based sample of adolescents (n = 1,620). Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40-50%) in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R(2) = 0.38, p<0.001). Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001) and the magnitude of brain response (R(2) = 0.32, p<0.001). Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.

  17. Global genetic variations predict brain response to faces.

    Directory of Open Access Journals (Sweden)

    Erin W Dickie

    2014-08-01

    Full Text Available Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼ 500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximum likelihood (GREML, we related this global genetic variance to that in the brain response to facial expressions, as assessed with functional magnetic resonance imaging (fMRI in a community-based sample of adolescents (n = 1,620. Brain response to facial expressions was measured in 25 regions constituting a face network, as defined previously. In 9 out of these 25 regions, common genetic variance explained a significant proportion of phenotypic variance (40-50% in their response to ambiguous facial expressions; this was not the case for angry facial expressions. Across the network, the strength of the genotype-phenotype relationship varied as a function of the inter-individual variability in the number of functional connections possessed by a given region (R(2 = 0.38, p<0.001. Furthermore, this variability showed an inverted U relationship with both the number of observed connections (R2 = 0.48, p<0.001 and the magnitude of brain response (R(2 = 0.32, p<0.001. Thus, a significant proportion of the brain response to facial expressions is predicted by common genetic variance in a subset of regions constituting the face network. These regions show the highest inter-individual variability in the number of connections with other network nodes, suggesting that the genetic model captures variations across the adolescent brains in co-opting these regions into the face network.

  18. Gut response induced by weaning in piglet features marked changes in immune and inflammatory response.

    Science.gov (United States)

    Bomba, Lorenzo; Minuti, Andrea; Moisá, Sonia J; Trevisi, Erminio; Eufemi, Elisa; Lizier, Michela; Chegdani, Fatima; Lucchini, Franco; Rzepus, Marcin; Prandini, Aldo; Rossi, Filippo; Mazza, Raffaele; Bertoni, Giuseppe; Loor, Juan J; Ajmone-Marsan, Paolo

    2014-12-01

    At weaning, piglets are exposed to many stressors, such as separation from the sow, mixing with other litters, end of lactational immunity, and a change in their environment and gut microbiota. The sudden change of feeding regime after weaning causes morphological and histological changes in the small intestine which are critical for the immature digestive system. Sixteen female piglets were studied to assess the effect of sorbic acid supplementation on the small intestine tissue transcriptome. At weaning day (T0, piglet age 28 days), four piglets were sacrificed and ileal tissue samples collected. The remaining 12 piglets were weighed and randomly assigned to different postweaning (T5, piglet age 33 days) diets. Diet A (n = 6) contained 5 g/kg of sorbic acid. In diet B (n = 6), the organic acids were replaced by barley flour. Total RNA was isolated and then hybridized to CombiMatrix CustomArray™ 90-K platform microarrays, screening about 30 K genes. Even though diet had no detectable effect on the transcriptome during the first 5 days after weaning, results highlighted some of the response mechanisms to the stress of weaning occurring in the piglet gut. A total of 205 differentially expressed genes were used for functional analysis using the bioinformatics tools BLAST2GO, Ingenuity Pathway Analysis 8.0, and Dynamic Impact Approach (DIA). Bioinformatic analysis revealed that apoptosis, RIG-I-like, and NOD-like receptor signaling were altered as a result of weaning. Interferons and caspases gene families were the most activated after weaning in response to piglets to multiple stressors. Results suggest that immune and inflammatory responses were activated and likely are a cause of small intestine atrophy as revealed by a decrease in villus height and villus/crypt ratio.

  19. Inflammatory responses to induced infectious endometritis in mares resistant or susceptible to persistent endometritis

    DEFF Research Database (Denmark)

    Christoffersen, Mette; Woodward, Elizabeth; Bojesen, Anders Miki

    2012-01-01

    The objective of the study was to evaluate the gene expression of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, tumor necrosis factor [TNF]-a, IL-1 receptor antagonist [ra] and serum amyloid A (SAA) in endometrial tissue and circulating leukocytes in response to uterine...... inoculation of 105 colony forming units (CFU) Escherichia coli in mares. Before inoculation, mares were classified as resistant or susceptible to persistent endometritis based on their uterine inflammatory response to infusion of 109 killed spermatozoa and histological assessment of the endometrial quality...

  20. Immune-Manipulation of the Inflammatory Response in Acute Pancreatitis. What Can Be Expected?

    Directory of Open Access Journals (Sweden)

    Corinaldesi R

    2004-05-01

    Full Text Available Severe acute pancreatitis still has a high mortality rate and multiple organ failure is considered to be a severe complication of the disease. Activated polymorphonuclear leukocytes have an important role in the development of multiple organ failure which may result from acute pancreatitis and they are an important pathogenetic factor in the severity of this disease. Therefore, a logical therapeutic approach is to limit the organ damage by selective suppression of inflammatory mediators involved in the systemic inflammatory response syndrome and protect against systemic complication. In this paper, we review the recent literature data on the possible manipulation of the immune response in acute pancreatitis.

  1. Brain stem auditory evoked responses in human infants and adults

    Science.gov (United States)

    Hecox, K.; Galambos, R.

    1974-01-01

    Brain stem evoked potentials were recorded by conventional scalp electrodes in infants (3 weeks to 3 years of age) and adults. The latency of one of the major response components (wave V) is shown to be a function both of click intensity and the age of the subject; this latency at a given signal strength shortens postnatally to reach the adult value (about 6 msec) by 12 to 18 months of age. The demonstrated reliability and limited variability of these brain stem electrophysiological responses provide the basis for an optimistic estimate of their usefulness as an objective method for assessing hearing in infants and adults.

  2. Abnormal electrical brain responses to pitch in congenital amusia.

    Science.gov (United States)

    Peretz, Isabelle; Brattico, Elvira; Tervaniemi, Mari

    2005-09-01

    Congenital amusia is a lifelong disability that prevents afflicted individuals from enjoying music as ordinary people do. The deficit is limited to music and cannot be explained by prior brain lesion, hearing loss, or any cognitive or socio-affective disturbance. Recent behavioral results suggest that this disorder is critically dependent on fine-grained pitch discrimination. Here, we present novel electrophysiological evidence that this disorder can be traced down to a right-lateralized N2-P3 response elicited by pitch changes. This abnormal brain response begins as early as 200 milliseconds after tone onset and may serve as a marker of an anomaly in music acquisition.

  3. Fibronectin Matrix Remodeling in the Regulation of the Inflammatory Response within the Lung: An Early Step in Lung Cancer Progression

    Science.gov (United States)

    2011-09-01

    the Inflammatory Response within the Lung: An Early Step in Lung Cancer Progression PRINCIPAL INVESTIGATOR: Paula J. McKeown-Longo, Ph.D...2011 4. TITLE AND SUBTITLE Fibronectin Matrix Remodeling in the Regulation of the 5a. CONTRACT NUMBER W81XWH-10-1-0755 Inflammatory Response within...hypothesis that force dependent unfolding of fibronectin in the tumor stroma drives an inflammatory response within the lung tumor microenvironment

  4. Behavioural and brain responses related to Internet search and memory.

    Science.gov (United States)

    Dong, Guangheng; Potenza, Marc N

    2015-10-01

    The ready availability of data via searches on the Internet has changed how many people seek and perhaps store and recall information, although the brain mechanisms underlying these processes are not well understood. This study investigated brain mechanisms underlying Internet-based vs. non-Internet-based searching. The results showed that Internet searching was associated with lower accuracy in recalling information as compared with traditional book searching. During functional magnetic resonance imaging, Internet searching was associated with less regional brain activation in the left ventral stream, the association area of the temporal-parietal-occipital cortices, and the middle frontal cortex. When comparing novel items with remembered trials, Internet-based searching was associated with higher brain activation in the right orbitofrontal cortex and lower brain activation in the right middle temporal gyrus when facing those novel trials. Brain activations in the middle temporal gyrus were inversely correlated with response times, and brain activations in the orbitofrontal cortex were positively correlated with self-reported search impulses. Taken together, the results suggest that, although Internet-based searching may have facilitated the information-acquisition process, this process may have been performed more hastily and be more prone to difficulties in recollection. In addition, people appear less confident in recalling information learned through Internet searching and that recent Internet searching may promote motivation to use the Internet.

  5. Protective value of piroxicam on the enhanced inflammatory response after whole body irradiation

    Energy Technology Data Exchange (ETDEWEB)

    el-Ghazaly, M.; Saleh, S.; Kenawy, S.; Roushdy, H.M.; Khayyal, M.T.

    1986-06-01

    The anti-inflammatory activity of piroxicam was assessed after whole body irradiation in rats. Two models of inflammation, the carrageenan-induced edema and the adjuvant-induced arthritis in rats have been utilised. Piroxicam at doses of 1, 5 and 10 mg kg-1 i.p. was effective in inhibiting the paw edema produced in both models of inflammation. The inflammatory response in irradiated was significantly higher than that produced in normal animals and was dependent on the radiation dose level used (0.5-2 Gy). The effect of piroxicam on the late inflammatory response produced by exposure to 2 Gy was studied by measuring the carrageenan-induced edema 4 h after irradiation and on the third and seventh day thereafter. The increase in paw volume was significantly suppressed in animals receiving the drug. Administration of piroxicam (5 mg kg-1) one hour before irradiation of animals at 0.5 Gy, produced inhibition to the exaggerated inflammatory response in irradiated animals. This suggests that piroxicam possibly owes its protective value to prevention of the increase in cellular permeability induced by radiation. Alternatively, the drug may exert this effect by inhibiting PG synthesis, thereby reducing their potentiating influence on the other mediators of inflammation. Furthermore, the inhibition of lysosomal enzyme release possibly induced by the drug may contribute to the probable reduction in the release of inflammatory mediators.

  6. Two large preoperative doses of erythropoietin do not reduce the systemic inflammatory response to cardiac surgery

    DEFF Research Database (Denmark)

    Poulsen, Troels Dirch; Andersen, Lars Willy; Steinbrüchel, Daniel

    2009-01-01

    OBJECTIVES: Cardiac surgery and cardiopulmonary bypass (CPB) induce an inflammatory reaction that may lead to tissue injury. Experimental studies suggest that recombinant human erythropoietin (EPO) independent of its erythropoietic effect may be used clinically as an anti-inflammatory drug. This ...... of inflammatory cytokines. In contrast, EPO may augment the TNF-alpha and NT-proBNP response. Although the long-term clinical impact remains unknown, the findings do not support use of EPO as an anti-inflammatory drug in patients undergoing cardiac surgery........ This study tested the hypothesis that 2 large doses of EPO administered shortly before CPB ameliorate the systemic inflammatory response to CPB. DESIGN AND SETTING: A prospective, double-blind, placebo-controlled and randomized study at a single tertiary care hospital. PARTICIPANTS: Patients scheduled...... concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-1beta receptor antagonist, IL-6, IL-10, and N-terminal probrain natriuretic peptide (NT-proBNP). Compared with placebo, EPO at day 3 after CPB augmented the TNF-alpha response (p

  7. The synthetic NCAM-derived peptide, FGL, modulates the transcriptional response to traumatic brain injury

    DEFF Research Database (Denmark)

    Pedersen, Martin Volmer; Helweg-Larsen, Rehannah Borup; Nielsen, Finn Cilius;

    2008-01-01

    Cerebral responses to traumatic brain injury (TBI) include up- and downregulation of a vast number of proteins involved in endogenous inflammatory responses and defense mechanisms developing postinjury. The present study analyzed the global gene expression profile in response to cryo-induced TBI...... at various time-points postlesion (6 h, 1 day and 4 days). The effects of injury, treatment, and injury-treatment interaction were observed. TBI alone rendered a large number of genes affected. Analysis of lesion and treatment interactions resulted in a clear effect of the interaction between injury and FGL......-treatment compared to injury and placebo-treatment. Genes affected by TBI alone included inflammation markers, protein kinases, ion channel members and growth factors. Genes encoding regulators of apoptosis, signal transduction and metabolism were altered by the interaction between FGL-treatment and TBI. FGL...

  8. The localisation of inflammatory cells and expression of associated proteoglycans in response to implanted chitosan.

    Science.gov (United States)

    Farrugia, Brooke L; Whitelock, John M; Jung, MoonSun; McGrath, Barbara; O'Grady, Robert L; McCarthy, Simon J; Lord, Megan S

    2014-02-01

    Implantation of a foreign material almost certainly results in the formation of a fibrous capsule around the implant however, mechanistic events leading to its formation are largely unexplored. Mast cells are an inflammatory cell type known to play a role in the response to material implants, through the release of pro-inflammatory proteases and cytokines from their α-granules following activation. This study examined the in vivo and in vitro response of mast cells to chitosan, through detection of markers known to be produced by mast cells or involved with the inflammatory response. Mast cells, identified as Leder stained positive cells, were shown to be present in response to material implants. Additionally, the mast cell receptor, c-kit, along with collagen, serglycin, perlecan and chondroitin sulphate were detected within the fibrous capsules, where distribution varied between material implants. In conjunction, rat mast cells (RBL-2H3) were shown to be activated following exposure to chitosan as indicated by the release of β-hexosaminidase. Proteoglycan and glycosaminoglycans produced by the cells showed similar expression and localisation when in contact with chitosan to when chemically activated. These data support the role that mast cells play in the inflammatory host response to chitosan implants, where mediators released from their α-granules impact on the formation of a fibrous capsule by supporting the production and organisation of collagen fibres.

  9. Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials

    Science.gov (United States)

    Tétreault, Pascal; Mansour, Ali; Vachon-Presseau, Etienne; Schnitzer, Thomas J.; Apkarian, A. Vania

    2016-01-01

    Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo’s effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active

  10. Interaction of inflammatory and anti-inflammatory responses in microglia by Staphylococcus aureus-derived lipoteichoic acid

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Bor-Ren [Department of Neurosurgery, Buddhist Tzu Chi General Hospital, Taichung Branch, Taichung, Taiwan (China); Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan (China); Tsai, Cheng-Fang [Department of Biotechnology, Asia University, Taichung, Taiwan (China); Lin, Hsiao-Yun [Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan (China); Tseng, Wen-Pei [Graduate Institute of Sports and Health, National Changhua University of Education, Changhua County, Taiwan (China); Huang, Shiang-Suo [Department of Pharmacology and Institute of Medicine, College of Medicine, Chung Shan Medical University, Taiwan (China); Wu, Chi-Rei [Graduate Institute of Chinese Pharmaceutical Sciences, College of Pharmacy, China Medical University, Taiwan (China); Lin, Chingju [Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan (China); Yeh, Wei-Lan [Cancer Research Center, Department of Medical Research, Changhua Christian Hospital, Changhua, Taiwan (China); Lu, Dah-Yuu, E-mail: dahyuu@mail.cmu.edu.tw [Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan (China)

    2013-05-15

    We investigated the interaction between proinflammatory and inflammatory responses caused by Staphylococcus aureus-derived lipoteichoic acid (LTA) in primary cultured microglial cells and BV-2 microglia. LTA induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein levels increase in a concentration- and time-dependent manner. Meanwhile, LTA also increased nitric oxide (NO) and PGE{sub 2} production in microglia. Administration of TLR2 antagonist effectively inhibited LTA-induced NO, iNOS, and COX-2 expression. Moreover, treatment of cells with LTA caused a time-dependent activation of ERK, p38, JNK, as well as AKT. We also found that LTA-induced iNOS and COX-2 up-regulation were attenuated by p38, JNK, and PI3-kinase inhibitors. On the other hand, LTA-enhanced HO-1 expression was attenuated by p38 and PI3-kinase inhibitors. Treatment of cells with NF-κB and AP-1 inhibitors antagonized LTA-induced iNOS and COX-2 expression. However, only NF-κB inhibitors reduced LTA-induced HO-1 expression in microglia. Furthermore, stimulation of cells with LTA also activated IκBα phosphorylation, p65 phosphorylation at Ser{sup 536}, and c-Jun phosphorylation. Moreover, LTA-induced increases of κB-DNA and AP-1-DNA binding activity were inhibited by p38, JNK, and PI3-kinase inhibitors. HO-1 activator CoPP IX dramatically reversed LTA-induced iNOS expression. Our results provided mechanisms linking LTA and inflammation/anti-inflammation, and indicated that LTA plays a regulatory role in microglia activation. - Highlights: • LTA causes an increase in iNOS, COX-2, and HO-1 expression in microglia. • LTA induces iNOS and COX-2 expression through TLR-2/NF-κB and AP-1 pathways. • HO-1 expression is regulated through p38, JNK, PI3K/AKT and AP-1 pathways. • Induced HO-1 reduces LTA-induced iNOS expression. • LTA plays a regulatory role on inflammatory/anti-inflammatory responses.

  11. Biological response modifiers and their potential use in the treatment of inflammatory skin diseases

    DEFF Research Database (Denmark)

    Villadsen, Louise S; Skov, Lone; Baadsgaard, Ole

    2003-01-01

    and fewer side-effects than the current systemic therapies now used for severe psoriasis, contact dermatitis and atopic dermatitis. In the pathogenesis of inflammatory skin diseases, the immune system plays a pivotal role, and this is where biological response modifiers such as monoclonal antibodies......In recent years, a more detailed understanding of the pathogenesis of several inflammatory skin diseases, combined with the developments within biotechnology, has made it possible to design more selective response modifiers. Biological response modifiers hold the potential for greater effectiveness......, recombinant cytokines, or fusion proteins may be effective. Several biological response modifiers have already shown positive results in phase II/III clinical trials in skin diseases, and many new biological response modifiers are in progress....

  12. Multi-session transcranial direct current stimulation (tDCS elicits inflammatory and regenerative processes in the rat brain.

    Directory of Open Access Journals (Sweden)

    Maria Adele Rueger

    Full Text Available Transcranial direct current stimulation (tDCS is increasingly being used in human studies as an adjuvant tool to promote recovery of function after stroke. However, its neurobiological effects are still largely unknown. Electric fields are known to influence the migration of various cell types in vitro, but effects in vivo remain to be shown. Hypothesizing that tDCS might elicit the recruitment of cells to the cortex, we here studied the effects of tDCS in the rat brain in vivo. Adult Wistar rats (n = 16 were randomized to either anodal or cathodal stimulation for either 5 or 10 consecutive days (500 µA, 15 min. Bromodeoxyuridine (BrdU was given systemically to label dividing cells throughout the experiment. Immunohistochemical analyses ex vivo included stainings for activated microglia and endogenous neural stem cells (NSC. Multi-session tDCS with the chosen parameters did not cause a cortical lesion. An innate immune response with early upregulation of Iba1-positive activated microglia occurred after both cathodal and anodal tDCS. The involvement of adaptive immunity as assessed by ICAM1-immunoreactivity was less pronounced. Most interestingly, only cathodal tDCS increased the number of endogenous NSC in the stimulated cortex. After 10 days of cathodal stimulation, proliferating NSC increased by ∼60%, with a significant effect of both polarity and number of tDCS sessions on the recruitment of NSC. We demonstrate a pro-inflammatory effect of both cathodal and anodal tDCS, and a polarity-specific migratory effect on endogenous NSC in vivo. Our data suggest that tDCS in human stroke patients might also elicit NSC activation and modulate neuroinflammation.

  13. Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model.

    Science.gov (United States)

    Hegazy, Hoda G; Ali, Elham H A; Elgoly, Amany H Mahmoud

    2015-02-01

    Butyl paraben is a preservative used in food, drugs and cosmetics. Neurotoxic effect was reported recently beside the potential estrogenic activity of parabens. There is controversy as to the potential harmful effects of butyl parabens, which are suspected to contribute to autism and learning disabilities. The purpose of this study was to examine the similarities between paraben intoxication signs in the rat brain and brain markers in an autistic like rat model. This study provides evidence of many parallels between the two, including (1) oxidative stress, (2) decreased reduced glutathione levels and elevated oxidised glutathione, (3) mitochondrial dysfunction, and (4) neuroinflammation and increased pro-inflammatory cytokine levels in the brain (tumour necrosis factor-alpha, interleukin-1-beta, and interleukin-6). (5) Increased protein oxidation reported by a significant increase in 3-nitrotyrosine (3-NT)/tyrosine ratio. (6) A marked disturbance was found in the production of energy carriers (AMP, ATP and AMP/ATP ratio) in comparison with the control. The evidence suggests that paraben may, to some extent, either cause or contribute to the brain physiopathology in ASDs or pathogens that produce the brain pathology observed in the diagnosed rat model of ASD.

  14. Is Alzheimer's Disease Autoimmune Inflammation of the Brain That Can be Treated With Nasal Nonsteroidal Anti-Inflammatory Drugs?

    Science.gov (United States)

    Lehrer, Steven; Rheinstein, Peter H

    2015-05-01

    The Alzheimer's Association recently reported that a woman's estimated lifetime risk of developing Alzheimer's at age 65 is 1 in 6, compared to nearly 1 in 11 for a man (ie, female to male ratio 1.8). Based on female to male ratio, Alzheimer's disease could well be an autoimmune disorder. Like Alzheimer's, multiple sclerosis, an autoimmune inflammation of the central nervous system, has a female to male ratio of 2.3. Also based on female to male ratio, Alzheimer's resembles the autoimmune inflammatory disease rheumatoid arthritis, which has a female to male ratio of 2.7. The reasons for the female preponderance in autoimmune disease are unclear, but nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and successfully employed to treat autoimmune anti-inflammatory disease and dramatically relieve symptoms. Moreover, oral NSAIDs consistently reduce the risk of Alzheimer's disease, although they have been totally ineffective as a treatment in multiple failed clinical trials. A basis for this failure might well be that the brain dose after oral administration is too small and not sufficiently early in the pathogenesis of the disorder. But NSAID brain dose could be significantly increased by delivering the NSAIDs intranasally.

  15. Generation of Reactive Oxygen Species (ROS) and Pro-Inflammatory Signaling in Human Brain Cells in Primary Culture.

    Science.gov (United States)

    Lukiw, Walter J; Bjattacharjee, Surjyadipta; Zhao, Yuhai; Pogue, Aileen I; Percy, Maire E

    2012-01-25

    The cellular generation of reactive oxygen species (ROS) has been implicated in contributing to the pathology of human neurological disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). To further understand the triggering and participation of ROS-generating species to pro-inflammatory and pathological signaling in human brain cells, in these experiments we studied the effects of 22 different substances (including various common drugs, interleukins, amyloid precursor protein, amyloid peptides and trace metals) at nanomolar concentrations, in a highly sensitive human neuronal-glial (HNG) cell primary co-culture assay. The evolution of ROS was assayed using the cell-permeate fluorescent indicator 2',7'-dichlorofluorescein diacetate (H2DCFDA), that reacts with major ROS species, including singlet oxygen, hydroxyl radicals or superoxides (λEx 488 nm; λEm 530 nm). Western analysis was performed for cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and cytosolic phospholipase A (cPLA2) to study the effects of induced ROS on inflammatory gene expression within the same brain cell sample. The data indicate that apart from acetylsalicylic acid (aspirin) and simvastatin, several neurophysiologically-relevant concentrations of Aβpeptides and neurotoxic trace metals variably induced ROS induction, COX-2 and cPLA2 expression. These findings have mechanistic implications for ROS-triggered inflammatory gene expression programs that may contribute to AD and PD neuropathologic mechanisms.

  16. Chronic combined stress induces selective and long-lasting inflammatory response evoked by changes in corticosterone accumulation and signaling in rat hippocampus.

    Science.gov (United States)

    Piskunov, Aleksey; Stepanichev, Mikhail; Tishkina, Anna; Novikova, Margarita; Levshina, Irina; Gulyaeva, Natalia

    2016-04-01

    Hippocampus is believed to be selectively vulnerable to stress. We hypothesized that this phenomenon may be mediated by relatively high vulnerability to neuroinflammation related to impairments of local glucocorticoid metabolism and signaling. We have evaluated inflammatory responses induced by acute or chronic combined stress in the cerebral cortex and hippocampus as well as circulating and brain corticosterone (CS) levels as well as expression of corticosterone target genes. The hippocampus showed higher stress-induced expression of the proinflammatory cytokine IL-1β as compared to the cerebral cortex. A month after the termination of the chronic stress, IL-1β mRNA in the cerebral cortex reached control level, while in the hippocampus it remained significantly increased. Under chronic stress, the maladaptive inflammatory response in hippocampus was accompanied by a significant increase in local CS levels, as compared to cerebral cortex. Under acute stress, the increased CS level induced changes in CS-regulated genes expression (CRF and IGF1), while this phenomenon was not observed after chronic stress. Thus, the hippocampus appears to be more vulnerable to stress-induced inflammation as compared to the neocortex and demonstrates persistent inflammatory response induced by chronic stress. Stress-induced maladaptive inflammatory response is associated with a selective increase in hippocampal CS accumulation and changes in CS signaling.

  17. Expression of Drosophila adenosine deaminase in immune cells during inflammatory response.

    Science.gov (United States)

    Novakova, Milena; Dolezal, Tomas

    2011-03-11

    Extra-cellular adenosine is an important regulator of inflammatory responses. It is generated from released ATP by a cascade of ectoenzymes and degraded by adenosine deaminase (ADA). There are two types of enzymes with ADA activity: ADA1 and ADGF/ADA2. ADA2 activity originates from macrophages and dendritic cells and is associated with inflammatory responses in humans and rats. Drosophila possesses a family of six ADGF proteins with ADGF-A being the main regulator of extra-cellular adenosine during larval stages. Herein we present the generation of a GFP reporter for ADGF-A expression by a precise replacement of the ADGF-A coding sequence with GFP using homologous recombination. We show that the reporter is specifically expressed in aggregating hemocytes (Drosophila immune cells) forming melanotic capsules; a characteristic of inflammatory response. Our vital reporter thus confirms ADA expression in sites of inflammation in vivo and demonstrates that the requirement for ADA activity during inflammatory response is evolutionary conserved from insects to vertebrates. Our results also suggest that ADA activity is achieved specifically within sites of inflammation by an uncharacterized post-transcriptional regulation based mechanism. Utilizing various mutants that induce melanotic capsule formation and also a real immune challenge provided by parasitic wasps, we show that the acute expression of the ADGF-A protein is not driven by one specific signaling cascade but is rather associated with the behavior of immune cells during the general inflammatory response. Connecting the exclusive expression of ADGF-A within sites of inflammation, as presented here, with the release of energy stores when the ADGF-A activity is absent, suggests that extra-cellular adenosine may function as a signal for energy allocation during immune response and that ADGF-A/ADA2 expression in such sites of inflammation may regulate this role.

  18. Mice deficient in interferon-gamma or interferon-gamma receptor 1 have distinct inflammatory responses to acute viral encephalomyelitis.

    Directory of Open Access Journals (Sweden)

    Eun-Young Lee

    Full Text Available Interferon (IFN-gamma is an important component of the immune response to viral infections that can have a role both in controlling virus replication and inducing inflammatory damage. To determine the role of IFN-gamma in fatal alphavirus encephalitis, we have compared the responses of wild type C57BL/6 (WTB6 mice with mice deficient in either IFN-gamma (GKO or the alpha-chain of the IFN-gamma receptor (GRKO after intranasal infection with a neuroadapted strain of sindbis virus. Mortalities of GKO and GRKO mice were similar to WTB6 mice. Both GKO and GRKO mice had delayed virus clearance from the brain and spinal cord, more infiltrating perforin(+ cells and lower levels of tumor necrosis factor (TNF-alpha and interleukin (IL-6 mRNAs than WTB6 mice. However, inflammation was more intense in GRKO mice than WTB6 or GKO mice with more infiltrating CD3(+ T cells, greater expression of major histocompatibility complex-II and higher levels of interleukin-17A mRNA. Fibroblasts from GRKO embryos did not develop an antiviral response after treatment with IFN-gamma, but showed increases in TNF-alpha, IL-6, CXCL9 and CXCL10 mRNAs although these increases developed more slowly and were less intense than those of WTB6 fibroblasts. These data indicate that both GKO and GRKO mice fail to develop an IFN-gamma-mediated antiviral response, but differ in regulation of the inflammatory response to infection. Therefore, GKO and GRKO cannot be considered equivalent when assessing the role of IFN-gamma in CNS viral infections.

  19. Global genetic variations predict brain response to faces

    DEFF Research Database (Denmark)

    Dickie, Erin W; Tahmasebi, Amir; French, Leon;

    2014-01-01

    Face expressions are a rich source of social signals. Here we estimated the proportion of phenotypic variance in the brain response to facial expressions explained by common genetic variance captured by ∼ 500,000 single nucleotide polymorphisms. Using genomic-relationship-matrix restricted maximu...

  20. Reproducibility of regional brain metabolic responses to lorazepam

    Energy Technology Data Exchange (ETDEWEB)

    Wang, G.J.; Volkow, N.D.; Overall, J. [Brookhaven National Lab., Upton, NY (United States)]|[SUNY, Stony Brook, NY (United States)] [and others

    1996-10-01

    Changes in regional brain glucose metabolism in response to benzodiazepine agonists have been used as indicators of benzodiazepine-GABA receptor function. The purpose of this study was to assess the reproducibility of these responses. Sixteen healthy right-handed men underwent scanning with PET and [{sup 18}F]fluorodeoxyglucose (FDG) twice: before placebo and before lorazepam (30 {mu}g/kg). The same double FDG procedure was repeated 6-8 wk later on the men to assess test-retest reproducibility. The regional absolute brain metabolic values obtained during the second evaluation were significantly lower than those obtained from the first evaluation regardless of condition (p {le} 0.001). Lorazepam significantly and consistently decreased both whole-brain metabolism and the magnitude. The regional pattern of the changes were comparable for both studies (12.3% {plus_minus} 6.9% and 13.7% {plus_minus} 7.4%). Lorazepam effects were the largest in the thalamus (22.2% {plus_minus} 8.6% and 22.4% {plus_minus} 6.9%) and occipital cortex (19% {plus_minus} 8.9% and 21.8% {plus_minus} 8.9%). Relative metabolic measures were highly reproducible both for pharmacolgic and replication condition. This study measured the test-retest reproducibility in regional brain metabolic responses, and although the global and regional metabolic values were significantly lower for the repeated evaluation, the response to lorazepam was highly reproducible. 1613 refs., 3 figs., 3 tabs.

  1. Syk/Src Pathway-Targeted Inhibition of Skin Inflammatory Responses by Carnosic Acid

    Directory of Open Access Journals (Sweden)

    Jueun Oh

    2012-01-01

    Full Text Available Carnosic acid (CA is a diterpene compound exhibiting antioxidative, anticancer, anti-angiogenic, anti-inflammatory, anti-metabolic disorder, and hepatoprotective and neuroprotective activities. In this study, the effect of CA on various skin inflammatory responses and its inhibitory mechanism were examined. CA strongly suppressed the production of IL-6, IL-8, and MCP-1 from keratinocyte HaCaT cells stimulated with sodium lauryl sulfate (SLS and retinoic acid (RA. In addition, CA blocked the release of nitric oxide (NO, tumor necrosis factor (TNF-α, and prostaglandin E2 (PGE2 from RAW264.7 cells activated by the toll-like receptor (TLR-2 ligands, Gram-positive bacterium-derived peptidoglycan (PGN and pam3CSK, and the TLR4 ligand, Gram-negative bacterium-derived lipopolysaccharide (LPS. CA arrested the growth of dermatitis-inducing Gram-positive and Gram-negative microorganisms such Propionibacterium acnes, Pseudomonas aeruginosa, and Staphylococcus aureus. CA also blocked the nuclear translocation of nuclear factor (NF-κB and its upstream signaling including Syk/Src, phosphoinositide 3-kinase (PI3K, Akt, inhibitor of κBα (IκBα kinase (IKK, and IκBα for NF-κB activation. Kinase assays revealed that Syk could be direct enzymatic target of CA in its anti-inflammatory action. Therefore, our data strongly suggest the potential of CA as an anti-inflammatory drug against skin inflammatory responses with Src/NF-κB inhibitory properties.

  2. Considering depression as a consequence of activation of the inflammatory response system

    NARCIS (Netherlands)

    Korf, J; Klein, HC; Versijpt, J; den Boer, J; ter Horst, GJ

    2002-01-01

    This paper summarizes the possible interrelation between peripheral and/or cerebral inflammation and depression. Often, depression is regarded as a consequence of life events, including disabling diseases. The question addressed here is whether activation of the inflammatory response system (IRS) ca

  3. Exploring the risk factors for sudden infant deaths and their role in inflammatory responses to infection

    Directory of Open Access Journals (Sweden)

    Caroline eBlackwell

    2015-03-01

    Full Text Available The risk factors for Sudden Infant Death Syndrome (SIDS parallel those associated with susceptibility to or severity of infectious diseases. There is no evidence that a single infectious agent is associated with SIDS; the common thread appears to be induction of inflammatory responses to infections. In this review, interactions between genetic and environmental risk factors for SIDS are assessed in relation to the hypothesis that many infant deaths result from dysregulation of inflammatory responses to minor infections. Risk factors are assessed in relation to three important stages of infection: 1 bacterial colonisation (frequency or density; 2 induction of temperature-dependent toxins; 3 induction or control of inflammatory responses.In this article we review the interactions among risk factors for SIDS for their effects on induction or control of inflammatory responses. The risk factors studied are genetic factors (sex, cytokine gene polymorphisms among ethnic groups at high or low risk of SID; developmental stage (changes in cortisol and testosterone levels associated with 2-4 month age range; environmental factors (virus infection, exposure to cigarette smoke. These interactions help to explain differences in the incidences of SIDS observed between ethnic groups prior to public health campaigns to reduce these infant deaths.

  4. The levels of RAC3 expression are up regulated by TNF in the inflammatory response

    Directory of Open Access Journals (Sweden)

    Cecilia Viviana Alvarado

    2014-01-01

    Full Text Available RAC3 is a coactivator of glucocorticoid receptor and nuclear factor-κB (NF-κB that is usually over-expressed in tumors and which also has important functions in the immune system. We investigated the role of the inflammatory response in the control of RAC3 expression levels in vivo and in vitro. We found that inflammation regulates RAC3 levels. In mice, sub-lethal doses of lipopolysaccharide induce the increase of RAC3 in spleen and the administration of the synthetic anti-inflammatory glucocorticoid dexamethasone has a similar effect. However, the simultaneous treatment with both stimuli is mutually antagonistic. In vitro stimulation of the HEK293 cell line with tumor necrosis factor (TNF, one of the cytokines induced by lipopolysaccharide, also increases the levels of RAC3 mRNA and protein, which correlates with an enhanced transcription dependent on the RAC3 gene promoter. We found that binding of the transcription factor NF-κB to the RAC3 gene promoter could be responsible for these effects. Our results suggest that increase of RAC3 during the inflammatory response could be a molecular mechanism involved in the control of sensitivity to both pro- and anti-inflammatory stimuli in order to maintain the normal healthy course of the immune response.

  5. Regulation of Inflammatory Responses in Shock-Related Syndromes by Synthetic Oligopeptides and Steroids

    NARCIS (Netherlands)

    M. van der Zee (Marten)

    2010-01-01

    textabstractInflammation is the body’s way of responding to disturbances in homeostasis. Depending on the triggering event and the site of inflammation, the inflammatory response has different physiological purposes and pathological consequences (Figure 1). Inducers of inflammation are either foreig

  6. Dietary L-arginine supplementation modulates lipopolysaccharide-induced systemic inflammatory response in broiler chickens

    Science.gov (United States)

    This study was conducted to evaluate whether dietary supplementation with L-arginine (Arg) could attenuate lipopolysaccharide (LPS)-induced systemic inflammatory response through LPS/TLR-4 signaling pathway in broilers. The experiment was designed as a 2 × 3 factorial arrangement (n = 8 cages/treatm...

  7. Influence of the blood bacterial load on the meningeal inflammatory response in Streptococcus pneumoniae meningitis

    DEFF Research Database (Denmark)

    Østergaard, C; O´Reilly, T; Brandt, C;

    2006-01-01

    BACKGROUND: Despite bacteraemia is present in the majority of patients with pneumococcal, little is known about the influence of the systemic infection on the meningeal inflammatory response. METHODS: To explore the role of systemic infection on the meningeal inflammation, experimental meningitis...

  8. Dietary L-arginine supplementation attenuates lipopolysaccharide-induced inflammatory response in broiler chickens

    Science.gov (United States)

    Two experiments were conducted to investigate the effect of dietary L-arginine (Arg) supplementation on inflammatory response and innate immunity of broilers. Experiment 1 was designed as a 2 × 3 factorial arrangement (n = 8 cages/treatment; 6 birds/cage) with 3 dietary Arg concentrations (1.05, 1.4...

  9. The levels of RAC3 expression are up regulated by TNF in the inflammatory response.

    Science.gov (United States)

    Alvarado, Cecilia Viviana; Rubio, María Fernanda; Fernández Larrosa, Pablo Nicolas; Panelo, Laura Carolina; Azurmendi, Pablo Javier; Ruiz Grecco, Marina; Martínez-Nöel, Giselle Astrid; Costas, Mónica Alejandra

    2014-01-01

    RAC3 is a coactivator of glucocorticoid receptor and nuclear factor-κB (NF-κB) that is usually over-expressed in tumors and which also has important functions in the immune system. We investigated the role of the inflammatory response in the control of RAC3 expression levels in vivo and in vitro. We found that inflammation regulates RAC3 levels. In mice, sub-lethal doses of lipopolysaccharide induce the increase of RAC3 in spleen and the administration of the synthetic anti-inflammatory glucocorticoid dexamethasone has a similar effect. However, the simultaneous treatment with both stimuli is mutually antagonistic. In vitro stimulation of the HEK293 cell line with tumor necrosis factor (TNF), one of the cytokines induced by lipopolysaccharide, also increases the levels of RAC3 mRNA and protein, which correlates with an enhanced transcription dependent on the RAC3 gene promoter. We found that binding of the transcription factor NF-κB to the RAC3 gene promoter could be responsible for these effects. Our results suggest that increase of RAC3 during the inflammatory response could be a molecular mechanism involved in the control of sensitivity to both pro- and anti-inflammatory stimuli in order to maintain the normal healthy course of the immune response.

  10. The time course of the inflammatory response to the Salmonella typhi vaccination

    NARCIS (Netherlands)

    Paine, N.J.; Ring, C.; Bosch, J.A.; Drayson, M.T.; Veldhuijzen van Zanten, J.J.C.S.

    2013-01-01

    The Salmonella typhi vaccination induces transient increases in inflammatory-responsive cytokines and molecules. For instance, it causes small, mild increases in interleukin-6 (IL-6) within a few hours and C-reactive protein (CRP) within 24 h. No study has charted either the time course of the infla

  11. Corticosterone treatment of pregnant low dose endotoxin-treated rats : Inhibition of the inflammatory response

    NARCIS (Netherlands)

    Faas, MM; Slot, K; Koiter, TR; Schuiling, GA

    2000-01-01

    PROBLEM: Can the endotoxin-induced inflammatory response, underlying experimental pre-eclampsia, in pregnant rats be inhibited by corticosterone? METHOD OF STUDY: On day 10 of pregnancy, rats were implanted with pellets containing 25% corticosterone and 75% cholesterol (n = 10) or with 100% choleste

  12. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology.

    Science.gov (United States)

    Millar, Jonathan E; Fanning, Jonathon P; McDonald, Charles I; McAuley, Daniel F; Fraser, John F

    2016-11-28

    Extracorporeal membrane oxygenation (ECMO) is a technology capable of providing short-term mechanical support to the heart, lungs or both. Over the last decade, the number of centres offering ECMO has grown rapidly. At the same time, the indications for its use have also been broadened. In part, this trend has been supported by advances in circuit design and in cannulation techniques. Despite the widespread adoption of extracorporeal life support techniques, the use of ECMO remains associated with significant morbidity and mortality. A complication witnessed during ECMO is the inflammatory response to extracorporeal circulation. This reaction shares similarities with the systemic inflammatory response syndrome (SIRS) and has been well-documented in relation to cardiopulmonary bypass. The exposure of a patient's blood to the non-endothelialised surface of the ECMO circuit results in the widespread activation of the innate immune system; if unchecked this may result in inflammation and organ injury. Here, we review the pathophysiology of the inflammatory response to ECMO, highlighting the complex interactions between arms of the innate immune response, the endothelium and coagulation. An understanding of the processes involved may guide the design of therapies and strategies aimed at ameliorating inflammation during ECMO. Likewise, an appreciation of the potentially deleterious inflammatory effects of ECMO may assist those weighing the risks and benefits of therapy.

  13. Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

    DEFF Research Database (Denmark)

    Khorooshi, Reza; Owens, Trevor

    2010-01-01

    Innate glial response is critical for the induction of inflammatory mediators and recruitment of leukocytes to sites of the injury in the CNS. We have examined the involvement of type I IFN signaling in the mouse hippocampus following sterile injury (transection of entorhinal afferents). Type I I...

  14. Macrophage CGI-58 Attenuates Inflammatory Responsiveness via Promotion of PPARγ Signaling

    Directory of Open Access Journals (Sweden)

    Dan Yang

    2016-02-01

    Full Text Available Background/Aims: Comparative gene identification-58 (CGI-58, an adipose triglyceride lipase (ATGL coactivator, strongly promotes ATGL-mediated triglyceride (TG catabolism. Beyond its function in promoting lipolysis, other features of CGI-58 have been proposed. Here, we investigated the role of CGI-58 in the regulation of inflammatory responsiveness in macrophages. Methods: Macrophage-specific GCI-58 transgenic mice (TG and wild type mice (WT were fed a high fat diet (HFD, and RAW264.7 cells were treated with lipopolysaccharide (LPS. The peroxisome proliferator-activated receptor (PPAR signaling was detected. The inflammatory responsiveness and mitochondrial function were examined. Results: TG mice showed lower serum levels of proinflammatory cytokines and better mitochondrial function in macrophages compared with WT control. Knockdown of CGI-58 in RAW264.7 cells aggravated LPS-induced inflammation and mitochondrial dysfunction. CGI-58 overexpression and silencing in macrophages induced and inhibited PPARγ expression and activity, respectively. Most importantly, the PPARγ-specific agonist rosiglitazone significantly suppressed inflammation and mitochondrial dysfunction induced by CGI-58 deficiency. Furthermore, knockdown of PPARγ in macrophages significantly dampened the role of CGI-58 in suppression of inflammation and mitochondrial dysfunction. Interestingly, CGI-58 inhibited histone deacetylation and the recruitment of histone deacetylase (HDAC to the PPARγ promoter. Finally, ATGL deficiency did not affect inflammatory responsiveness and PPARγ signaling in macrophages. Conclusion: These results demonstrate that macrophage CGI-58 enhances PPARγ signaling and thus suppresses inflammatory responsiveness and mitochondrial dysfunction.

  15. Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome

    NARCIS (Netherlands)

    S.S. Iyer; W.P. Pulskens; J.J. Sadler; L.M. Butter; G.J. Teske; T.K. Ulland; S.C. Eisenbarth; S. Florquin; R.A. Flavell; J.C. Leemans; F.S. Sutterwala

    2009-01-01

    Dying cells are capable of activating the innate immune system and inducing a sterile inflammatory response. Here, we show that necrotic cells are sensed by the Nlrp3 inflammasome resulting in the subsequent release of the proinflammatory cytokine IL-1 beta. Necrotic cells produced by pressure disru

  16. Reduction of the inflammatory response in patients undergoing minimally invasive coronary artery bypass grafting

    NARCIS (Netherlands)

    Gu, YJ; Mariani, MA; van Oeveren, W; Grandjean, JG; Boonstra, PW

    1998-01-01

    Background. The aim of this prospective study was to determine whether the inflammation-associated clinical morbidity as well as the subclinical markers of the inflammatory response are reduced in patients who undergo minimally invasive coronary artery bypass grafting without cardiopulmonary bypass.

  17. Histamine regulates the inflammatory response of the tunicate Styela plicata.

    Science.gov (United States)

    García-García, Erick; Gómez-González, Nuria E; Meseguer, José; García-Ayala, Alfonsa; Mulero, Victoriano

    2014-10-01

    Histamine is stored inside hemocytes of the tunicate Styela plicata (Chordata, Tunicata, Ascidiacea), but no evidence on its role in the regulation of the immune response of this species has been reported. We examined whether histamine participated in the regulation of inflammation and host defense in S. plicata. The presence of histamine inside S. plicata hemocytes was confirmed by flow cytometry, and histamine release was detected by ELISA, after in vitro hemocyte stimulation with different PAMPs. In vitro hemocyte treatment with histamine, or specific histamine-receptor agonists, reduced their phagocytic ability. Injection of histamine into the tunic recruited hemocytes to the site of injection. Systemic injection of histamine, or the histamine-releasing agent compound 48/80, decreased the phagocytic ability of hemocytes. Histamine promoted the constriction of tunic hemolymph vessels in vivo, having a direct effect on vasoconstriction in tunic explants. These results provide for the first time clear evidence for the involvement of histamine in the regulation of inflammation and host defense in tunicates.

  18. Antibody Response against Parvovirus in Patients with Inflammatory Rheumatological Diseases

    Directory of Open Access Journals (Sweden)

    SH Raeisi

    2011-07-01

    Full Text Available Introduction: Some viral infections have been suggested to trigger or cause autoimmune diseases. One of these viruses is parvovirus B19 which can have various rheumatologic manifestations. In this study we investigated the association between parvovirus and rheumatoid arthritis (RA, systemic lupus erythematosis(SLE, systemic sclerosis(SSc and undifferentiated arthritis at the Rheumatological Clinic, Imam Khomeini hospital. Methods: In this sectional case-control study, IgM and IgG antibodies against parvovirus B19 were measured with ELISA in 41 patients with RA, 28 patients with SLE, 13 patients with SSc, 8 patients with undifferentiated arthritis as well as 90 healthy controls. The ELISA kit (DRG, Germany was semi-quantitative and qualititative. Results: Parvovirus B19 IgM was detected in one patient with RA, one with SSc and four in the control group. IgG anti- B19-specific antibody was detected in 58.5% of RA patients, 67.9% of SLE patients, 69. 2% of SSc patients, 87.5% of undifferentiated arthritis patients as compared to 53.3% of controls. The results were compared between the patient and control groups(p>0.05. Conclusion: According to the results, there was no significant correlation for the antibody titer against parvovirus B19 in the patient and control group. The highly positive response of IgG against parvovirus in undifferentiated arthritis implies the need for more research.

  19. Association between brain natriuretic peptide, markers of inflammation and the objective and subjective response to cardiac resynchronization therapy

    DEFF Research Database (Denmark)

    Brouwers, Corline; Versteeg, Henneke; Meine, Mathias;

    2014-01-01

    Introduction: Studies suggest that cardiac resynchronization therapy (CRT) can induce a decrease in brain natriuretic peptide (BNP) and systemic inflammation, which may be associated with CRT-response. However, the evidence is inconclusive. We examined levels of BNP and inflammatory markers from...... ventricular end systolic volume; subjective CRT-response was defined as an improvement of ⩾10 points in patient-reported health status assessed with the Kansas City Cardiomyopathy Questionnaire. Plasma BNP and markers of inflammation (CRP, IL-6, TNFα, sTNFr1 and sTNFr2) were measured at three time points......=27.31, pinflammation. This indicates that response to CRT...

  20. Allelic variation on murine chromosome 11 modifies host inflammatory responses and resistance to Bacillus anthracis.

    Science.gov (United States)

    Terra, Jill K; France, Bryan; Cote, Christopher K; Jenkins, Amy; Bozue, Joel A; Welkos, Susan L; Bhargava, Ragini; Ho, Chi-Lee; Mehrabian, Margarete; Pan, Calvin; Lusis, Aldons J; Davis, Richard C; LeVine, Steven M; Bradley, Kenneth A

    2011-12-01

    Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (LT), as well as by genetic variation within the host. To identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the LT-responsive CAST/Ei strain introgressed on a LT-resistant C57BL/6 (B6) background was screened for response to LT. Three congenic strains containing CAST/Ei regions of chromosome 11 were identified that displayed a rapid inflammatory response to LT similar to, but more severe than that driven by a LT-responsive allele of the inflammasome constituent NRLP1B. Importantly, increased response to LT in congenic mice correlated with greater resistance to infection by the Sterne strain of B. anthracis. The genomic region controlling the inflammatory response to LT was mapped to 66.36-74.67 Mb on chromosome 11, a region that encodes the LT-responsive CAST/Ei allele of Nlrp1b. However, known downstream effects of NLRP1B activation, including macrophage pyroptosis, cytokine release, and leukocyte infiltration could not fully explain the response to LT or the resistance to B. anthracis Sterne in congenic mice. Further, the exacerbated response in congenic mice is inherited in a recessive manner while the Nlrp1b-mediated response to LT is dominant. Finally, congenic mice displayed increased responsiveness in a model of sepsis compared with B6 mice. In total, these data suggest that allelic variation of one or more chromosome 11 genes in addition to Nlrp1b controls the severity of host response to multiple inflammatory stimuli and contributes to resistance to B. anthracis Sterne. Expression quantitative trait locus analysis revealed 25 genes within this region as high priority candidates for contributing to the host response to LT.

  1. Allelic variation on murine chromosome 11 modifies host inflammatory responses and resistance to Bacillus anthracis.

    Directory of Open Access Journals (Sweden)

    Jill K Terra

    2011-12-01

    Full Text Available Anthrax is a potentially fatal disease resulting from infection with Bacillus anthracis. The outcome of infection is influenced by pathogen-encoded virulence factors such as lethal toxin (LT, as well as by genetic variation within the host. To identify host genes controlling susceptibility to anthrax, a library of congenic mice consisting of strains with homozygous chromosomal segments from the LT-responsive CAST/Ei strain introgressed on a LT-resistant C57BL/6 (B6 background was screened for response to LT. Three congenic strains containing CAST/Ei regions of chromosome 11 were identified that displayed a rapid inflammatory response to LT similar to, but more severe than that driven by a LT-responsive allele of the inflammasome constituent NRLP1B. Importantly, increased response to LT in congenic mice correlated with greater resistance to infection by the Sterne strain of B. anthracis. The genomic region controlling the inflammatory response to LT was mapped to 66.36-74.67 Mb on chromosome 11, a region that encodes the LT-responsive CAST/Ei allele of Nlrp1b. However, known downstream effects of NLRP1B activation, including macrophage pyroptosis, cytokine release, and leukocyte infiltration could not fully explain the response to LT or the resistance to B. anthracis Sterne in congenic mice. Further, the exacerbated response in congenic mice is inherited in a recessive manner while the Nlrp1b-mediated response to LT is dominant. Finally, congenic mice displayed increased responsiveness in a model of sepsis compared with B6 mice. In total, these data suggest that allelic variation of one or more chromosome 11 genes in addition to Nlrp1b controls the severity of host response to multiple inflammatory stimuli and contributes to resistance to B. anthracis Sterne. Expression quantitative trait locus analysis revealed 25 genes within this region as high priority candidates for contributing to the host response to LT.

  2. Energy Drink Administration in Combination with Alcohol Causes an Inflammatory Response and Oxidative Stress in the Hippocampus and Temporal Cortex of Rats

    Science.gov (United States)

    Díaz, Alfonso; Treviño, Samuel; Guevara, Jorge; Muñoz-Arenas, Guadalupe; Brambila, Eduardo; Espinosa, Blanca; Moreno-Rodríguez, Albino; Lopez-Lopez, Gustavo; Peña-Rosas, Ulises; Venegas, Berenice; Handal-Silva, Anabella; Morán-Perales, José Luis; Flores, Gonzalo; Aguilar-Alonso, Patricia

    2016-01-01

    Energy drinks (EDs) are often consumed in combination with alcohol because they reduce the depressant effects of alcohol. However, different researches suggest that chronic use of these psychoactive substances in combination with alcohol can trigger an oxidative and inflammatory response. These processes are regulated by both a reactive astrogliosis and an increase of proinflammatory cytokines such as IL-1β, TNF-α, and iNOS, causing cell death (apoptosis) at the central and peripheral nervous systems. Currently, mechanisms of toxicity caused by mixing alcohol and ED in the brain are not well known. In this study, we evaluated the effect of chronic alcohol consumption in combination with ED on inflammatory response and oxidative stress in the temporal cortex (TCx) and hippocampus (Hp) of adult rats (90 days old). Our results demonstrated that consuming a mixture of alcohol and ED for 60 days induced an increase in reactive gliosis, IL-1β, TNF-α, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide, in the TCx and Hp. We also found immunoreactivity to caspase-3 and a decrease of synaptophysin in the same brain regions. The results suggested that chronic consumption of alcohol in combination with ED causes an inflammatory response and oxidative stress, which induced cell death via apoptosis in the TCx and Hp of the adult rats. PMID:27069534

  3. Energy Drink Administration in Combination with Alcohol Causes an Inflammatory Response and Oxidative Stress in the Hippocampus and Temporal Cortex of Rats

    Directory of Open Access Journals (Sweden)

    Alfonso Díaz

    2016-01-01

    Full Text Available Energy drinks (EDs are often consumed in combination with alcohol because they reduce the depressant effects of alcohol. However, different researches suggest that chronic use of these psychoactive substances in combination with alcohol can trigger an oxidative and inflammatory response. These processes are regulated by both a reactive astrogliosis and an increase of proinflammatory cytokines such as IL-1β, TNF-α, and iNOS, causing cell death (apoptosis at the central and peripheral nervous systems. Currently, mechanisms of toxicity caused by mixing alcohol and ED in the brain are not well known. In this study, we evaluated the effect of chronic alcohol consumption in combination with ED on inflammatory response and oxidative stress in the temporal cortex (TCx and hippocampus (Hp of adult rats (90 days old. Our results demonstrated that consuming a mixture of alcohol and ED for 60 days induced an increase in reactive gliosis, IL-1β, TNF-α, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide, in the TCx and Hp. We also found immunoreactivity to caspase-3 and a decrease of synaptophysin in the same brain regions. The results suggested that chronic consumption of alcohol in combination with ED causes an inflammatory response and oxidative stress, which induced cell death via apoptosis in the TCx and Hp of the adult rats.

  4. The role of multiple negative social relationships in inflammatory cytokine responses to a laboratory stressor

    Directory of Open Access Journals (Sweden)

    Sunmi Song

    2015-06-01

    Full Text Available The present study examined the unique impact of perceived negativity in multiple social relationships on endocrine and inflammatory responses to a laboratory stressor. Via hierarchical cluster analysis, those who reported negative social exchanges across relationships with a romantic partner, family, and their closest friend had higher mean IL-6 across time and a greater increase in TNF-α from 15 min to 75 min post stress. Those who reported negative social exchanges across relationships with roommates, family, and their closest friend showed greater IL-6 responses to stress. Differences in mean IL-6 were accounted for by either depressed mood or hostility, whereas differences in the cytokine stress responses remained significant after controlling for those factors. Overall, this research provides preliminary evidence to suggest that having multiple negative relationships may exacerbate acute inflammatory responses to a laboratory stressor independent of hostility and depressed mood.

  5. Cooperative dynamics in auditory brain response

    CERN Document Server

    Kwapien, J; Liu, L C; Ioannides, A A

    1998-01-01

    Simultaneous estimates of the activity in the left and right auditory cortex of five normal human subjects were extracted from Multichannel Magnetoencephalography recordings. Left, right and binaural stimulation were used, in separate runs, for each subject. The resulting time-series of left and right auditory cortex activity were analysed using the concept of mutual information. The analysis constitutes an objective method to address the nature of inter-hemispheric correlations in response to auditory stimulations. The results provide a clear evidence for the occurrence of such correlations mediated by a direct information transport, with clear laterality effects: as a rule, the contralateral hemisphere leads by 10-20ms, as can be seen in the average signal. The strength of the inter-hemispheric coupling, which cannot be extracted from the average data, is found to be highly variable from subject to subject, but remarkably stable for each subject.

  6. Infants' brain responses to speech suggest analysis by synthesis.

    Science.gov (United States)

    Kuhl, Patricia K; Ramírez, Rey R; Bosseler, Alexis; Lin, Jo-Fu Lotus; Imada, Toshiaki

    2014-08-01

    Historic theories of speech perception (Motor Theory and Analysis by Synthesis) invoked listeners' knowledge of speech production to explain speech perception. Neuroimaging data show that adult listeners activate motor brain areas during speech perception. In two experiments using magnetoencephalography (MEG), we investigated motor brain activation, as well as auditory brain activation, during discrimination of native and nonnative syllables in infants at two ages that straddle the developmental transition from language-universal to language-specific speech perception. Adults are also tested in Exp. 1. MEG data revealed that 7-mo-old infants activate auditory (superior temporal) as well as motor brain areas (Broca's area, cerebellum) in response to speech, and equivalently for native and nonnative syllables. However, in 11- and 12-mo-old infants, native speech activates auditory brain areas to a greater degree than nonnative, whereas nonnative speech activates motor brain areas to a greater degree than native speech. This double dissociation in 11- to 12-mo-old infants matches the pattern of results obtained in adult listeners. Our infant data are consistent with Analysis by Synthesis: auditory analysis of speech is coupled with synthesis of the motor plans necessary to produce the speech signal. The findings have implications for: (i) perception-action theories of speech perception, (ii) the impact of "motherese" on early language learning, and (iii) the "social-gating" hypothesis and humans' development of social understanding.

  7. Modulatory Effect of Gliadin Peptide 10-mer on Epithelial Intestinal CACO-2 Cell Inflammatory Response.

    Directory of Open Access Journals (Sweden)

    Antonella Capozzi

    Full Text Available Celiac Disease (CD is a chronic inflammatory enteropathy, triggered in genetically susceptible individuals by dietary gluten. Gluten is able to elicit proliferation of specific T cells and secretion of inflammatory cytokines in the small intestine. In this study we investigated the possibility that p10-mer, a decapeptide from durum wheat (QQPQDAVQPF, which was previously shown to prevent the activation of celiac peripheral lymphocytes, may exert an inhibitory effect on peptic-tryptic digested gliadin (PT-Gly-stimulated intestinal carcinoma CACO-2 cells. In these cells, incubated with PT-Gly or p31-43 α-gliadin derived peptide in the presence or in the absence of p10-mer, IRAK1 activation and NF-kB, ERK1/2 and p38 MAPK phosphorylation were measured by immunoblotting, Cyclooxigenase 2 (COX-2 activity by PGE-2 release assay, and production of cytokines in the cell supernatants by ELISA. Our results showed that pre-treatment of CACO-2 cells with p10-mer significantly inhibited IRAK1 activation and NF-kB, ERK1/2 and p38 MAPK phosphorylation, as well as COX-2 activity (i.e. PGE-2 release and production of the IL-6 and IL-8 pro-inflammatory cytokines, induced by gliadin peptides. These findings demonstrate the inhibitory effect of the p10-mer peptide on inflammatory response in CACO-2 cells. The results of the present study show that this p10-mer peptide can modulate "in vitro" the inflammatory response induced by gliadin peptides, allowing to move towards new therapeutic strategies. Turning off the inflammatory response, may in fact represent a key target in the immunotherapy of celiac disease.

  8. Let-7e modulates the inflammatory response in vascular endothelial cells through ceRNA crosstalk

    Science.gov (United States)

    Lin, Zongwei; Ge, Junfeng; Wang, Zhe; Ren, Jianwei; Wang, Xiaowei; Xiong, Hui; Gao, Jing; Zhang, Yan; Zhang, Qunye

    2017-01-01

    The inflammatory responses of vascular endothelial cells (VECs) are critical in the development of many cardio-cerebrovascular diseases. Let-7e is an important regulator of endothelial function and inflammation. However, the effects and mechanisms of let-7e on VECs inflammation have not been studied until recently. Thus, we investigated these issues and found that in addition to proliferation, apoptosis and cell adhesion, let-7e was also implicated in the regulation of inflammatory responses through a complex network, including IκBβ and lncRNA lnc-MKI67IP-3. Let-7e promoted NF-κB activation and translocation to the nucleus by inhibiting its target gene (IκBβ) expression and subsequently increased the expression of inflammatory and adhesion molecules. Meanwhile, lnc-MKI67IP-3 acted as a sponge or competing endogenous RNA (ceRNA) for let-7e, suppressing its pro-inflammatory effects, and let-7e decreased lnc-MKI67IP-3 expression, thereby forming a positive feedback loop to aggravate inflammation. Moreover, let-7e, lnc-MKI67IP-3 and IκBβ were also abnormal in oxLDL-treated VECs and atherosclerotic plaques. The present study revealed let-7e as a pro-inflammatory mediator and a novel regulatory mechanism for the NF-κB pathway through ceRNA crosstalk, comprising let-7e and its target IκBβ and the ceRNA lnc-MKI67IP-3. Thus, this molecule might play important roles in the inflammatory responses of VECs and development of atherosclerosis. PMID:28195197

  9. Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

    OpenAIRE

    Yuan Cao; Di Zhao; An-Tao Xu; Jun Shen; Zhi-Hua Ran

    2015-01-01

    Objective: To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants). Data Sources: We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators). The following terms were used: "inflammatory bowel disease (IBD)" OR "Crohn′s dise...

  10. Arginine transport and nitric oxide production: role in the inflammatory response

    OpenAIRE

    Barilli, Amelia

    2008-01-01

    The research concerns the characterization of the pathways responsible for the recruitment of L-arginine, the obliged substrate for nitric oxide biosynthesis, in human cells. Endothelial cells and monocytes/macrophages have been employed, as the cell types more directly linked to NO pathway. As for human endothelium, only system y+ is involved in the inflammatory response: both TNFα and rapamycin, an mTOR inhibitor employed in clinical angioplasty, lead to a massive increase of CAT-mediated a...

  11. Inflammatory response in chronic degenerative endometritis mares treated with platelet-rich plasma.

    Science.gov (United States)

    Reghini, Maria Fernanda S; Ramires Neto, Carlos; Segabinazzi, Lorenzo G; Castro Chaves, Maria Manoela B; Dell'Aqua, Camila de Paula F; Bussiere, Maria Clara C; Dell'Aqua, José Antonio; Papa, Frederico O; Alvarenga, Marco Antonio

    2016-07-15

    Degenerative changes of the endometrium are directly related to age and fertility in mares. Chronic degenerative endometritis (CDE) is correlated with uterine fluid retention and reduced ability to clear uterine inflammation. Recent research in the areas of equine surgery and sports medicine has shown that platelet-rich plasma (PRP) treatment acts as an immunomodulator of the inflammatory response. Therefore, the aim of this study was to determine if the uterine infusion of PRP could modulate the local inflammatory response and modify the intrauterine NO concentrations after artificial insemination (AI) in both normal mares and those with CDE. Thirteen mares with endometrium classified as grade III on the histology (mares with CDE) and eight mares with endometrial histological classification I or II-a normal mares were selected to investigate the effect of PRP therapy. The mares were inseminated with fresh semen in two consecutive cycles in a crossover study design. Thereby, each mare served as its own control and the treatment was performed with intrauterine PRP infusion four hours after AI. The percentage of neutrophils in uterine cytology (CIT, %), uterine fluid accumulation observed on ultrasonography (FLU, mm) and nitric oxide concentration of uterine fluid (NO, μM) were analyzed before and 24 hours after AI. The results reported that mares with CDE (CIT, 68.3 ± 3.27, FLU, 10.7 ± 1.61) have a higher (P inflammatory response after AI than normal mares (CIT, 24.4 ± 3.56, FLU, 0), but NO concentrations did not differ (P > 0.05) between categories of mares. In treated cycles with PRP, the intrauterine inflammatory response decrease (P inflammatory response to semen in mares with CDE but did not reduce NO concentrations in intrauterine fluid.

  12. Soft regulation of inflammatory immune responses%炎症免疫反应软调节

    Institute of Scientific and Technical Information of China (English)

    魏伟

    2016-01-01

    炎症反应和免疫反应在整体、组织、细胞和分子等各层次密不可分。该文提出炎症免疫反应( inflammatory immune responses, IIR)是机体炎症免疫相关细胞依据内外环境变化所表现出的适度或异常的系统反应;简述了参与IIR的炎症免疫细胞(巨噬细胞、树突细胞、T 细胞、B 细胞等及其亚型)、非炎症免疫细胞(如胶质细胞、内皮细胞、上皮细胞、成纤维细胞、滑膜细胞、肝细胞等)及细胞因子/受体信号转导的研究进展,指出了目前临床上使用的影响IIR药物存在的问题,提出炎症免疫反应软调节( soft regulation of inflammato-ry immune responses,SRIIR)是研发治疗IIR相关疾病创新药物的新方向。%Inflammation reaction and immune response are in-separable in the levels of system, tissue, cell and molecule. In-flammatory immune responses ( IIR) is proposed in this paper, which is defined a moderate or abnormal system responses of in-flammatory immune related cells in responding to the internal and external environment changes of body. It is described briefly that the research progresses of inflammatory immune cells ( e. g. , macrophages, dendritic cells, T cells and B cells, etc. ) and non-inflammatory immune cells ( e. g. , glial cells, endothe-lial cells, epithelial cells, fibroblasts, synovial cells and liver cells, etc. ) , and cytokines/receptor signal transduction in-volved in IIR. Moreover, the existing problems about regulating IIR drugs clinically are summarized. It is firstly put forward that soft regulation of inflammatory immune responses ( SRIIR) is a new direction of discovery and development of new drugs for the treatment of IIR related diseases.

  13. Training increases anabolic response and reduces inflammatory response to a single practice in elite male adolescent volleyball players.

    Science.gov (United States)

    Nemet, Dan; Portal, Shawn; Zadik, Zvi; Pilz-Burstein, Rutie; Adler-Portal, Dana; Meckel, Yoav; Eliakim, Alon

    2012-01-01

    We examined the effect of training on hormonal and inflammatory response to a single volleyball practice in elite adolescent players. Fourteen male, elite, national team-level, Israeli volleyball players (age, 16.3±1.1 years, Tanner stage 4-5) participated in the study. Blood samples were collected before and immediately after a typical 60-min volleyball practice, before and after 7 weeks of training during the initial phases of the volleyball season. Hormonal measurements included the anabolic hormones growth hormone (GH), insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, and testosterone; the catabolic hormone cortisol; the pro-inflammatory markers interleukin (IL) 6, and the anti-inflammatory marker IL-1 receptor antagonist. Training led to a significant improvement of both anaerobic and aerobic properties. Before the training intervention, the typical volleyball practice was associated with a significant increase of GH and testosterone and also with a significant increase of IL-6. Training resulted in a significantly greater GH response (ΔGH, 2.5±2.4 vs. 4.7±3.0 ng/mL, before and after training, respectively; pvolleyball practice. The results suggest that, along with the improvement of anaerobic and aerobic characteristics, training leads to a greater anabolic and reduced inflammatory response to exercise.

  14. Inflammatory response of a prostate stromal cell line induced by Trichomonas vaginalis.

    Science.gov (United States)

    Im, S J; Han, I H; Kim, J H; Gu, N Y; Seo, M Y; Chung, Y H; Ryu, J S

    2016-04-01

    While Trichomonas vaginalis, a cause of sexually transmitted infection, is known as a surface-dwelling protozoa, trichomonads have been detected in prostatic tissue from benign prostatic hyperplasia and prostatitis by immunoperoxidase assay or PCR. However, the immune response of prostate stromal cells infected with T. vaginalis has not been investigated. Our objective was to investigate whether T. vaginalis could induce an inflammatory response in prostate stromal cells. Incubation of a human prostate stromal myofibroblast cells (WPMY-1) with live T. vaginalis T016 increased expression of the inflammatory chemokines CXCL8 and CCL2. In addition, TLR4, ROS, MAPK and NF-κB expression increased, while inhibitors of TLR4, ROS, MAPKs and NF-κB reduced CXCL8 and CCL2 production. Medium conditioned by incubation of WPMY-1 cells with T. vaginalis stimulated the migration of human neutrophils and monocytes (THP-1 cells). We conclude that T. vaginalis increases CXCL8 and CCL2 production by human prostate stromal cells by activating TLR4, ROS, MAPKs and NF-κB, and this in turn attracts neutrophils and monocytes and leads to an inflammatory response. This study is the first attempt to demonstrate an inflammatory reaction in prostate stromal cells caused by T. vaginalis.

  15. The HMGB1 signaling pathway activates the inflammatory response in Schwann cells.

    Science.gov (United States)

    Man, Li-Li; Liu, Fan; Wang, Ying-Jie; Song, Hong-Hua; Xu, Hong-Bo; Zhu, Zi-Wen; Zhang, Qing; Wang, Yong-Jun

    2015-10-01

    Schwann cells are not only myelinating cells, but also function as immune cells and express numerous innate pattern recognition receptors, including the Toll-like receptors. Injury to peripheral nerves activates an inflammatory response in Schwann cells. However, it is unclear whether specific endogenous damage-associated molecular pattern molecules are involved in the inflammatory response following nerve injury. In the present study, we demonstrate that a key damage-associated molecular pattern molecule, high mobility group box 1 (HMGB1), is upregulated following rat sciatic nerve axotomy, and we show colocalization of the protein with Schw-ann cells. HMGB1 alone could not enhance expression of Toll-like receptors or the receptor for advanced glycation end products (RAGE), but was able to facilitate migration of Schwann cells. When Schwann cells were treated with HMGB1 together with lipopolysaccharide, the expression levels of Toll-like receptors and RAGE, as well as inflammatory cytokines were upregulated. Our novel findings demonstrate that the HMGB1 pathway activates the inflammatory response in Schwann cells following peripheral nerve injury.

  16. Beneficial Effects of Fractions of Nardostachys jatamansi on Lipopolysaccharide-Induced Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Gi-Sang Bae

    2014-01-01

    Full Text Available It has been previously shown that Nardostachys jatamansi (NJ exhibits anti-inflammatory properties against lipopolysaccharide (LPS challenges. However, the potency of NJ constituents against LPS-induced inflammatory responses has not been examined. In this present study, we determined which NJ extract fractions exhibit inhibitory effects against LPS-induced inflammatory responses. Among the NJ fractions, NJ-1, NJ-3, NJ-4, and NJ-6 inhibited LPS-induced production of NO. The NJ-3, NJ-4, and NJ-6 fractions also inhibited the production of cytokines, such as IL-1β, IL-6, and TNF-α. However, NJ-1, NJ-3, NJ-4, and NJ-6 showed differential inhibitory mechanisms against LPS-induced inflammatory responses. NJ-1, NJ-3, and NJ-4 inhibited LPS-induced activation of c-jun NH2-terminal kinase (JNK and p38 but did not affect activation of extracellular signal-regulated kinase (ERK or NF-κB. On the other hand, NJ-6 inhibited activation of MAPKs and NF-κB. In addition, in vivo experiments revealed that administration of NJ-1, NJ-3, NJ-4, and NJ-6 reduced LPS-induced endotoxin shock, with NJ-6 especially showing a marked protective effect. Taken together, these results provide the evidence for the potential of selective NJ fractions against LPS-induced inflammation. Thus, it will be advantageous to further isolate and determine single effective compounds from these potent fractions.

  17. Gut-Brain Interactions in Inflammatory Bowel Disease: A Clinician’s Perspective

    Directory of Open Access Journals (Sweden)

    Theodore M Bayless

    1995-01-01

    Full Text Available While most physicians and some patients consider psychosocial factors important in aggravating already existing inflammatory bowel disease (IBD, most of the information is based on a few recent scientific studies, varied anecdotal observations and a tendency for patients and some physicians to view psychosocial and stress-related issues with speculation, bias and some stigmatization. Patients with proctitis who have experienced recrudescence of mucosal friability and rectal bleeding within a day of a severe life stress provide a dramatic example of such anecdotes. Time-lag studies have indicated that stress, especially major life events, precedes illness aggravation in patients with IBD but that stress is not disease-specific. The symptoms studied, pain and diarrhea, were more likely to be physiological responses to acute stress rather than reflections of increased disease activity. Current scientific research supposes the prospect that environmental factors influence disease susceptibility through the central nervous system. Stress is associated with alterations in both humoral and cellular immune mechanisms in humans and in experimental animals. While psychosocial factors may not initiate inflammation in IBD, it is possible that they lead to alterations in the immune response and thereby alter disease activity. Mind-gut interactions affect salivation, gastric secretion, gastric motility and colonic motility, as well as numerous other gastrointestinal functions. These ‘physiological’ responses are expected in the IBD patient and perhaps will be accentuated by inflammation and its multiple effects on gut function. Because 10 to 13% of the general population have a tendency to suffer from irritable bowel syndrome (IBS, it is expected that the same percentage of IBD patients will have both IBD and IBS. An example of clinically relevant alterations in pathophysiology is the association of acute proctosigmoiditis with an increase in IBS symptoms

  18. Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sun Ae [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of); Choi, Hyoung Chul, E-mail: hcchoi@med.yu.ac.kr [Department of Pharmacology, Aging-Associated Vascular Disease Research Center, College of Medicine, Yeungnam University, Daegu 705-717 (Korea, Republic of)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer PTEN was induced by metformin and inhibited by compound C and AMPK siRNA. Black-Right-Pointing-Pointer Metformin suppressed TNF-{alpha}-induced COX-2 and iNOS mRNA expression. Black-Right-Pointing-Pointer Compound C and bpv (pic) increased iNOS and COX-2 protein expression. Black-Right-Pointing-Pointer NF-{kappa}B activation was restored by inhibiting AMPK and PTEN. Black-Right-Pointing-Pointer AMPK and PTEN regulated TNF-{alpha}-induced ROS production in VSMCs. -- Abstract: Atherosclerosis is a chronic inflammation of the coronary arteries. Vascular smooth muscle cells (VSMCs) stimulated by cytokines and chemokines accelerate the inflammatory response and migrate to the injured endothelium during the progression of atherosclerosis. Activation of AMP activated protein kinase (AMPK), a key sensor maintaining metabolic homeostasis, suppresses the inflammatory response. However, how AMPK regulates the inflammatory response is poorly understood. To identify the mechanism of this response, we focused on phosphatase and tensin homolog (PTEN), which is a negative regulator of inflammation. We investigated that activation of AMPK-induced PTEN expression and suppression of the inflammatory response through the AMPK-PTEN pathway in VSMCs. We treated with the well-known AMPK activator metformin to induce PTEN expression. PTEN was induced by metformin (2 mM) and inhibited by compound C (10 {mu}M) and AMPK siRNA. Tumor necrosis factor-alpha (TNF-{alpha}) was used to induce inflammation. The inflammatory response was confirmed by cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, and activation of nuclear factor (NF)-{kappa}B. Metformin suppressed COX-2 and iNOS mRNA and protein expression dose dependently. Treatment with compound C and bpv (pic) in the presence of metformin, iNOS and COX-2 protein expression increased. NF-{kappa}B activation decreased in response to metformin and was restored by inhibiting AMPK

  19. Sex-Steroid Hormone Manipulation Reduces Brain Response to Reward

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Henningsson, Susanne; Pinborg, Anja

    2016-01-01

    Mood disorders are twice as frequent in women than in men. Risk mechanisms for major depression include adverse responses to acute changes in sex-steroid hormone levels, eg, postpartum in women. Such adverse responses may involve an altered processing of rewards. Here, we examine how women...... regional brain activity related to the magnitude of risk during choice and to monetary reward. The GnRHa intervention caused a net reduction in ovarian sex steroids (estradiol and testosterone) and increased depression symptoms. Compared with placebo, GnRHa reduced amygdala's reactivity to high monetary......'s vulnerability for mood disorders is linked to sex-steroid dynamics by investigating the effects of a pharmacologically induced fluctuation in ovarian sex steroids on the brain response to monetary rewards. In a double-blinded placebo controlled study, healthy women were randomized to receive either placebo...

  20. Activation of Alveolar Macrophages after Plutonium Oxide Inhalation in Rats: Involvement in the Early Inflammatory Response

    Energy Technology Data Exchange (ETDEWEB)

    Van der Meeren, A.; Tourdes, F.; Gremy, O.; Grillon, G.; Abram, M.C.; Poncy, J.L.; Griffiths, N. [CEA, DSV, DRR, SRCA, Centre DAM Ile de France, F-91297 Bruyeres Le Chatel, Arpajon (France)

    2008-07-01

    Alveolar macrophages play an important role in the distribution, clearance and inflammatory reactions after particle inhalation, which may influence long-term events such as fibrosis and tumorigenesis. The objectives of the present study were to investigate the early inflammatory events after plutonium oxide inhalation in rats and involvement of alveolar macrophages. Lung changes were studied from 3 days to 3 months after inhalation of PuO{sub 2} or different isotopic compositions (70% or 97% {sup 239}Pu) and initial lung deposits (range 2.1 to 43.4 kBq/rat). Analyses of bronchoalveolar lavages showed early increases in the numbers of granulocytes, lymphocytes and multi-nucleated macrophages. The activation of macrophages was evaluated ex vivo by measurement of inflammatory mediator levels in culture supernatants. TNF-alpha and chemokine MCP-1, MIP-2 and CINC-1 production was elevated from 7 days after inhalation and remained so up to 3 months. In contrast, IL-1 beta, IL-6 and IL-10 production was unchanged. At 6 weeks, pulmonary macrophage numbers and activation state were increased as observed from an immunohistochemistry study of lung sections with anti-ED1. Similarly, histological analyses of lung sections also showed evidence of inflammatory responses. In conclusion, our results indicate early inflammatory changes in the lungs of PuO{sub 2}-contaminated animals and the involvement of macrophages in this process. A dose-effect relationship was observed between the amount of radionuclide inhaled or retained at the time of analysis and inflammatory mediator production by alveolar macrophages 14 days after exposure. For similar initial lung deposits, the inflammatory manifestation appears higher for 97% {sup 239}Pu than for 70% {sup 239}Pu. (authors)

  1. Leptospira interrogans induces uterine inflammatory responses and abnormal expression of extracellular matrix proteins in dogs.

    Science.gov (United States)

    Wang, Wei; Gao, Xuejiao; Guo, Mengyao; Zhang, Wenlong; Song, Xiaojing; Wang, Tiancheng; Zhang, Zecai; Jiang, Haichao; Cao, Yongguo; Zhang, Naisheng

    2014-10-01

    Leptospira interrogans (L. interrogans), a worldwide zoonosis, infect humans and animals. In dogs, four syndromes caused by leptospirosis have been identified: icteric, hemorrhagic, uremic (Stuttgart disease) and reproductive (abortion and premature or weak pups), and also it caused inflammation. Extracellular matrix (ECM) is a complex mixture of matrix molecules that is crucial to the reproduction. Both inflammatory response and ECM are closed relative to reproductive. The aim of this study was to clarify how L. interrogans affected the uterus of dogs, by focusing on the inflammatory responses, and ECM expression in dogs uterine tissue infected by L. interrogans. In the present study, 27 dogs were divided into 3 groups, intrauterine infusion with L. interrogans, to make uterine infection, sterile EMJH, and normal saline as a control, respectively. The uteruses were removed by surgical operation in 10, 20, and 30 days, respectively. The methods of histopathological analysis, ELISA, Western blot and qPCR were used. The results showed that L. interrogans induced significantly inflammatory responses, which were characterized by inflammatory cellular infiltration and high expression levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in uterine tissue of these dogs. Furthermore, L. interrogans strongly down-regulated the expression of ECM (collagens (CL) IV, fibronectins (FN) and laminins (LN)) in mRNA and protein levels. These data indicated that strongly inflammatory responses, and abnormal regulation of ECM might contribute to the proliferation of dogs infected by L. interrogans.

  2. High-intensity interval training induces a modest systemic inflammatory response in active, young men

    Directory of Open Access Journals (Sweden)

    Zwetsloot KA

    2014-01-01

    Full Text Available Kevin A Zwetsloot,1 Casey S John,1 Marcus M Lawrence,1 Rebecca A Battista,1 R Andrew Shanely1,2 1Department of Health, Leisure, and Exercise Science, Appalachian State University, Boone, NC, USA; 2Human Performance Laboratory, North Carolina Research Campus, Appalachian State University, Kannapolis, NC, USA Abstract: The purpose of this study was to determine: 1 the extent to which an acute session of high-intensity interval training (HIIT increases systemic inflammatory cytokines and chemokines, and 2 whether 2 weeks of HIIT training alters the inflammatory response. Eight recreationally active males (aged 22±2 years performed 2 weeks of HIIT on a cycle ergometer (six HIIT sessions at 8–12 intervals; 60-second intervals, 75-second active rest at a power output equivalent to 100% of their predetermined peak oxygen uptake (VO2max. Serum samples were collected during the first and sixth HIIT sessions at rest and immediately, 15, 30, and 45 minutes post-exercise. An acute session of HIIT induced significant increases in interleukin (IL-6, IL-8, IL-10, tumor necrosis factor-α, and monocyte chemotactic protein-1 compared with rest. The concentrations of interferon-γ, granulocyte macrophage-colony-stimulating factor, and IL-1β were unaltered with an acute session of HIIT. Two weeks of training did not alter the inflammatory response to an acute bout of HIIT exercise. Maximal power achieved during a VO2max test significantly increased 4.6%, despite no improvements in VO2max after 2 weeks of HIIT. These data suggest that HIIT exercise induces a small inflammatory response in young, recreationally active men; however, 2 weeks of HIIT does not alter this response. Keywords: cycle ergometer, inflammatory cytokines, exercise training

  3. Technical Approach Determines Inflammatory Response after Surgical and Transcatheter Aortic Valve Replacement.

    Directory of Open Access Journals (Sweden)

    Gabor Erdoes

    Full Text Available To investigate the periprocedural inflammatory response in patients with isolated aortic valve stenosis undergoing surgical aortic valve replacement (SAVR or transcatheter aortic valve implantation (TAVI with different technical approaches.Patients were prospectively allocated to one of the following treatments: SAVR using conventional extracorporeal circulation (CECC, n = 47 or minimized extracorporeal circulation (MECC, n = 15, or TAVI using either transapical (TA, n = 15 or transfemoral (TF, n = 24 access. Exclusion criteria included infection, pre-procedural immunosuppressive or antibiotic drug therapy and emergency indications. We investigated interleukin (IL-6, IL-8, IL-10, human leukocyte antigen (HLA-DR, white blood cell count, high-sensitivity C-reactive protein (hs-CRP and soluble L-selectin (sCD62L levels before the procedure and at 4, 24, and 48 h after aortic valve replacement. Data are presented for group interaction (p-values for inter-group comparison as determined by the Greenhouse-Geisser correction.SAVR on CECC was associated with the highest levels of IL-8 and hs-CRP (p<0.017, and 0.007, respectively. SAVR on MECC showed the highest descent in levels of HLA-DR and sCD62L (both p<0.001 in the perioperative period. TA-TAVI showed increased intraprocedural concentration and the highest peak of IL-6 (p = 0.017. Significantly smaller changes in the inflammatory markers were observed in TF-TAVI.Surgical and interventional approaches to aortic valve replacement result in inflammatory modulation which differs according to the invasiveness of the procedure. As expected, extracorporeal circulation is associated with the most marked pro-inflammatory activation, whereas TF-TAVI emerges as the approach with the most attenuated inflammatory response. Factors such as the pre-treatment patient condition and the extent of myocardial injury also significantly affect inflammatory biomarker patterns. Accordingly, TA-TAVI is to be classified not

  4. Inflammatory response in Colombian children with severe protein-energymalnutrition before and after nutritional intervention

    Directory of Open Access Journals (Sweden)

    Claudia Velasquez

    2010-06-01

    Full Text Available Aim: To evaluate the changes in C-reactive protein and pro-inflammatory cytokines in severely malnourished children, before nutritional intervention and at the moment of restoring appetite. Methodology: To assess changes in inflammatory mediators, 20 severely malnourished children under 5 years of age, 10 with kwashiorkor and 10 with marasmus were studied. Hemoglobin, total serum proteins, albumin, ferritin, transferrin, ceruloplasmin, C-reactive protein and pro-inflammatory cytokines (IL-8, IL-1β, IL-6,IL-10,TNF-α, and IL-12p70 were determined. Results: Upon hospital admission, the mean values of C-reactive protein in kwashiorkor and marasmus patients (16.3±19.0 mg/l and 23.1±27.9 mg/l, respectively indicated an inflammatory response process with no difference between both groups (p=1.0. Total protein, albumin, transferrin and ceruloplasmin in children with kwashiorkor were significantly lower than in marasmic children (p=0.003, p=0.007, p=0.035, p=0.007, respectively. All cytokines, except IL-12p70, showed significantly higher concentrations in kwashiorkor than in marasmic children. After the stabilization phase, concentrations of C-reactive protein decreased significantly in both groups and albumin increased to normal values, but cytokines remained high. Conclusion: These results show that malnourished children are able to synthesize C-reactive protein in response to an infectious process. Additionally, higher levels of pro-inflammatory cytokines and depletion of albumin in children with kwashiorkor suggest that these inflammatory mediators could be critical biomarkers during clinical phases of kwashiorkor.

  5. GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.

    Directory of Open Access Journals (Sweden)

    Nicoletta Loberto

    Full Text Available Current anti-inflammatory strategies for the treatment of pulmonary disease in cystic fibrosis (CF are limited; thus, there is continued interest in identifying additional molecular targets for therapeutic intervention. Given the emerging role of sphingolipids (SLs in various respiratory disorders, including CF, drugs that selectively target the enzymes associated with SL metabolism are under development. Miglustat, a well-characterized iminosugar-based inhibitor of β-glucosidase 2 (GBA2, has shown promise in CF treatment because it reduces the inflammatory response to infection by P. aeruginosa and restores F508del-CFTR chloride channel activity. This study aimed to probe the molecular basis for the anti-inflammatory activity of miglustat by examining specifically the role of GBA2 following the infection of CF bronchial epithelial cells by P. aeruginosa. We also report the anti-inflammatory activity of another potent inhibitor of GBA2 activity, namely N-(5-adamantane-1-yl-methoxypentyl-deoxynojirimycin (Genz-529648. In CF bronchial cells, inhibition of GBA2 by miglustat or Genz-529648 significantly reduced the induction of IL-8 mRNA levels and protein release following infection by P. aeruginosa. Hence, the present data demonstrate that the anti-inflammatory effects of miglustat and Genz-529648 are likely exerted through inhibition of GBA2.

  6. Pioglitazone does not affect vascular or inflammatory responses after endotoxemia in humans.

    Science.gov (United States)

    Schaller, G; Kolodjaschna, J; Pleiner, J; Mittermayer, F; Kapiotis, S; Schmetterer, L; Wolzt, M

    2008-08-01

    PPARgamma agonists have been proposed to exert more than metabolic benefits, particularly by anti-inflammatory mechanisms. We hypothesized that pioglitazone might modulate inflammatory and vascular responses to lipopolysaccharide (LPS). In a placebo-controlled parallel-group study in 18 healthy male subjects, the E. coli endotoxin model of inflammation (20 IU/kg i. v.) was employed to test the effect of 60 mg pioglitazone over nine days on inflammatory cytokines. Macrovascular function and microvascular blood flow were assessed by brachial artery ultrasound and retinal blood flow parameters, respectively. Pioglitazone increased brachial artery diameter by 5.6% but had no effect on other outcome parameters under resting conditions. LPS increased cytokine levels to peak concentrations of 91.3+/-22.5 ng/ml (IL-6), 261.4+/-60.0 ng/ml (TNFalpha), and 524.5+/-15.3 ng/ml (VCAM-1). The endotoxin caused microvascular vasodilation and increased retinal white blood cell flux, while baseline brachial artery diameter remained unchanged. Pioglitazone had no effect on inflammatory cytokine or adhesion molecule release but mitigated LPS-induced hypotension (p<0.05). Neither brachial artery function nor microvascular blood flow was altered by pioglitazone. In conclusion, acute immune reactions to LPS are not affected by pioglitazone, which exerts subtle vascular effects alone and during endotoxemia. The anti-inflammatory properties of short-term pioglitazone to endotoxins in healthy subjects are therefore limited.

  7. Avian leukosis virus subgroup J triggers caspase-1-mediated inflammatory response in chick livers.

    Science.gov (United States)

    Liu, Xue-lan; Shan, Wen-jie; Jia, Li-juan; Yang, Xu; Zhang, Jin-jing; Wu, Ya-rong; Xu, Fa-zhi; Li, Jin-nian

    2016-04-02

    Many pathogens trigger caspase-1-mediated innate immune responses. Avian leukosis virus subgroup J (ALV-J) causes serious immunosuppression and diverse tumors in chicks. The caspase-1 inflammasome mechanism of response to ALV-J invading remains unclear. Here we investigated the expression of caspase-1, the inflammasome adaptor NLRP3, IL-1β and IL-18 in response to ALV-J infection in the liver of chick. We found caspase-1 mRNA expression was elevated at 5 dpi and peaked at 7 dpi in ALV-J infected animals. Corresponding to this, the expressions of NLRP3 and proinflammatory cytokines IL-1β and IL-18 were significantly increased at 5 or 7 dpi. In addition, caspase-1 protein expression and inflammatory cell infiltration were induced after virus infection. These results indicated that ALV-J infection could trigger the caspase-1- mediated inflammatory response in chicks. Thus, an understanding of the inflammatory responses can provide a better insight into the pathogenicity of ALV-J and a possible anti-virus target for ALV-J infection.

  8. Potential Use of Salivary Markers for Longitudinal Monitoring of Inflammatory Immune Responses to Vaccination

    Directory of Open Access Journals (Sweden)

    Pei Wen Lim

    2016-01-01

    Full Text Available Vaccination, designed to trigger a protective immune response against infection, is a trigger for mild inflammatory responses. Vaccination studies can address the question of inflammation initiation, levels, and resolution as well as its regulation for respective studied pathogens. Such studies largely based on analyzing the blood components including specific antibodies and cytokines were usually constrained by number of participants and volume of collected blood sample. Hence, blood-based studies may not be able to cover the full dynamic range of inflammation responses induced by vaccination. In this review, the potential of using saliva in addition to blood for studying the kinetics of inflammatory response studies was assessed. Saliva sampling is noninvasive and has a great potential to be used for studies aimed at analysing the magnitude, time course, and variance in immune responses, including inflammation after vaccination. Based on a literature survey of inflammatory biomarkers that can be determined in saliva and an analysis of how these biomarkers could help to understand the mechanisms and dynamics of immune reactivity and inflammation, we propose that the saliva-based approach might have potential to add substantial value to clinical studies, particularly in vulnerable populations such as infants, toddlers, and ill individuals.

  9. Fasciola hepatica Kunitz type molecule decreases dendritic cell activation and their ability to induce inflammatory responses.

    Directory of Open Access Journals (Sweden)

    Cristian R Falcón

    Full Text Available The complete repertoire of proteins with immunomodulatory activity in Fasciola hepatica (Fh has not yet been fully described. Here, we demonstrated that Fh total extract (TE reduced LPS-induced DC maturation, and the DC ability to induce allogeneic responses. After TE fractionating, a fraction lower than 10 kDa (F<10 kDa was able to maintain the TE properties to modulate the DC pro- and anti-inflammatory cytokine production induced by LPS. In addition, TE or F<10 kDa treatment decreased the ability of immature DC to stimulate the allogeneic responses and induced a novo allogeneic CD4+CD25+Foxp3+ T cells. In contrast, treatment of DC with T/L or F<10 kDa plus LPS (F<10/L induced a regulatory IL-27 dependent mechanism that diminished the proliferative and Th1 and Th17 allogeneic responses. Finally, we showed that a Kunitz type molecule (Fh-KTM, present in F<10 kDa, was responsible for suppressing pro-inflammatory cytokine production in LPS-activated DC, by printing tolerogenic features on DC that impaired their ability to induce inflammatory responses. These results suggest a modulatory role for this protein, which may be involved in the immune evasion mechanisms of the parasite.

  10. Wild skylarks seasonally modulate energy budgets but maintain energetically costly inflammatory immune responses throughout the annual cycle

    NARCIS (Netherlands)

    Hegemann, A.; Matson, K.D.; Versteegh, M.A.; Tieleman, B.I.

    2012-01-01

    A central hypothesis of ecological immunology is that immune defences are traded off against competing physiological and behavioural processes. During energetically demanding periods, birds are predicted to switch from expensive inflammatory responses to less costly immune responses. Acute phase res

  11. Wild Skylarks Seasonally Modulate Energy Budgets but Maintain Energetically Costly Inflammatory Immune Responses throughout the Annual Cycle

    NARCIS (Netherlands)

    Hegemann, Arne; Matson, Kevin D.; Versteegh, Maaike A.; Tieleman, B. Irene

    2012-01-01

    A central hypothesis of ecological immunology is that immune defences are traded off against competing physiological and behavioural processes. During energetically demanding periods, birds are predicted to switch from expensive inflammatory responses to less costly immune responses. Acute phase res

  12. Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis.

    Science.gov (United States)

    Rimessi, Alessandro; Bezzerri, Valentino; Patergnani, Simone; Marchi, Saverio; Cabrini, Giulio; Pinton, Paolo

    2015-02-04

    The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1β accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosa-dependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca(2+) uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1β and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca(2+) in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca(2+)-dependent control of inflammation.

  13. Relationship between Inflammatory Response and Estimated Complication Rate after Total Hip Arthroplasty

    Institute of Scientific and Technical Information of China (English)

    Xu-Xu Chen; Tao Wang; Jian Li; Hui Kang

    2016-01-01

    Background:After total hip arthroplasty (THA),there is a noteworthy inflammatory response.The inflammatory response is associated with postoperative recovery and complications.However,there had been few reports on the relationship between inflammatory response and postoperative complication rate.The aim of the present study was to investigate early inflammatory response in the first 3 days after THA,and to identify the relationship between inflammatory response and estimated complication rate after surgery.Methods:It was a prospective,nonrandomized cohort study.There were 148 patients who underwent unilateral THA in our hospital enrolled.Blood samples were collected preoperatively in the morning of the surgery and at 24,48,and 72 h after surgery.C-reactive protein (CRP) and interleukin-6 (IL-6) in peripheral blood were measured.The modified physiological and operative severity score for the enumeration of the morbidity (POSSUM) was recorded pre-and intra-operatively.Based on the score,estimated complication rate was calculated.Harris score was used to assess hip function before and after surgery.Results:IL-6 levels reached the peak at 24 h after surgery and CRP at 48 h.After that,both of the levels decreased.The mean Harris scores significantly increased from 41.62 ± 23.47 before surgery to 72.75 ± 9.13 at 3 days after surgery.The Harris scores after surgery did not have a significant relation with either IL-6 or CRP peak levels (P=0.165,P =0.34 l,respectively).Both CRP and IL-6 peak levels significantly and positively correlated with estimated complication rate after surgery.The estimated complication rate calculated using the POSSUM system was 43 cases of 148 patients.Actually,there were only 28 cases that were observed to get postoperative complications during hospitalization.However,there was no significant difference between estimated and observed complication rates (P =0.078).In the group with complications,the CRP and IL-6 peak levels were significantly

  14. Whey protein enhances normal inflammatory responses during cutaneous wound healing in diabetic rats

    Directory of Open Access Journals (Sweden)

    Ebaid Hossam

    2011-12-01

    Full Text Available Abstract Background Prolonged wound healing is a complication of diabetes that contributes to mortality. Impaired wound healing occurs as a consequence of excessive reactive oxygen species (ROS production. Whey protein (WP is able to reduce the oxygen radicals and increase the levels of the antioxidant glutathione. Thus, the aim of this study was to determine whether dietary supplementation with WP could enhance normal inflammatory responses during wound healing in diabetic rats. Animals were assigned into a wounded control group (WN, a wounded diabetic group (WD and a wounded diabetic group orally supplemented with whey protein (WDWP at a dose of 100 mg/kg body weight. Results Whey protein was found to significantly decrease the levels of malondialdehyde (MDA, nitric oxide (NO and ROS. A significant restoration of the glutathione level was observed in WDWP rats. During the early wound healing stage, IL-1β, TNF-α, IL-6, IL-4 and neutrophil infiltration were significantly decreased in WD mice. WP supplementation was found to restore the levels of these inflammatory markers to the levels observed in control animals. In addition, the time required for wound healing was significantly prolonged in diabetic rats. WP was found to significantly decrease the time required for wound healing in WDWP rats. Conclusion In conclusion, dietary supplementation with WP enhances the normal inflammatory responses during wound healing in diabetic mice by restoring the levels of oxidative stress and inflammatory cytokines.

  15. Identification of a common gene expression response in different lung inflammatory diseases in rodents and macaques.

    Directory of Open Access Journals (Sweden)

    Jeroen L A Pennings

    Full Text Available To identify gene expression responses common to multiple pulmonary diseases we collected microarray data for acute lung inflammation models from 12 studies and used these in a meta-analysis. The data used include exposures to air pollutants; bacterial, viral, and parasitic infections; and allergic asthma models. Hierarchical clustering revealed a cluster of 383 up-regulated genes with a common response. This cluster contained five subsets, each characterized by more specific functions such as inflammatory response, interferon-induced genes, immune signaling, or cell proliferation. Of these subsets, the inflammatory response was common to all models, interferon-induced responses were more pronounced in bacterial and viral models, and a cell division response was more prominent in parasitic and allergic models. A common cluster containing 157 moderately down-regulated genes was associated with the effects of tissue damage. Responses to influenza in macaques were weaker than in mice, reflecting differences in the degree of lung inflammation and/or virus replication. The existence of a common cluster shows that in vivo lung inflammation in response to various pathogens or exposures proceeds through shared molecular mechanisms.

  16. Histamine H(3 receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility.

    Directory of Open Access Journals (Sweden)

    Dimitry N Krementsov

    Full Text Available Histamine H(3 receptor (Hrh3/H(3R is primarily expressed by neurons in the central nervous system (CNS where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H(3R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE, the principal autoimmune model of multiple sclerosis (MS, related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H(3R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H(3RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H(3R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H(3R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.

  17. Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial.

    Science.gov (United States)

    Wagner, Gerd; Herbsleb, Marco; de la Cruz, Feliberto; Schumann, Andy; Brünner, Franziska; Schachtzabel, Claudia; Gussew, Alexander; Puta, Christian; Smesny, Stefan; Gabriel, Holger W; Reichenbach, Jürgen R; Bär, Karl-Jürgen

    2015-10-01

    Interventional studies suggest that changes in physical fitness affect brain function and structure. We studied the influence of high intensity physical exercise on hippocampal volume and metabolism in 17 young healthy male adults during a 6-week exercise program compared with matched controls. We further aimed to relate these changes to hypothesized changes in exercised-induced brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). We show profound improvement of physical fitness in most subjects and a positive correlation between the degree of fitness improvement and increased BDNF levels. We unexpectedly observed an average volume decrease of about 2%, which was restricted to right hippocampal subfields CA2/3, subiculum, and dentate gyrus and which correlated with fitness improvement and increased BDNF levels negatively. This result indicates that mainly those subjects who did not benefit from the exercise program show decreased hippocampal volume, reduced BDNF levels, and increased TNF-α concentrations. While spectroscopy results do not indicate any neuronal loss (unchanged N-acetylaspartate levels) decreased glutamate-glutamine levels were observed in the right anterior hippocampus in the exercise group only. Responder characteristics need to be studied in more detail. Our results point to an important role of the inflammatory response after exercise on changes in hippocampal structure.

  18. Immunoregulatory Role of B7-H1 in Chronicity of Inflammatory Responses

    Institute of Scientific and Technical Information of China (English)

    Haidong Dong; Xianming Chen

    2006-01-01

    Pathogenesis of most chronic human diseases, including chronic infections, autoimmune diseases and cancers, often involves a persistent, unresolved inflammatory response. The molecular mechanisms that determine the conversion of an acute inflammatory response into a chronic process had puzzled researchers for many years. Recent studies reveal that B7-H1 (CD274, PD-L1), a newly identified co-stimulatory molecule, possesses dual functions of co-stimulation of naive T cells and inhibition of activated effector T cells. The aberrant cellular expression and deregulated function of B7-H1 have been reported during chronic viral and intracellular bacterial infection, as well as in many autoimmune diseases and cancers. Importantly, the deregulation of B7-H1's dual functions appears to be associated with a prolonged and incomplete immune response by luring naive T cells for activation and dampening activated effector T cells. Moreover, development of strategies targeting B7-H1 signals provides a new and promising approach to manipulate the devastating diseases associated with chronic inflammation. Thus,B7-H1 may play a critical immunoregulatory role in the chronicity of inflammatory responses.

  19. A New Experimental Polytrauma Model in Rats: Molecular Characterization of the Early Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Sebastian Weckbach

    2012-01-01

    Full Text Available Background. The molecular mechanisms of the immune response after polytrauma are highly complex and far from fully understood. In this paper, we characterize a new standardized polytrauma model in rats based on the early molecular inflammatory and apoptotic response. Methods. Male Wistar rats (250 g, 6–10/group were anesthetized and exposed to chest trauma (ChT, closed head injury (CHI, or Tib/Fib fracture including a soft tissue trauma (Fx + STT or to the following combination of injuries: (1 ChT; (2 ChT + Fx + STT; (3 ChT + CHI; (4 CHI; (5 polytrauma (PT = ChT + CHI + Fx + STT. Sham-operated rats served as negative controls. The inflammatory response was quantified at 2 hours and 4 hours after trauma by analysis of “key” inflammatory mediators, including selected cytokines and complement components, in serum and bronchoalveolar (BAL fluid samples. Results. Polytraumatized (PT rats showed a significant systemic and intrapulmonary release of cytokines, chemokines, and complement anaphylatoxins, compared to rats with isolated injuries or selected combinations of injuries. Conclusion. This new rat model appears to closely mimic the early immunological response of polytrauma observed in humans and may provide a valid basis for evaluation of the complex pathophysiology and future therapeutic immune modulatory approaches in experimental polytrauma.

  20. Global analysis of neutrophil responses to Neisseria gonorrhoeae reveals a self-propagating inflammatory program.

    Directory of Open Access Journals (Sweden)

    Anna Sintsova

    2014-09-01

    Full Text Available An overwhelming neutrophil-driven response causes both acute symptoms and the lasting sequelae that result from infection with Neisseria gonorrhoeae. Neutrophils undergo an aggressive opsonin-independent response to N. gonorrhoeae, driven by the innate decoy receptor CEACAM3. CEACAM3 is exclusively expressed by human neutrophils, and drives a potent binding, phagocytic engulfment and oxidative killing of Opa-expressing bacteria. In this study, we sought to explore the contribution of neutrophils to the pathogenic inflammatory process that typifies gonorrhea. Genome-wide microarray and biochemical profiling of gonococcal-infected neutrophils revealed that CEACAM3 engagement triggers a Syk-, PKCδ- and Tak1-dependent signaling cascade that results in the activation of an NF-κB-dependent transcriptional response, with consequent production of pro-inflammatory cytokines. Using an in vivo model of N. gonorrhoeae infection, we show that human CEACAM-expressing neutrophils have heightened migration toward the site of the infection where they may be further activated upon Opa-dependent binding. Together, this study establishes that the role of CEACAM3 is not restricted to the direct opsonin-independent killing by neutrophils, since it also drives the vigorous inflammatory response that typifies gonorrhea. By carrying the potential to mobilize increasing numbers of neutrophils, CEACAM3 thereby represents the tipping point between protective and pathogenic outcomes of N. gonorrhoeae infection.

  1. Functional Role of Milk Fat Globule-Epidermal Growth Factor VIII in Macrophage-Mediated Inflammatory Responses and Inflammatory/Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Young-Su Yi

    2016-01-01

    Full Text Available Inflammation involves a series of complex biological processes mediated by innate immunity for host defense against pathogen infection. Chronic inflammation is considered to be one of the major causes of serious diseases, including a number of autoimmune/inflammatory diseases, cancers, cardiovascular diseases, and neurological diseases. Milk fat globule-epidermal growth factor 8 (MFG-E8 is a secreted protein found in vertebrates and was initially discovered as a critical component of the milk fat globule. Previously, a number of studies have reported that MFG-E8 contributes to various biological functions including the phagocytic removal of damaged and apoptotic cells from tissues, the induction of VEGF-mediated neovascularization, the maintenance of intestinal epithelial homeostasis, and the promotion of mucosal healing. Recently, emerging studies have reported that MFG-E8 plays a role in inflammatory responses and inflammatory/autoimmune diseases. This review describes the characteristics of MFG-E8-mediated signaling pathways, summarizes recent findings supporting the roles of MFG-E8 in inflammatory responses and inflammatory/autoimmune diseases, and discusses MFG-E8 targeting as a potential therapeutic strategy for the development of anti-inflammatory/autoimmune disease drugs.

  2. Functional Role of Milk Fat Globule-Epidermal Growth Factor VIII in Macrophage-Mediated Inflammatory Responses and Inflammatory/Autoimmune Diseases.

    Science.gov (United States)

    Yi, Young-Su

    2016-01-01

    Inflammation involves a series of complex biological processes mediated by innate immunity for host defense against pathogen infection. Chronic inflammation is considered to be one of the major causes of serious diseases, including a number of autoimmune/inflammatory diseases, cancers, cardiovascular diseases, and neurological diseases. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a secreted protein found in vertebrates and was initially discovered as a critical component of the milk fat globule. Previously, a number of studies have reported that MFG-E8 contributes to various biological functions including the phagocytic removal of damaged and apoptotic cells from tissues, the induction of VEGF-mediated neovascularization, the maintenance of intestinal epithelial homeostasis, and the promotion of mucosal healing. Recently, emerging studies have reported that MFG-E8 plays a role in inflammatory responses and inflammatory/autoimmune diseases. This review describes the characteristics of MFG-E8-mediated signaling pathways, summarizes recent findings supporting the roles of MFG-E8 in inflammatory responses and inflammatory/autoimmune diseases, and discusses MFG-E8 targeting as a potential therapeutic strategy for the development of anti-inflammatory/autoimmune disease drugs.

  3. Brain stem auditory evoked responses in chronic alcoholics.

    OpenAIRE

    Chan, Y W; McLeod, J G; Tuck, R R; Feary, P A

    1985-01-01

    Brain stem auditory evoked responses (BAERs) were performed on 25 alcoholic patients with Wernicke-Korsakoff syndrome, 56 alcoholic patients without Wernicke-Korsakoff syndrome, 24 of whom had cerebellar ataxia, and 37 control subjects. Abnormal BAERs were found in 48% of patients with Wernicke-Korsakoff syndrome, in 25% of alcoholic patients without Wernicke-Korsakoff syndrome but with cerebellar ataxia, and in 13% of alcoholic patients without Wernicke-Korsakoff syndrome or ataxia. The mean...

  4. Pro-inflammatory responses of human bronchial epithelial cells to acute nitrogen dioxide exposure.

    Science.gov (United States)

    Ayyagari, Vijayalakshmi N; Januszkiewicz, Adolph; Nath, Jayasree

    2004-04-15

    Nitrogen dioxide (NO2) is an environmental oxidant, known to be associated with lung epithelial injury. In the present study, cellular pro-inflammatory responses following exposure to a brief high concentration of NO2 (45 ppm) were assessed, using normal human bronchial epithelial (NHBE) cells as an in vitro model of inhalation injury. Generation and release of pro-inflammatory mediators such as nitric oxide (NO), IL-8, TNF-alpha, IFN-gamma and IL-1beta were assessed at different time intervals following NO2 exposure. Effects of a pre-existing inflammatory condition was tested by treating the NHBE cells with different inflammatory cytokines such as IFN-gamma, IL-8, TNF-alpha, IL-1beta, either alone or in combination, before exposing them to NO2. Immunofluorescence studies confirmed oxidant-induced formation of 3-nitrotyrosine in the NO2-exposed cells. A marked increase in the levels of nitrite (as an index of NO) and IL-8 were observed in the NO2-exposed cells, which were further enhanced in the presence of the cytokines. Effects of various NO inhibitors combined, with immunofluorescence and Western blotting data, indicated partial contribution of the nitric oxide synthases (NOSs) toward the observed increase in nitrite levels. Furthermore, a significant increase in IL-1beta and TNF-alpha generation was observed in the NO2-exposed cells. Although NO2 exposure alone did induce slight cytotoxicity (<12%), but presence of inflammatory cytokines such as TNF-alpha and IFN-gamma resulted in an increased cell death (28-36%). These results suggest a synergistic role of inflammatory mediators, particularly of NO and IL-8, in NO2-mediated early cellular changes. Our results also demonstrate an increased sensitivity of the cytokine-treated NHBE cells toward NO2, which may have significant functional implications in vivo.

  5. Evaluation of the effects of fructose on oxidative stress and inflammatory parameters in rat brain.

    Science.gov (United States)

    Lopes, Abigail; Vilela, Thais Ceresér; Taschetto, Luciane; Vuolo, Franciele; Petronilho, Fabricia; Dal-Pizzol, Felipe; Streck, Emilio Luiz; Ferreira, Gustavo Costa; Schuck, Patrícia Fernanda

    2014-12-01

    Hereditary fructose intolerance is an autosomal recessive disorder characterized by the accumulation of fructose in tissues and biological fluids of patients. The disease results from a deficiency of aldolase B, responsible for metabolizing fructose in the liver, kidney, and small intestine. We investigated the effect of acute fructose administration on oxidative stress and neuroinflammatory parameters in the cerebral cortex of 30-day-old Wistar rats. Animals received subcutaneous injection of sodium chloride (0.9 %) (control group) or fructose solution (5 μmol/g) (fructose group). One hour later, the animals were euthanized and the cerebral cortex was isolated. Oxidative stress (levels of thiobarbituric acid-reactive substances (TBA-RS), carbonyl content, nitrate and nitrite levels, 2',7'-dihydrodichlorofluorescein (DCFH) oxidation, glutathione (GSH) levels, as well as the activities of catalase (CAT) and superoxide dismutase (SOD)) and neuroinflammatory parameters (TNF-α, IL-1β, and IL-6 levels and myeloperoxidase (MPO) activity) were investigated. Acute fructose administration increased levels of TBA-RS and carbonyl content, indicating lipid peroxidation and protein damage. Furthermore, SOD activity increased, whereas CAT activity was decreased. The levels of GSH, nitrate, and nitrite and DCFH oxidation were not altered by acute fructose administration. Finally, cytokines IL-1β, IL-6, and TNF-α levels, as well as MPO activity, were not altered. Our present data indicate that fructose provokes oxidative stress in the cerebral cortex, which induces oxidation of lipids and proteins and changes of CAT and SOD activities. It seems therefore reasonable to propose that antioxidants may serve as an adjuvant therapy to diets or to other pharmacological agents used for these patients, to avoid oxidative damage to the brain.

  6. Aerobic exercise reduces neuronal responses in food reward brain regions.

    Science.gov (United States)

    Evero, Nero; Hackett, Laura C; Clark, Robert D; Phelan, Suzanne; Hagobian, Todd A

    2012-05-01

    Acute exercise suppresses ad libitum energy intake, but little is known about the effects of exercise on food reward brain regions. After an overnight fast, 30 (17 men, 13 women), healthy, habitually active (age = 22.2 ± 0.7 yr, body mass index = 23.6 ± 0.4 kg/m(2), Vo(2peak) = 44.2 ± 1.5 ml·kg(-1)·min(-1)) individuals completed 60 min of exercise on a cycle ergometer or 60 min of rest (no-exercise) in a counterbalanced, crossover fashion. After each condition, blood oxygen level-dependent responses to high-energy food, low-energy food, and control visual cues, were measured by functional magnetic resonance imaging. Exercise, compared with no-exercise, significantly (P Exercise alone significantly (P exercise alone significantly (P Exercise reduced neuronal responses in brain regions consistent with reduced pleasure of food, reduced incentive motivation to eat, and reduced anticipation and consumption of food. Reduced neuronal response in these food reward brain regions after exercise is in line with the paradigm that acute exercise suppresses subsequent energy intake.

  7. Functional Roles of p38 Mitogen-Activated Protein Kinase in Macrophage-Mediated Inflammatory Responses

    Directory of Open Access Journals (Sweden)

    Yanyan Yang

    2014-01-01

    Full Text Available Inflammation is a natural host defensive process that is largely regulated by macrophages during the innate immune response. Mitogen-activated protein kinases (MAPKs are proline-directed serine and threonine protein kinases that regulate many physiological and pathophysiological cell responses. p38 MAPKs are key MAPKs involved in the production of inflammatory mediators, including tumor necrosis factor-α (TNF-α and cyclooxygenase-2 (COX-2. p38 MAPK signaling plays an essential role in regulating cellular processes, especially inflammation. In this paper, we summarize the characteristics of p38 signaling in macrophage-mediated inflammation. In addition, we discuss the potential of using inhibitors targeting p38 expression in macrophages to treat inflammatory diseases.

  8. 缺氧诱导因子-1α对创伤性脑损伤大鼠炎性反应和血管生成因子表达的影响%Effect of hypoxia-inducible factor-1α on inflammatory response and angiogenic factor expression in rats with traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    靳春杰; 方贵龙; 权伟; 江荣才; 张建宁

    2016-01-01

    brain injury (TBI).Methods The fluid percussion model was applied to induce TBI in rats.A total of 600 rats were divided into sham operation group,TBI group,TBI + HIF-1 α silence group and TBI + control virus group according to the random number table,with 150 rats in each.Virus-mediated HIF-1 α silence gene and control virus were delivered 24 h before the fluid percussion injury.After 3,7 and 14 d,brain injury area and morphological changes in injured region were detected by HE staining,expressions of vascular endothelial cell markers (vWF) and HIF-1 α were detected by Western blot method,and expressions of vascular endothelial growth factor (VEGF),matrix metalloproteinase-9 (MMP-9),tumor necrosis factor-α (TNF-α),interleukin 6 (IL-6) and nuclear factor-κB (NF-κB) in peripheral blood and brain tissue were detected by ELISA method.Rat neural function was dynamically assessed using the modified neurological severity score (mNSS).Results (1) Brain injury area and edema area in TBI + HIF-1 α silence group were higher than those in TBI group at all time points (P < 0.05).(2) Compared with sham operation group and TBI + control virus group,expression of HIF-1α in TBI group gradually increased and remained high at 7 and 14 d postinjury (P < 0.05).Compared with TBI group,expression of vWF in TBI + HIF-1αsilence group decreased at all time points (P < 0.05) and inhibited angiogenesis.(3) TBI + HIF-lα silence group versus TBI group showed remarkably decreased VEGF at all time points,increased expressions of TNF-α,IL-6 and NF-κB at all time point,and increased expression of MMP-9 at 7 and 14 d postinjury (all P <0.05).(4) TBI + HIF-1α silence group versus TBI group showed significant difference in mNSS at 7 and 14 d postinjury (all P < 0.05).Conclusions After TBI,high expression of HIF-1αcan facilitate vascular formation and inhibit inflammatory reaction related factor expression,inducing the mitigation of brain edema and brain injury

  9. Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana [School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC (Canada); Klegeris, Andis [Department of Biology, University of British Columbia Okanagan, Kelowna, BC (Canada); Little, Jonathan P., E-mail: jonathan.little@ubc.ca [School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC (Canada)

    2014-03-28

    Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observed link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.

  10. Effects of propofol and isoflurane on haemodynamics and the inflammatory response in cardiopulmonary bypass surgery.

    Science.gov (United States)

    Sayed, S; Idriss, N K; Sayyedf, H G; Ashry, A A; Rafatt, D M; Mohamed, A O; Blann, A D

    2015-01-01

    Cardiopulmonary bypass (CPB) causes reperfusion injury that when most severe is clinically manifested as a systemic inflammatory response syndrome. The anaesthetic propofol may have anti-inflammatory properties that may reduce such a response. We hypothesised differing effects of propofol and isoflurane on inflammatory markers in patients having CBR Forty patients undergoing elective CPB were randomised to receive either propofol or isoflurane for maintenance of anaesthesia. CRP, IL-6, IL-8, HIF-1α (ELISA), CD11 and CD18 expression (flow cytometry), and haemoxygenase (HO-1) promoter polymorphisms (PCR/electrophoresis) were measured before anaesthetic induction, 4 hours post-CPB, and 24 hours later. There were no differences in the 4 hours changes in CRP, IL-6, IL-8 or CD18 between the two groups, but those in the propofol group had higher HIF-1α (P = 0.016) and lower CD11 expression (P = 0.026). After 24 hours, compared to the isoflurane group, the propofol group had significantly lower levels of CRP (P < 0.001), IL-6 (P < 0.001) and IL-8 (P < 0.001), with higher levels CD11 (P = 0.009) and CD18 (P = 0.002) expression. After 24 hours, patients on propofol had increased expression of shorter HO-1 GT(n) repeats than patients on isoflurane (P = 0.001). Use of propofol in CPB is associated with a less adverse inflammatory profile than is isofluorane, and an increased up-regulation of HO-1. This supports the hypothesis that propofol has anti-inflammatory activity.

  11. Substance P ameliorates collagen II-induced arthritis in mice via suppression of the inflammatory response

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Hyun Sook [College of Medicine, East-West Medical Research Institute, Kyung Hee University, 1, Hoegi-dong, Dongdaemun-gu, Seoul 130-702 (Korea, Republic of); Son, Youngsook, E-mail: ysson@khu.ac.kr [Graduate School of Biotechnology and Department of Genetic Engineering, College of Life Science, Kyung Hee University Global Campus, Seochun-dong, Kiheung-ku, Yong In 441-706 (Korea, Republic of)

    2014-10-10

    Highlights: • SP can increase IL-10 levels and reduce TNF-α and IL-17 levels in RA. • SP causes the increase in T{sub reg}, M2 macrophage, and MSCs in RA. • SP-induced immune suppression leads to the blockade of RA progression. • SP can be used as the therapeutics for autoimmune-related inflammatory diseases. - Abstract: Current rheumatoid arthritis (RA) therapies such as biologics inhibiting pathogenic cytokines substantially delay RA progression. However, patient responses to these agents are not always complete and long lasting. This study explored whether substance P (SP), an 11 amino acids long endogenous neuropeptide with the novel ability to mobilize mesenchymal stem cells (MSC) and modulate injury-mediated inflammation, can inhibit RA progression. SP efficacy was evaluated by paw swelling, clinical arthritis scoring, radiological analysis, histological analysis of cartilage destruction, and blood levels of tumor necrosis factor-alpha (TNF-α) interleukin (IL)-10, and IL-17 in vivo. SP treatment significantly reduced local inflammatory signs, mean arthritis scores, degradation of joint cartilage, and invasion of inflammatory cells into the synovial tissues. Moreover, the SP treatment markedly reduced the size of spleens enlarged by excessive inflammation in CIA, increased IL-10 levels, and decreased TNF-α and IL-17 levels. Mobilization of stem cells and induction of T{sub reg} and M2 type macrophages in the circulation were also increased by the SP treatment. These effect of SP might be associated with the suppression of inflammatory responses in RA and, furthermore, blockade of RA progression. Our results propose SP as a potential therapeutic for autoimmune-related inflammatory diseases.

  12. Ethanol Extract of Sarcodon asparatus Mitigates Inflammatory Responses in Lipopolysaccharide-Challenged Mice and Murine Macrophages.

    Science.gov (United States)

    Chung, Min-Yu; Jung, Sung Keun; Lee, Hye-Jin; Shon, Dong Hwa; Kim, Hyun-Ku

    2015-11-01

    A number of compounds isolated from mushrooms have exhibited disease-modifying effects. We sought to investigate the mechanisms responsible for the anti-inflammatory effects of an extract from the mushroom species Sarcodon asparatus (SAE). Male BALB/c mice (N=42; 6 weeks old) were randomly assigned to four treatment groups. Intraperitoneal administration of SAE significantly attenuated lipopolysaccharide (LPS)-mediated increases in alanine aminotransferase (ALT) activity. LPS also increased serum levels of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, which were dose-dependently and significantly attenuated by SAE. Correlative relationships between serum ALT activity and proinflammatory cytokines suggested that SAE-mediated suppression of liver injury was partly attributable to the attenuation of serum inflammatory responses. SAE significantly decreased hepatic NO(•) production and subsequent 3-nitrotyrosine formation, and the hepatic NO(•) production significantly correlated with serum ALT and cytokine levels, suggesting that SAE mitigates liver injury in association with inflammatory processes, likely by suppressing NO(•) production. Anti-inflammatory activity and further mechanisms of SAE were evaluated using RAW264.7 with LPS challenge. Noncytotoxic levels of SAE significantly attenuated NO(•) production in RAW264.7 cells and also markedly suppressed the expression of iNOS and other proinflammatory mediators, including COX-2 and IL-6, which were upregulated in the presence of LPS. SAE inhibited the phosphorylation of p65, an observation that occurred independently of IKKαβ-mediated IκBα phosphorylation. Collectively, our results demonstrate that SAE suppressed NO(•)-mediated inflammation by inhibiting p65 transcriptional activation without affecting IKKαβ-mediated IκBα phosphorylation. Further studies are warranted to examine the major compounds responsible for these effects and the mechanisms responsible for the p65

  13. Diet-induced obesity reprograms the inflammatory response of the murine lung to inhaled endotoxin

    Energy Technology Data Exchange (ETDEWEB)

    Tilton, Susan C., E-mail: susan.tilton@pnnl.gov [Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Waters, Katrina M.; Karin, Norman J.; Webb-Robertson, Bobbie-Jo M.; Zangar, Richard C. [Pacific Northwest National Laboratory, Richland, WA 99352 (United States); Lee, K. Monica [Battelle Toxicology Northwest, Richland, WA 99352 (United States); Bigelow, Diana J.; Pounds, Joel G.; Corley, Richard A. [Pacific Northwest National Laboratory, Richland, WA 99352 (United States)

    2013-03-01

    The co-occurrence of environmental factors is common in complex human diseases and, as such, understanding the molecular responses involved is essential to determine risk and susceptibility to disease. We have investigated the key biological pathways that define susceptibility for pulmonary infection during obesity in diet-induced obese (DIO) and regular weight (RW) C57BL/6 mice exposed to inhaled lipopolysaccharide (LPS). LPS induced a strong inflammatory response in all mice as indicated by elevated cell counts of macrophages and neutrophils and levels of proinflammatory cytokines (MDC, MIP-1γ, IL-12, RANTES) in the bronchoalveolar lavage fluid. Additionally, DIO mice exhibited 50% greater macrophage cell counts, but decreased levels of the cytokines, IL-6, TARC, TNF-α, and VEGF relative to RW mice. Microarray analysis of lung tissue showed over half of the LPS-induced expression in DIO mice consisted of genes unique for obese mice, suggesting that obesity reprograms how the lung responds to subsequent insult. In particular, we found that obese animals exposed to LPS have gene signatures showing increased inflammatory and oxidative stress response and decreased antioxidant capacity compared with RW. Because signaling pathways for these responses can be common to various sources of environmentally induced lung damage, we further identified biomarkers that are indicative of specific toxicant exposure by comparing gene signatures after LPS exposure to those from a parallel study with cigarette smoke. These data show obesity may increase sensitivity to further insult and that co-occurrence of environmental stressors result in complex biosignatures that are not predicted from analysis of individual exposures. - Highlights: ► Obesity modulates inflammatory markers in BAL fluid after LPS exposure. ► Obese animals have a unique transcriptional signature in lung after LPS exposure. ► Obesity elevates inflammatory stress and reduces antioxidant capacity in the lung

  14. The Role of Hyperglycemia in Mechanisms of Exacerbated Inflammatory Responses within the Oral Cavity

    OpenAIRE

    Amir, Jamie; Waite, Matthew; Tobler, Jeffrey; Catalfamo, Dana L.; Koutouzis, Theofilos; Katz, Joseph; Wallet, Shannon M.

    2011-01-01

    Immune modulating factors are necessary for pathogen clearance, but also contribute to host tissues damage, as those seen in periodontal diseases. Many of these responses can be exacerbated by host conditions including type 2 diabetes [T2D], where toll-like receptor 4 [TLR4] and the receptor for advanced glycated end products [RAGE] play a significant role. Here we investigate causality associated with the increase in inflammatory markers observed in periodontally diseased patients with T2D u...

  15. Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain.

    Science.gov (United States)

    DeKosky, S T; Styren, S D; O'Malley, M E; Goss, J R; Kochanek, P; Marion, D; Evans, C H; Robbins, P D

    1996-01-01

    Traumatic brain injury (TBI) induces astrocytic and microglial activation and proliferation and augmented production of the cytokine interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF). The increase in NGF temporally follows the increase in IL-1 beta, suggesting that the IL-1 beta up-regulation after trauma directly induces the increase in NGF. We examined the effect of IL-1 receptor antagonist protein (IL-1ra) on microglial proliferation and NGF production in rat cortex, following two different models of TBI. Rabbit fibroblasts infected with a retroviral vector containing the human IL-1ra gene were implanted into the wound cavity immediately following a cortical stab wound or 6 hours after a weight drop-induced trauma. Both microglial proliferation and NGF up-regulation were decreased significantly in animals receiving IL-1ra-expressing cells compared with animals receiving naive (untransfected) fibroblasts. These data demonstrate that the increase in NGF after central nervous system trauma is directly mediated through IL-1 beta and that blocking IL-1 beta following brain injury leads to suppression of an NGF-mediated reparative response. Such blockade of inflammation, however, may prove to be of significant therapeutic benefit in human brain injury and other inflammatory states.

  16. Acute-phase inflammatory response in idiopathic sudden deafness: pathogenic implications.

    Science.gov (United States)

    López-González, Miguel A; Abrante, Antonio; López-Lorente, Carmen; Gómez, Antonio; Domínguez, Emilio; Esteban, Francisco

    2012-01-01

    The acute-phase inflammatory response in the peripheral bloodstream can be an expression of transient cerebral ischaemia in idiopathic sudden deafness. For this, a neurological and otorhinolaryngological examination of each patient, performing tests on audiometry, and tympanometry, haemogram, and cranial magnetic resonance were performed. The acute-phase inflammatory response manifests as an increased neutrophil/lymphocyte ratio that is detected 48-72 hours after the appearance of sudden deafness. This study shows that there is an acute-phase response in the peripheral bloodstream with an increased neutrophil/lymphocyte ratio as an expression of an inflammatory process that can be caused by transient cerebral ischaemia in sudden deafness. In addition, the increased neutrophil/lymphocyte ratio can rule out a viral origin of sudden deafness, since a viral infection lowers the neutrophil count and increases the lymphocyte count, thus reducing the neutrophil/lymphocyte ratio. These findings aid in understanding the pathogenic mechanisms involved in sudden deafness and offer better treatment to the patient.

  17. Acute-Phase Inflammatory Response in Idiopathic Sudden Deafness: Pathogenic Implications

    Directory of Open Access Journals (Sweden)

    Miguel A. López-González

    2012-01-01

    Full Text Available The acute-phase inflammatory response in the peripheral bloodstream can be an expression of transient cerebral ischaemia in idiopathic sudden deafness. For this, a neurological and otorhinolaryngological examination of each patient, performing tests on audiometry, and tympanometry, haemogram, and cranial magnetic resonance were performed. The acute-phase inflammatory response manifests as an increased neutrophil/lymphocyte ratio that is detected 48–72 hours after the appearance of sudden deafness. This study shows that there is an acute-phase response in the peripheral bloodstream with an increased neutrophil/lymphocyte ratio as an expression of an inflammatory process that can be caused by transient cerebral ischaemia in sudden deafness. In addition, the increased neutrophil/lymphocyte ratio can rule out a viral origin of sudden deafness, since a viral infection lowers the neutrophil count and increases the lymphocyte count, thus reducing the neutrophil/lymphocyte ratio. These findings aid in understanding the pathogenic mechanisms involved in sudden deafness and offer better treatment to the patient.

  18. TLR4-mediated blunting of inflammatory responses to eccentric exercise in young women.

    Science.gov (United States)

    Fernandez-Gonzalo, Rodrigo; De Paz, José A; Rodriguez-Miguelez, Paula; Cuevas, María J; González-Gallego, Javier

    2014-01-01

    This study assessed the inflammatory response mediated by the toll-like receptor 4 (TLR4) signaling pathway after acute eccentric exercise before and after an eccentric training program in women. Twenty women performed two acute eccentric bouts using a squat machine over a ~9 week interval. The training group (TG) carried out an eccentric training program during 6 weeks, while the control group (CG) did not follow any training. Protein content of markers involved in the TLR4-mediated activation of several nuclear transcription factors, such as nuclear factor κB (NF-κB), and interferon regulatory transcription factor 3 (IRF3), was analyzed. The inflammatory response after the first acute bout was similar between TG and CG, showing an upregulation of all the markers analyzed, with the exception of IRF3. After the second bout, the upregulation of TLR4 signaling pathway was blunted in TG, but not in CG, through both the myeloid differentiation factor 88- and toll/interleukin-1 receptor domain containing adapter inducing interferon-β-dependent pathways. These results highlight the role of the TLR4 in controlling the exercise-induced inflammatory response in young women. More importantly, these data suggest eccentric training may help to prevent TLR4 activation principally through NF-κB, and perhaps IRF3, downstream signaling in this population.

  19. PKC activation induces inflammatory response and cell death in human bronchial epithelial cells.

    Directory of Open Access Journals (Sweden)

    Hyunhee Kim

    Full Text Available A variety of airborne pathogens can induce inflammatory responses in airway epithelial cells, which is a crucial component of host defence. However, excessive inflammatory responses and chronic inflammation also contribute to different diseases of the respiratory system. We hypothesized that the activation of protein kinase C (PKC is one of the essential mechanisms of inflammatory response in airway epithelial cells. In the present study, we stimulated human bronchial lung epithelial (BEAS-2B cells with the phorbol ester Phorbol 12, 13-dibutyrate (PDBu, and examined gene expression profile using microarrays. Microarray analysis suggests that PKC activation induced dramatic changes in gene expression related to multiple cellular functions. The top two interaction networks generated from these changes were centered on NFκB and TNF-α, which are two commonly known pathways for cell death and inflammation. Subsequent tests confirmed the decrease in cell viability and an increase in the production of various cytokines. Interestingly, each of the increased cytokines was differentially regulated at mRNA and/or protein levels by different sub-classes of PKC isozymes. We conclude that pathological cell death and cytokine production in airway epithelial cells in various situations may be mediated through PKC related signaling pathways. These findings suggest that PKCs can be new targets for treatment of lung diseases.

  20. Modulation of untruthful responses with noninvasive brain stimulation

    Directory of Open Access Journals (Sweden)

    Shirley eFecteau

    2013-02-01

    Full Text Available Deceptive abilities have long been studied in relation to personality traits. More recently, studies explored the neural substrates associated with deceptive skills suggesting a critical role of the prefrontal cortex. Here we investigated whether noninvasive brain stimulation over the dorsolateral prefrontal cortex (DLPFC could modulate generation of untruthful responses about subject’s personal life across contexts (i.e., deceiving on guilt-free questions on daily activities; generating previously memorized lies about past experience; and producing spontaneous lies about past experience, as well as across modality responses (verbal and motor responses. Results reveal that real, but not sham, transcranial direct current stimulation (tDCS over the DLPFC can reduce response latency for untruthful over truthful answers across contexts and modality responses. Also, contexts of lies seem to incur a different hemispheric laterality. These findings add up to previous studies demonstrating that it is possible to modulate some processes involved in generation of untruthful answers by applying noninvasive brain stimulation over the DLPFC and extend these findings by showing a differential hemispheric contribution of DLPFCs according to contexts.

  1. Food-induced brain responses and eating behaviour.

    Science.gov (United States)

    Smeets, Paul A M; Charbonnier, Lisette; van Meer, Floor; van der Laan, Laura N; Spetter, Maartje S

    2012-11-01

    The brain governs food intake behaviour by integrating many different internal and external state and trait-related signals. Understanding how the decisions to start and to stop eating are made is crucial to our understanding of (maladaptive patterns of) eating behaviour. Here, we aim to (1) review the current state of the field of 'nutritional neuroscience' with a focus on the interplay between food-induced brain responses and eating behaviour and (2) highlight research needs and techniques that could be used to address these. The brain responses associated with sensory stimulation (sight, olfaction and taste), gastric distension, gut hormone administration and food consumption are the subject of increasing investigation. Nevertheless, only few studies have examined relations between brain responses and eating behaviour. However, the neural circuits underlying eating behaviour are to a large extent generic, including reward, self-control, learning and decision-making circuitry. These limbic and prefrontal circuits interact with the hypothalamus, a key homeostatic area. Target areas for further elucidating the regulation of food intake are: (eating) habit and food preference formation and modification, the neural correlates of self-control, nutrient sensing and dietary learning, and the regulation of body adiposity. Moreover, to foster significant progress, data from multiple studies need to be integrated. This requires standardisation of (neuroimaging) measures, data sharing and the application and development of existing advanced analysis and modelling techniques to nutritional neuroscience data. In the next 20 years, nutritional neuroscience will have to prove its potential for providing insights that can be used to tackle detrimental eating behaviour.

  2. Closed head injury--an inflammatory disease?

    Science.gov (United States)

    Schmidt, Oliver I; Heyde, Christoph E; Ertel, Wolfgang; Stahel, Philip F

    2005-04-01

    Closed head injury (CHI) remains the leading cause of death and persisting neurological impairment in young individuals in industrialized nations. Research efforts in the past years have brought evidence that the intracranial inflammatory response in the injured brain contributes to the neuropathological sequelae which are, in large part, responsible for the adverse outcome after head injury. The presence of hypoxia and hypotension in the early resuscitative period of brain-injured patients further aggravates the inflammatory response in the brain due to ischemia/reperfusion-mediated injuries. The profound endogenous neuroinflammatory response after CHI, which is phylogenetically aimed at defending the intrathecal compartment from invading pathogens and repairing lesioned brain tissue, contributes to the development of cerebral edema, breakdown of the blood-brain barrier, and ultimately to delayed neuronal cell death. However, aside from these deleterious effects, neuroinflammation has been recently shown to mediate neuroreparative mechanisms after brain injury as well. This "dual effect" of neuroinflammation was the focus of extensive experimental and clinical research in the past years and has lead to an expanded basic knowledge on the cellular and molecular mechanisms which regulate the intracranial inflammatory response after CHI. Thus, head injury has recently evolved as an inflammatory and immunological disease much more than a pure traumatological, neurological, or neurosurgical entity. The present review will summarize the so far known mechanisms of posttraumatic neuroinflammation after CHI, based on data from clinical and experimental studies, with a special focus on the role of pro-inflammatory cytokines, chemokines, and the complement system.

  3. Injury Response of Resected Human Brain Tissue In Vitro.

    Science.gov (United States)

    Verwer, Ronald W H; Sluiter, Arja A; Balesar, Rawien A; Baaijen, Johannes C; de Witt Hamer, Philip C; Speijer, Dave; Li, Yichen; Swaab, Dick F

    2015-07-01

    Brain injury affects a significant number of people each year. Organotypic cultures from resected normal neocortical tissue provide unique opportunities to study the cellular and neuropathological consequences of severe injury of adult human brain tissue in vitro. The in vitro injuries caused by resection (interruption of the circulation) and aggravated by the preparation of slices (severed neuronal and glial processes and blood vessels) reflect the reaction of human brain tissue to severe injury. We investigated this process using immunocytochemical markers, reverse transcriptase quantitative polymerase chain reaction and Western blot analysis. Essential features were rapid shrinkage of neurons, loss of neuronal marker expression and proliferation of reactive cells that expressed Nestin and Vimentin. Also, microglia generally responded strongly, whereas the response of glial fibrillary acidic protein-positive astrocytes appeared to be more variable. Importantly, some reactive cells also expressed both microglia and astrocytic markers, thus confounding their origin. Comparison with post-mortem human brain tissue obtained at rapid autopsies suggested that the reactive process is not a consequence of epilepsy.

  4. Protective effect of kaempferol on LPS plus ATP-induced inflammatory response in cardiac fibroblasts.

    Science.gov (United States)

    Tang, Xi-Lan; Liu, Jian-Xun; Dong, Wei; Li, Peng; Li, Lei; Hou, Jin-Cai; Zheng, Yong-Qiu; Lin, Cheng-Ren; Ren, Jun-Guo

    2015-02-01

    Inflammatory response is an important mechanism in the pathogenesis of cardiovascular diseases. Cardiac fibroblasts play a crucial role in cardiac inflammation and might become a potential therapeutic target in cardiovascular diseases. Kaempferol, a flavonoid commonly existing in many edible fruits, vegetables, and Chinese herbs, is well known to possess anti-inflammatory property and thus has a therapeutic potential for the treatment of inflammatory diseases. To date, the effect of kaempferol on cardiac fibroblasts inflammation is unknown. In this study, we investigated the anti-inflammatory effect of kaempferol on lipopolysaccharide (LPS) plus ATP-induced cardiac fibroblasts and explored the underlying mechanisms. Our results showed that kaempferol at concentrations of 12.5 and 25 μg/mL significantly suppressed the release of TNF-α, IL-1β, IL-6, and IL-18 and inhibited activation of NF-κB and Akt in LPS plus ATP-induced cardiac fibroblasts. These findings suggest that kaempferol attenuates cardiac fibroblast inflammation through suppression of activation of NF-κB and Akt.

  5. The monoacylglycerol lipase inhibitor JZL184 decreases inflammatory response in skeletal muscle contusion in rats.

    Science.gov (United States)

    Jiang, Shu-Kun; Zhang, Miao; Tian, Zhi-Ling; Wang, Meng; Zhao, Rui; Wang, Lin-Lin; Li, Shan-Shan; Liu, Min; Li, Jiao-Yong; Zhang, Meng-Zhou; Guan, Da-Wei

    2015-08-15

    Muscle wound healing process is a typical inflammation-evoked event. The monoacylglycerol lipase (MAGL) inhibitor (4-nitrophenyl)4-[bis(1,3-benzodioxol -5-yl)-hydroxymethyl]piperidine-1-carboxylate (JZL184) has been previously reported to reduce inflammation in colitis and acute lung injury in mice, which provide a new strategy for primary care of skeletal muscle injury. We investigated the effect of JZL184 on inflammation in rat muscle contusion model, and found decreased neutrophil and macrophage infiltration and pro-inflammatory cytokine expression. With extension of post-traumatic interval, myofiber regeneration was significantly hindered with increased collagen types I and ІІІ mRNAfibroblast infiltration as well as promoted fibrosis. Furthermore, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-morpholin-4-ylpyrazole-3-carboxamide (AM281, a selective cannabinoid CB1 receptor antagonist) and [6-iodo-2-methyl-1-(2-morpholin-4-ylethyl)indol-3-yl]-(4-methoxyphenyl)methanone (AM630, a selective cannabinoid CB2 receptor antagonist) treatment alleviated the anti-inflammatory effect of JZL184. Our findings demonstrate that JZL184 is able to inhibit the inflammatory response and interfere with contused muscle healing, in which the anti-inflammatory action may be mediated through cannabinoid CB1 and CB2 receptors.

  6. Francisella Infection in Cultured Tilapia in Thailand and the Inflammatory Cytokine Response.

    Science.gov (United States)

    Jantrakajorn, Sasibha; Wongtavatchai, Janenuj

    2016-06-01

    Francisella infections developed in freshwater Nile Tilapia Oreochromis niloticus and red tilapia Oreochromis spp. farms in Thailand during 2012-2014. The diseased fish were lethargic and pale in color and showed numerous white nodules in their enlarged spleens. Histopathological examination and electron microscopy suggested that the white nodules were multifocal granulomas consisting of coccobacilli within vacuolated cells. Isolation of Francisella-like bacteria was achieved from 42 of 100 samples, while polymerase chain reaction confirmed Francisella infections in all samples. Analysis of the 16S rRNA gene from samples obtained from three different geographical culture areas revealed more than 99% similarity with F. noatunensis subsp. orientalis. The influence of Francisella infection on inflammatory cytokines was determined on splenic cells of fish intraperitoneally injected with the bacteria (0.8 × 10(5) colony-forming units per fish). Infected tilapia showed significantly greater expression of the pro-inflammatory genes interleukin-1β (IL-1β) and tumor necrotic factor-α (TNF-α) within 24 h postinjection (hpi) and for up to 96 hpi. However, down-regulation of an anti-inflammatory gene, transforming growth factor-β (TGF-β) was observed as early as 24 hpi. This investigation demonstrates that an imbalance between pro- and anti-inflammatory cytokines in response to the infection may account for the substantial number of granulomas in fish hematopoietic tissues that was found in the later stage of the disease. Received September 9, 2015; accepted December 13, 2015.

  7. Caffeine prevents LPS-induced inflammatory responses in RAW264.7 cells and zebrafish.

    Science.gov (United States)

    Hwang, Ji-Hyun; Kim, Kui-Jin; Ryu, Su-Jung; Lee, Boo-Yong

    2016-03-25

    Caffeine is a white crystalline xanthine alkaloid found in the seeds of coffee plants and leaves of the tea bush. In this study, we evaluated whether caffeine exerts anti-inflammatory effects on lipopolysaccharide (LPS)-induced inflammation both in vitro and in vivo. RAW264.7 cells were treated with various concentrations of caffeine in the presence or absence of LPS. Caffeine decreased the LPS-induced inflammatory mediator, nitric oxide (NO). Caffeine treatment also reduced the expression of pro-inflammatory genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-3, IL-6 and IL-12, and decreased both IL-6 secretion and phosphorylated p38MAPK expression in LPS-treated RAW264.7 cells. Caffeine inhibited nuclear translocation of nuclear factor κB (NF-κB) via IκBα phosphorylation. In addition, caffeine inhibited LPS-induced NO production in zebrafish. These results suggest that caffeine may suppress LPS-induced inflammatory responses in RAW264.7 cells by regulating NF-κB activation and MAPK phosphorylation.

  8. Food Restriction Affects Inflammatory Response and Nutritional State in Tuco-tucos (Ctenomys talarum).

    Science.gov (United States)

    Merlo, Julieta Leticia; Cutrera, Ana Paula; Zenuto, Roxana Rita

    2016-12-01

    Insufficient or unbalanced food intake typically has a negative impact on immune responses. The understanding of this effect is, however, hampered by the effect that food has on general condition, which, in turn, affects immunity, and the interaction among general condition, immunocompetence, and concurrent infections. The goal of this study was to determine the effects of food restriction and methionine supplementation on immunity in tuco-tucos (Ctenomys talarum). Effects of diet manipulations on nutritional state, inflammatory response to phytohemagglutinin (PHA), and other immune parameters (bacterial killing capacity, natural antibodies, and leukocyte profile) were evaluated. Health and stress parameters and endoparasite loads were assessed to understand more deeply potential effects of treatments on immune status. Individuals under food restriction presented an altered nutritional state as well as increased stress levels (higher N: L ratios) compared with individuals fed ad libitum, and a marked reduction in the inflammatory response to PHA. Supplementation with methionine did not affect any of the parameters analyzed. Endoparasite loads were not affected by treatments. Our results support the idea that food insufficiency can modulate the individual's immune responsiveness through the lack of adequate essential nutrients, metabolic fuel and energetic reserves, or by a detrimental effect of the stress caused by nutrient limitation. We show that the response to PHA previously reported as nonenergetically costly for C. talarum, implies a nutritional cost; an opposite pattern to that previously found for the adaptive antibody response to sheep red blood cells in the same species.

  9. Pathogen-mediated inflammatory atherosclerosis is mediated in part via Toll-like receptor 2-induced inflammatory responses.

    Science.gov (United States)

    Hayashi, Chie; Madrigal, Andres G; Liu, Xinyan; Ukai, Takashi; Goswami, Sulip; Gudino, Cynthia V; Gibson, Frank C; Genco, Caroline A

    2010-01-01

    Studies in humans have established that polymorphisms in genes encoding the innate immune Toll-like receptors (TLRs) are associated with inflammatory atherosclerosis. In hyperlipidemic mice, TLR2 and TLR4 have been reported to contribute to atherosclerosis progression. Human and mouse studies support a role for the oral pathogen Porphyromonas gingivalis in atherosclerosis, although the mechanisms by which this pathogen stimulates inflammatory atherosclerosis via innate immune system activation is not known. Using a genetically defined apolipoprotein E-deficient (ApoE(-/-)) mouse model we demonstrate that pathogen-mediated inflammatory atherosclerosis occurs via both TLR2-dependent and TLR2-independent mechanisms. P. gingivalis infection in mice possessing functional TLR2 induced the accumulation of macrophages as well as inflammatory mediators including CD40, IFN-gamma and the pro-inflammatory cytokines IL-1 beta, IL-6 and tumor necrosis factor-alpha in atherosclerotic lesions. The expression of these inflammatory mediators was reduced in atherosclerotic lesions from P. gingivalis-infected TLR2-deficient (TLR2(-/-)) mice. These studies provide a mechanistic link between an innate immune receptor and pathogen-accelerated atherosclerosis by a clinically and biologically relevant bacterial pathogen.

  10. A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses

    Science.gov (United States)

    Tripathi, Shashank; Balasubramaniam, Vinod R. M. T.; Grant, Alesha; Maestre, Ana M.; Sourisseau, Marion; Krammer, Florian; Fernandez-Sesma, Ana; Lim, Jean K.

    2017-01-01

    Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis. PMID:28278235

  11. Systematic review genetic biomarkers associated with anti-TNF treatment response in inflammatory bowel diseases

    DEFF Research Database (Denmark)

    Sørensen, Signe Bek; Nielsen, J V; Bo Bojesen, Anders

    2016-01-01

    : To identify polymorphisms and candidate genes from the literature that are associated with anti-tumour necrosis factor (TNF) treatment response in patients with inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis. METHODS: We performed a PubMed literature search and retrieved...... studies reporting original data on association between polymorphisms and anti-TNF treatment response and conducted a meta-analysis. RESULTS: A functional polymorphism in FCGR3A was significantly associated with anti-TNF treatment response among CD patients using biological response criterion (decrease...... in an explorative analysis. CONCLUSIONS: There are no genetic markers currently available which are adequately predictive of anti-TNF response for use in the clinic. Genetic markers bear the advantage that they do not change over time. Therefore, hypothesis-free approaches, testing a large number of polymorphisms...

  12. The Effects of 12 Weeks Regular Aerobic Exercise on Brain-derived Neurotrophic Factor and Inflammatory Factors in Juvenile Obesity and Type 2 Diabetes Mellitus

    OpenAIRE

    Lee, Sung Soo; Yoo, Jae Ho; Kang, Sung; Woo, Jin Hee; Shin, Ki Ok; Kim, Kwi Beak; Cho, Su Youn; Roh, Hee Tae; Kim, Young Il

    2014-01-01

    [Purpose] The purpose of this study was to investigate the effects of 12 weeks regular aerobic exercise on brain-derived neurotrophic factor (BDNF) and inflammatory factors in juvenile obesity and type 2 diabetes mellitus (T2DM). Obesity and T2DM, typically common among adults, have recently become more prevalent in the Korean juvenile population, affecting not only their lipid profiles and oxidant stress levels, but also their BDNF and inflammatory factor levels. [Subjects] This study enroll...

  13. Oxidative and pro-inflammatory impact of regular and denicotinized cigarettes on blood brain barrier endothelial cells: is smoking reduced or nicotine-free products really safe?

    Science.gov (United States)

    2014-01-01

    Background Both active and passive tobacco smoke (TS) potentially impair the vascular endothelial function in a causative and dose-dependent manner, largely related to the content of reactive oxygen species (ROS), nicotine, and pro-inflammatory activity. Together these factors can compromise the restrictive properties of the blood–brain barrier (BBB) and trigger the pathogenesis/progression of several neurological disorders including silent cerebral infarction, stroke, multiple sclerosis and Alzheimer’s disease. Based on these premises, we analyzed and assessed the toxic impact of smoke extract from a range of tobacco products (with varying levels of nicotine) on brain microvascular endothelial cell line (hCMEC/D3), a well characterized human BBB model. Results Initial profiling of TS showed a significant release of reactive oxygen (ROS) and reactive nitrogen species (RNS) in full flavor, nicotine-free (NF, “reduced-exposure” brand) and ultralow nicotine products. This release correlated with increased oxidative cell damage. In parallel, membrane expression of endothelial tight junction proteins ZO-1 and occludin were significantly down-regulated suggesting the impairment of barrier function. Expression of VE-cadherin and claudin-5 were also increased by the ultralow or nicotine free tobacco smoke extract. TS extract from these cigarettes also induced an inflammatory response in BBB ECs as demonstrated by increased IL-6 and MMP-2 levels and up-regulation of vascular adhesion molecules, such as VCAM-1 and PECAM-1. Conclusions In summary, our results indicate that NF and ultralow nicotine cigarettes are potentially more harmful to the BBB endothelium than regular tobacco products. In addition, this study demonstrates that the TS-induced toxicity at BBB ECs is strongly correlated to the TAR and NO levels in the cigarettes rather than the nicotine content. PMID:24755281

  14. Glial cells, but not neurons, exhibit a controllable response to a localized inflammatory microenvironment in vitro

    Directory of Open Access Journals (Sweden)

    Salah eSommakia

    2014-11-01

    Full Text Available The ability to design long-lasting intracortical implants hinges on understanding the factors leading to the loss of neuronal density and the formation of the glial scar. In this study, we modify a common in vitro mixed cortical culture model using lipopolysaccharide (LPS to examine the responses of microglia, astrocytes, and neurons to microwire segments. We also use dip-coated polyethylene glycol (PEG, which we have previously shown can modulate impedance changes neural microelectrodes, to control the cellular responses. We find that microglia, as expected, exhibit an elevated response to LPS-coated microwire for distances of up to 150 µm, and that this elevated response can be mitigated by co-depositing PEG with LPS. Astrocytes exhibit a more complex, distance-dependent response, whereas neurons do not appear to be affected by the type or magnitude of glial response within this in vitro model. The discrepancy between our in vitro responses and typically observed in vivo responses suggest the importance of using a systems approach to understand the responses of the various brain cell types in a chronic in vivo setting, as well as the necessity of studying the roles of cell types not native to the brain. Our results further indicate that the loss of neuronal density observed in vivo is not a necessary consequence of elevated glial activation.

  15. Brain involvement in patients with inflammatory bowel disease: a voxel-based morphometry and diffusion tensor imaging study

    Energy Technology Data Exchange (ETDEWEB)

    Zikou, Anastasia K.; Astrakas, Loukas G.; Tzarouchi, Loukia C.; Argyropoulou, Maria I. [University of Ioannina, Department of Radiology, Medical School, Ioannina (Greece); Kosmidou, Maria; Tsianos, Epameinondas [University of Ioannina, 1st Department of Internal Medicine (Hepato-Gastroenterology Unit), Medical School, Ioannina (Greece)

    2014-10-15

    To investigate structural brain changes in inflammatory bowel disease (IBD). Brain magnetic resonance imaging (MRI) was performed on 18 IBD patients (aged 45.16 ± 14.71 years) and 20 aged-matched control subjects. The imaging protocol consisted of a sagittal-FLAIR, a T1-weighted high-resolution three-dimensional spoiled gradient-echo sequence, and a multisession spin-echo echo-planar diffusion-weighted sequence. Differences between patients and controls in brain volume and diffusion indices were evaluated using the voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) methods, respectively. The presence of white-matter hyperintensities (WMHIs) was evaluated on FLAIR images. VBM revealed decreased grey matter (GM) volume in patients in the fusiform and the inferior temporal gyrus bilaterally, the right precentral gyrus, the right supplementary motor area, the right middle frontal gyrus and the left superior parietal gyrus (p < 0.05). TBSS showed decreased axial diffusivity (AD) in the right corticospinal tract and the right superior longitudinal fasciculus in patients compared with controls. A larger number of WMHIs was observed in patients (p < 0.05). Patients with IBD show an increase in WMHIs and GM atrophy, probably related to cerebral vasculitis and ischaemia. Decreased AD in major white matter tracts could be a secondary phenomenon, representing Wallerian degeneration. (orig.)

  16. Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum?

    Directory of Open Access Journals (Sweden)

    Raquel M Gonçalves

    Full Text Available BACKGROUND: The mechanisms by which humans regulate pro- and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Although Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma concentrations of seven cytokines and two soluble tumor necrosis factor (TNF-α receptors, and evaluated clinical and laboratory outcomes, in Brazilians with acute uncomplicated infections with P. vivax (n = 85, P. falciparum (n = 30, or both species (n = 12, and in 45 asymptomatic carriers of low-density P. vivax infection. Symptomatic vivax malaria patients, compared to those infected with P. falciparum or both species, had more intense paroxysms, but they had no clear association with a pro-inflammatory imbalance. To the contrary, these patients had higher levels of the regulatory cytokine interleukin (IL-10, which correlated positively with parasite density, and elevated IL-10/TNF-α, IL-10/interferon (IFN-γ, IL-10/IL-6 and sTNFRII/TNF-α ratios, compared to falciparum or mixed-species malaria patient groups. Vivax malaria patients had the highest levels of circulating soluble TNF-α receptor sTNFRII. Levels of regulatory cytokines returned to normal values 28 days after P. vivax clearance following chemotherapy. Finally, asymptomatic carriers of low P. vivax parasitemias had substantially lower levels of both inflammatory and regulatory cytokines than did patients with clinical malaria due to either species. CONCLUSIONS: Controlling fast-multiplying P. falciparum blood stages requires a strong inflammatory response to prevent fulminant infections, while reducing inflammation-related tissue damage with early regulatory cytokine responses may be a more cost-effective strategy in infections with the less virulent P. vivax parasite. The early induction

  17. Biaryl amide compounds reduce the inflammatory response in macrophages by regulating Dectin-1.

    Science.gov (United States)

    Hyung, Kyeong Eun; Lee, Mi Ji; Lee, Yun-Jung; Lee, Do Ik; Min, Hye Young; Park, So-Young; Min, Kyung Hoon; Hwang, Kwang Woo

    2016-03-01

    Macrophages are archetypal innate immune cells that play crucial roles in the recognition and phagocytosis of invading pathogens, which they identify using pattern recognition receptors (PRRs). Dectin-1 is essential for antifungal immune responses, recognizing the fungal cellular component β-glucan, and its role as a PRR has been of increasing interest. Previously, we discovered and characterized a novel biaryl amide compound, MPS 03, capable of inhibiting macrophage phagocytosis of zymosan. Therefore, in this study we aimed to identify other biaryl amide compounds with greater effectiveness than MPS 03, and elucidate their cellular mechanisms. Several MPS 03 derivatives were screened, four of which reduced zymosan phagocytosis in a similar manner to MPS 03. To establish whether such phagocytosis inhibition influenced the production of inflammatory mediators, pro-inflammatory cytokine and nitric oxide (NO) levels were measured. The production of TNF-α, IL-6, IL-12, and NO was significantly reduced in a dose-dependent manner. Moreover, the inflammation-associated MAPK signaling pathway was also affected by biaryl amide compounds. To investigate the underlying cellular mechanism, PRR expression was measured. MPS 03 and its derivatives were found to inhibit zymosan phagocytosis by decreasing Dectin-1 expression. Furthermore, when macrophages were stimulated by zymosan after pretreatment with biaryl amide compounds, downstream transcription factors such as NFAT, AP-1, and NF-κB were downregulated. In conclusion, biaryl amide compounds reduce zymosan-induced inflammatory responses by downregulating Dectin-1 expression. Therefore, such compounds could be used to inhibit Dectin-1 in immunological experiments and possibly regulate excessive inflammatory responses.

  18. The hemic response of white-spotted bamboo sharks (Chiloscyllium plagiosum) with inflammatory disease.

    Science.gov (United States)

    Alexander, Amy B; Parkinson, Lily A; Grant, Krystan R; Carlson, Eric; Campbell, Terry W

    2016-05-01

    As elasmobranch medicine becomes more commonplace, there continues to be confusion with techniques and evaluation of the shark hemogram and it remains unknown if they are able to mount an inflammatory hemic response. The aims of this study were to compare two total white blood cell (WBC) count techniques, establish a reference interval for captive white-spotted bamboo sharks (Chiloscyllium plagiosum), and determine if elasmobranchs are capable of mounting an inflammatory hemic response. Correlation statistics were performed on hematologic results for healthy female bamboo sharks to assess the use of Natt-Herrick's and phloxine methods. Total WBC counts and differentials were obtained from males with severe traumatic clasper wounds and compared to the healthy females. We elected clasper amputation as the preferred treatment intervention and post-operative hematology was performed one month later. There was poor correlation of leukocyte counts between the two WBC count methods. Hematologic values were established for the females and males pre- and post-operatively. Males with wounds had a marked leukocytosis and heterophilia. Post-operative blood work showed a resolution of total WBC count and a trend toward resolution of the heterophilia. This study provides hematologic values for white-spotted bamboo sharks and confirms that the Natt-Herrick's method is preferred for lymphocytic species. Hematologic differences present in males with clasper wounds suggests that elasmobranchs do mount an inflammatory hemic response. Treatment via clasper amputation proved to be a safe and efficient means for clinical treatment that led to a trend toward resolution of the inflammatory leukogram. Zoo Biol. 35:251-259, 2016. © 2016 Wiley Periodicals, Inc.

  19. Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection

    Directory of Open Access Journals (Sweden)

    Feng Yonghui

    2012-08-01

    Full Text Available Abstract Background During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. Methods To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs, macrophages, CD4+ T and regulatory T cells (Treg were assessed by FACS. Results Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Conclusions Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses.

  20. Observation on the change of inflammatory stress and metabolic status of patients with severe traumatic brain injury during the perioperative period of standard large trauma craniotomy

    Institute of Scientific and Technical Information of China (English)

    Lei Luan

    2016-01-01

    Objective:To observe and study the change state of inflammatory stress and metabolic status of patients with severe traumatic brain injury during the perioperative period of standard large trauma craniotomy. Methods:A total of 58 surgical patients with severe traumatic brain injury in our hospital from January 2013 to July 2015 were selected as the study object, and 29 cases of them were divided into control group (conventional craniotomy group) and other 29 cases into observation group (standard large trauma craniotomy group) by the differences of operation methods, then the cerebral metabolism, proteometabolism and inflammatory stress indexes of two groups before the surgery and at first, third and fifth day after the surgery were compared. Results:The cerebral metabolism, proteometabolism and inflammatory stress indexes of two groups before the surgery all had no significant differences, the cerebral metabolism, proteometabolism and inflammatory stress indexes of observation group at first, third and fifth day after the surgery were all better than those of control group, the differences of two groups at differences time after the surgery were all significant. Conclusion:The bad fluctuations of inflammatory stress and metabolic status of patients with severe traumatic brain injury during the perioperative period of standard large trauma craniotomy are smaller than those of conventional craniotomy, so the standard large trauma craniotomy are more suitable for the patients with severe traumatic brain injury.

  1. Anti-inflammatory activities of isorhamnetin-3-O-galactoside against HMGB1-induced inflammatory responses in both HUVECs and CLP-induced septic mice.

    Science.gov (United States)

    Kim, Tae Hoon; Ku, Sae-Kwang; Bae, Jong-Sup

    2013-02-01

    High mobility group box 1 (HMGB1) protein is a crucial nuclear cytokine that elicits severe vascular inflammatory diseases. Oenanthe javanica (water dropwort) extract has anti-arrhythmic, neuroprotective and anti-diabetic activity. However, isorhamnetin-3-O-galactoside (I3G), an active compound from O. javanica, is not researched well for its biological activity. Here, we investigated the anti-inflammatory activities of I3G by monitoring the effects of I3G on the lipopolysaccharide (LPS) or cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1 or CLP-mediated modulation of inflammatory responses. I3G potently inhibited the release of HMGB1 and down-regulated HMGB1-dependent inflammatory responses in human endothelial cells. I3G also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. Further studies revealed that I3G suppressed the production of tumor necrosis factor-α and activation of nuclear factor-κB by HMGB1. In addition, I3G reduced CLP-induced HMGB1 release and sepsis-related mortality. Given these results, I3G should be viewed as a candidate therapeutic agent for the treatment of severe vascular inflammatory diseases such as sepsis or septic shock via inhibition of the HMGB1 signaling pathway.

  2. Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro-inflammatory Cytokine Response.

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    Felix W Santiago

    Full Text Available Mayaro virus (MAYV, an alphavirus similar to chikungunya virus (CHIKV, causes an acute debilitating disease which results in the development of long-term arthralgia in more than 50% of infected individuals. Currently, the immune response and its role in the development of MAYV-induced persistent arthralgia remain unknown. In this study, we evaluated the immune response of individuals with confirmed MAYV infection in a one-year longitudinal study carried out in Loreto, Peru. We report that MAYV infection elicits robust immune responses that result in the development of a strong neutralizing antibody response and the secretion of pro-inflammatory immune mediators. The composition of these inflammatory mediators, in some cases, differed to those previously observed for CHIKV. Key mediators such as IL-13, IL-7 and VEGF were strongly induced following MAYV infection and were significantly increased in subjects that eventually developed persistent arthralgia. Although a strong neutralizing antibody response was observed in all subjects, it was not sufficient to prevent the long-term outcomes of MAYV infection. This study provides initial immunologic insight that may eventually contribute to prognostic tools and therapeutic treatments against this emerging pathogen.

  3. Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro-inflammatory Cytokine Response.

    Science.gov (United States)

    Santiago, Felix W; Halsey, Eric S; Siles, Crystyan; Vilcarromero, Stalin; Guevara, Carolina; Silvas, Jesus A; Ramal, Cesar; Ampuero, Julia S; Aguilar, Patricia V

    2015-01-01

    Mayaro virus (MAYV), an alphavirus similar to chikungunya virus (CHIKV), causes an acute debilitating disease which results in the development of long-term arthralgia in more than 50% of infected individuals. Currently, the immune response and its role in the development of MAYV-induced persistent arthralgia remain unknown. In this study, we evaluated the immune response of individuals with confirmed MAYV infection in a one-year longitudinal study carried out in Loreto, Peru. We report that MAYV infection elicits robust immune responses that result in the development of a strong neutralizing antibody response and the secretion of pro-inflammatory immune mediators. The composition of these inflammatory mediators, in some cases, differed to those previously observed for CHIKV. Key mediators such as IL-13, IL-7 and VEGF were strongly induced following MAYV infection and were significantly increased in subjects that eventually developed persistent arthralgia. Although a strong neutralizing antibody response was observed in all subjects, it was not sufficient to prevent the long-term outcomes of MAYV infection. This study provides initial immunologic insight that may eventually contribute to prognostic tools and therapeutic treatments against this emerging pathogen.

  4. Individual brain-frequency responses to self-selected music.

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    Höller, Yvonne; Thomschewski, Aljoscha; Schmid, Elisabeth Verena; Höller, Peter; Crone, Julia Sophia; Trinka, Eugen

    2012-12-01

    Music is a stimulus which may give rise to a wide range of emotional and cognitive responses. Therefore, brain reactivity to music has become a focus of interest in cognitive neuroscience. It is possible that individual preference moderates the effectof music on the brain. In the present study we examined whether there are common effects of listening to music even if each subject in a sample chooses their own piece of music. We invited 18 subjects to bring along their favorite relaxing music, and their favourite stimulating music. Additionally, a condition with tactile stimulation on the foot and a baseline condition (rest) without stimulation were used. The tactile stimulation was chosen to provide a simple, non-auditory condition which would be identical for all subjects. The electroencephalogram was recorded for each of the 3 conditions and during rest. We found responses in the alpha range mainly on parietal and occipital sites that were significant compared to baseline in 13 subjects during relaxing music, 15 subjects during activating music, and 16 subjects during tactile stimulation. Most subjects showed an alpha desynchronization in a lower alpha range followed by a synchronization in an upper frequency range. However, some subjects showed an increase in this area, whereas others showed a decrease only. In addition, many subjects showed reactivity in the beta range. Beta activity was especially increased while listening to activating music and during tactile stimulation in most subjects. We found interindividual differences in the response patterns even though the stimuli provoked comparable subjective emotions (relaxation, activation), and even if the stimulus was the same for all subjects (somatosensory stimulation). We suggest that brain responsivity to music should be examined individually by considering individual characteristics.

  5. Inflammatory cytokines and plasma redox status responses in hypertensive subjects after heat exposure

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    S.F. Fonseca

    2016-03-01

    Full Text Available Hypertension is characterized by a pro-inflammatory status, including redox imbalance and increased levels of pro-inflammatory cytokines, which may be exacerbated after heat exposure. However, the effects of heat exposure, specifically in individuals with inflammatory chronic diseases such as hypertension, are complex and not well understood. This study compared the effects of heat exposure on plasma cytokine levels and redox status parameters in 8 hypertensive (H and 8 normotensive (N subjects (age: 46.5±1.3 and 45.6±1.4 years old, body mass index: 25.8±0.8 and 25.6±0.6 kg/m2, mean arterial pressure: 98.0±2.8 and 86.0±2.3 mmHg, respectively. They remained at rest in a sitting position for 10 min in a thermoneutral environment (22°C followed by 30 min in a heated environmental chamber (38°C and 60% relative humidity. Blood samples were collected before and after heat exposure. Plasma cytokine levels were measured using sandwich ELISA kits. Plasma redox status was determined by thiobarbituric acid reactive substances (TBARS levels and ferric reducing ability of plasma (FRAP. Hypertensive subjects showed higher plasma levels of IL-10 at baseline (P<0.05, although levels of this cytokine were similar between groups after heat exposure. Moreover, after heat exposure, hypertensive individuals showed higher plasma levels of soluble TNF receptor (sTNFR1 and lower TBARS (P<0.01 and FRAP (P<0.05 levels. Controlled hypertensive subjects, who use angiotensin-converting-enzyme inhibitor (ACE inhibitors, present an anti-inflammatory status and balanced redox status. Nevertheless, exposure to a heat stress condition seems to cause an imbalance in the redox status and an unregulated inflammatory response.

  6. Muscle cells challenged with saturated fatty acids mount an autonomous inflammatory response that activates macrophages

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    Pillon Nicolas J

    2012-10-01

    Full Text Available Abstract Obesity is associated with chronic low-grade inflammation. Within adipose tissue of mice fed a high fat diet, resident and infiltrating macrophages assume a pro-inflammatory phenotype characterized by the production of cytokines which in turn impact on the surrounding tissue. However, inflammation is not restricted to adipose tissue and high fat-feeding is responsible for a significant increase in pro-inflammatory cytokine expression in muscle. Although skeletal muscle is the major disposer of dietary glucose and a major determinant of glycemia, the origin and consequence of muscle inflammation in the development of insulin resistance are poorly understood. We used a cell culture approach to investigate the vectorial crosstalk between muscle cells and macrophages upon exposure to physiological, low levels of saturated and unsaturated fatty acids. Inflammatory pathway activation and cytokine expression were analyzed in L6 muscle cells expressing myc-tagged GLUT4 (L6GLUT4myc exposed to 0.2 mM palmitate or palmitoleate. Conditioned media thereof, free of fatty acids, were then tested for their ability to activate RAW264.7 macrophages. Palmitate -but not palmitoleate- induced IL-6, TNFα and CCL2 expression in muscle cells, through activation of the NF-κB pathway. Palmitate (0.2 mM alone did not induce insulin resistance in muscle cells, yet conditioned media from palmitate-challenged muscle cells selectively activated macrophages towards a pro-inflammatory phenotype. These results demonstrate that low concentrations of palmitate activate autonomous inflammation in muscle cells to release factors that turn macrophages pro-inflammatory. We hypothesize that saturated fat-induced, low-grade muscle cell inflammation may trigger resident skeletal muscle macrophage polarization, possibly contributing to insulin resistance in vivo.

  7. The role of pathogen-associated molecular patterns in inflammatory responses against alginate based microcapsules.

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    Paredes-Juarez, Genaro A; de Haan, Bart J; Faas, Marijke M; de Vos, Paul

    2013-12-28

    Alginate-based microcapsules are used for immunoisolation of cells to release therapeutics on a minute-to-minute basis. Unfortunately, alginate-based microcapsules are suffering from varying degrees of success, which is usually attributed to differences in tissue responses. This results in failure of the therapeutic cells. In the present study we show that commercial, crude alginates may contain pathogen-associated molecular patterns (PAMPs), which are recognized by the sensors of the innate immune system. Known sensors are Toll-like receptors (TLRs), NOD receptors, and C-type lectins. By using cell-lines with a non-functional adaptor molecule essential in Toll-like receptor signaling, i.e. MyD88, we were able to show that alginates signal mainly via MyD88. This was found for low-G, intermediate-G, and high-G alginates applied in calcium-beads, barium-beads as well as in alginate-PLL-alginate capsules. These alginates did stimulate TLRs 2, 5, 8, and 9 but not TLR4 (LPS receptor). Upon implantation in rats these alginates provoked a strong inflammatory response resulting in fibrosis of the capsules. Analysis demonstrated that commercial alginates contain the PAMPs peptidoglycan, lipoteichoic acid, and flagellin. By applying purification procedures, these PAMPs were largely removed. This was associated with deletion of the inflammatory tissue responses as confirmed by an implantation experiment in rats. Our data also show that alginate itself does not provoke TLR mediated responses. We were able to unravel the sensor mechanism by which contaminants in alginates may provoke inflammatory responses.

  8. Signal Transduction Pathways Involved in Brain Death-Induced Renal Injury

    NARCIS (Netherlands)

    Bouma, H. R.; Ploeg, R. J.; Schuurs, T. A.

    2009-01-01

    Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to endoth

  9. Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

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    Stéphane Mandard

    2013-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγ ability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARα and PPARβ/δ against the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig. In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits.

  10. HMGB1 Promotes Systemic Lupus Erythematosus by Enhancing Macrophage Inflammatory Response

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    Mudan Lu

    2015-01-01

    Full Text Available Background/Purpose. HMGB1, which may act as a proinflammatory mediator, has been proposed to contribute to the pathogenesis of multiple chronic inflammatory and autoimmune diseases including systemic lupus erythematosus (SLE; however, the precise mechanism of HMGB1 in the pathogenic process of SLE remains obscure. Method. The expression of HMGB1 was measured by ELISA and western blot. The ELISA was also applied to detect proinflammatory cytokines levels. Furthermore, nephritic pathology was evaluated by H&E staining of renal tissues. Results. In this study, we found that HMGB1 levels were significantly increased and correlated with SLE disease activity in both clinical patients and murine model. Furthermore, gain- and loss-of-function analysis showed that HMGB1 exacerbated the severity of SLE. Of note, the HMGB1 levels were found to be associated with the levels of proinflammatory cytokines such as TNF-α and IL-6 in SLE patients. Further study demonstrated that increased HMGB1 expression deteriorated the severity of SLE via enhancing macrophage inflammatory response. Moreover, we found that receptor of advanced glycation end products played a critical role in HMGB1-mediated macrophage inflammatory response. Conclusion. These findings suggested that HMGB1 might be a risk factor for SLE, and manipulation of HMGB1 signaling might provide a therapeutic strategy for SLE.

  11. [Inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide-stimulated human mast cells].

    Science.gov (United States)

    Zhou, Yun-jiang; Wang, Hu; Li, Li; Sui, He-huan; Huang, Jia-jun

    2015-06-01

    This study is to investigate the inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide(LPS)-stimulated HMC-1 mast cells. The cytotoxicity of kaempferol to HMC-1 mast cells were analyzed by using MTT assay and then the administration concentrations of kaempferol were established. Histamine, IL-6, IL-8, IL-1β and TNF-α were measured using ELISA assay in activated HMC-1 mast cells after incubation with various concentrations of kaempferol (10, 20 and 40 µmol.L-1). Western blot was used to test the protein expression of p-IKKβ, IκBα, p-IκBα and nucleus NF-κB of LPS-induced HMC-1 mast cells after incubation with different concentrations of kaempferol. The optimal concentrations of kaempferol were defined as the range from 5 µmol.L-1 to 40 µmol.L-1. Kaempferol significantly decreased the release of histamine, IL-6, IL-8, IL-1β and TNF-α of activated HMC-1 mast cells (Pkaempferol, the protein expression of p-IKKβ, p-IKBa and nucleus NF-κB (p65) markedly reduced in LPS-stimulated HMC-1 mast cells (Pkaempferol markedly inhibit mast cell-mediated inflammatory response. At the same time, kaempferol can inhibit the activation of IKKβ, block the phosphorylation of IκBα, prevent NF-KB entering into the nucleus, and then decrease the release of inflammatory mediators.

  12. Role of histamine in the inhibitory effects of phycocyanin in experimental models of allergic inflammatory response

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    D. Remirez

    2002-01-01

    Full Text Available It has recently been reported that phycocyanin, a biliprotein found in the blue-green microalgae Spirulina, exerts anti-inflammatory effects in some animal models of inflammation. Taking into account these findings, we decided to elucidate whether phycocyanin might exert also inhibitory effects in the induced allergic inflammatory response and on histamine release from isolated rat mast cells. In in vivo experiments, phycocyanin (100, 200 and 300 mg/kg post-orally (p.o. was administered 1 h before the challenge with 1 μg of ovalbumin (OA in the ear of mice previously sensitized with OA. One hour later, myeloperoxidase activity and ear edema were assessed. Phycocyanin significantly reduced both parameters. In separate experiments, phycocyanin (100 and 200 mg/kg p.o. also reduced the blue spot area induced by intradermal injections of histamine, and the histamine releaser compound 48/80 in rat skin. In concordance with the former results, phyco-cyanin also significantly reduced histamine release induced by compound 48/80 from isolated peritoneal rat mast cells. The inhibitory effects of phycocyanin were dose dependent. Taken together, our results suggest that inhibition of allergic inflammatory response by phycocyanin is mediated, at least in part, by inhibition of histamine release from mast cells.

  13. Shikonin Inhibits Inflammatory Response in Rheumatoid Arthritis Synovial Fibroblasts via lncRNA-NR024118

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    Ke-ya Yang

    2015-01-01

    Full Text Available Background. Shikonin is a major chemical component of zicao that possesses anti-inflammatory properties and the ability to mediate cellular and humoral immunity, especially in rheumatoid arthritis (RA. We investigated the impact of shikonin on inflammatory response in RA synovial fibroblasts using the CAIA model. Methods. Severe polyarticular arthritis was induced in Balb/c female mice. Expressions of lncRNA-NR024118, SOCS3, proinflammatory cytokines, and MMPs were evaluated using RT-RCR. Histone acetylation and SOCS3 protein expression were assessed by ChIP assay and western blot, respectively. Results. Mice treated with shikonin showed an abrogation of soft tissue and bone lesions. Shikonin remarkably enhanced the expression of NR024118 and SOCS3 and suppressed the secretion and expression of IL-6, IL-8, and MMPs. Proliferation of cultured RA synovial fibroblasts in the presence of IL-1β was also significantly inhibited by shikonin. Moreover, shikonin dose-dependently increased acetylation of histone H3 at the promoter of NR024118. Finally, NR024118 overexpression and interference significantly changed SOCS3 expression and NR024118 interference could reverse regulation of shikonin on SOCS3, proinflammatory cytokines, and MMPs expression level in MH7A cells. Conclusion. Our results reveal that, in the CAIA mouse model of RA, shikonin has disease modifying activity that is attributable to the inhibition of inflammatory response via lncRNA-NR024118.

  14. Protective effect of taraxasterol against rheumatoid arthritis by the modulation of inflammatory responses in mice.

    Science.gov (United States)

    Jiang, Shu-Hua; Ping, Li-Feng; Sun, Feng-Yan; Wang, Xiao-Lei; Sun, Zhi-Juan

    2016-12-01

    Taraxasterol is an effective component of dandelion that has anti-inflammatory effects in vivo and in vitro. The present study was performed to explore whether taraxasterol exhibits a protective effect against rheumatoid arthritis through the modulation of inflammatory responses in mice. Eight-week-old CCR9-deficient mice were injected with a collagen II monoclonal antibody cocktail to create a rheumatoid arthritis model. In the experimental group, arthritic model mice were treated with 10 mg/kg taraxasterol once per day for 5 days. Treatment with taraxasterol significantly increased the pain thresholds and reduced the clinical arthritic scores of the mice in the experimental group compared with those of the model group. Furthermore, treatment with taraxasterol significantly suppressed tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and nuclear factor-κB protein expression levels compared with those in the rheumatoid arthritis model mice. Taraxasterol treatment also significantly reduced nitric oxide, prostaglandin E2 and cyclooxygenase-2 levels compared with those in the rheumatoid arthritis model group. These observations indicate that the protective effect of taraxasterol against rheumatoid arthritis is mediated via the modulation of inflammatory responses in mice.

  15. Macrophage pro-inflammatory response to Francisella novicida infection is regulated by SHIP.

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    Kishore V L Parsa

    2006-07-01

    Full Text Available Francisella tularensis, a Gram-negative facultative intracellular pathogen infecting principally macrophages and monocytes, is the etiological agent of tularemia. Macrophage responses to F. tularensis infection include the production of pro-inflammatory cytokines such as interleukin (IL-12, which is critical for immunity against infection. Molecular mechanisms regulating production of these inflammatory mediators are poorly understood. Herein we report that the SH2 domain-containing inositol phosphatase (SHIP is phosphorylated upon infection of primary murine macrophages with the genetically related F. novicida, and negatively regulates F. novicida-induced cytokine production. Analyses of the molecular details revealed that in addition to activating the MAP kinases, F. novicida infection also activated the phosphatidylinositol 3-kinase (PI3K/Akt pathway in these cells. Interestingly, SHIP-deficient macrophages displayed enhanced Akt activation upon F. novicida infection, suggesting elevated PI3K-dependent activation pathways in absence of SHIP. Inhibition of PI3K/Akt resulted in suppression of F. novicida-induced cytokine production through the inhibition of NFkappaB. Consistently, macrophages lacking SHIP displayed enhanced NFkappaB-driven gene transcription, whereas overexpression of SHIP led to decreased NFkappaB activation. Thus, we propose that SHIP negatively regulates F. novicida-induced inflammatory cytokine response by antagonizing the PI3K/Akt pathway and suppressing NFkappaB-mediated gene transcription. A detailed analysis of phosphoinositide signaling may provide valuable clues for better understanding the pathogenesis of tularemia.

  16. Lipid Bodies: Inflammatory Organelles Implicated in Host-Trypanosoma cruzi Interplay during Innate Immune Responses

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    Heloisa D'Avila

    2012-01-01

    Full Text Available The flagellated protozoa Trypanosoma cruzi is the causal agent of Chagas' disease, a significant public health issue and still a major cause of morbidity and mortality in Latin America. Acute Chagas' disease elicits a strong inflammatory response. In order to control the parasite multiplication, cells of the monocytic lineage are highly mobilized. Monocyte differentiation leads to the formation of phagocytosing macrophages, which are strongly activated and direct host defense. A distinguishing feature of Chagas' disease-triggered macrophages is the presence of increased numbers of distinct cytoplasmic organelles termed lipid bodies or lipid droplets. These organelles are actively formed in response to the parasite and are sites for synthesis and storage of inflammatory mediators. This review covers current knowledge on lipid bodies elicited by the acute Chagas' disease within inflammatory macrophages and discusses the role of these organelles in inflammation. The increased knowledge of lipid bodies in pathogenic mechanisms of infections may not only contribute to the understanding of pathogen-host interactions but may also identify new targets for intervention.

  17. Acute-Phase Inflammatory Response to Single-Bout HIIT and Endurance Training: A Comparative Study

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    Felix Kaspar

    2016-01-01

    Full Text Available Objective. This study compared acute and late effect of single-bout endurance training (ET and high-intensity interval training (HIIT on the plasma levels of four inflammatory cytokines and C-reactive protein and insulin-like growth factor 1. Design. Cohort study with repeated-measures design. Methods. Seven healthy untrained volunteers completed a single bout of ET and HIIT on a cycle ergometer. ET and HIIT sessions were held in random order and at least 7 days apart. Blood was drawn before the interventions and 30 min and 2 days after the training sessions. Plasma samples were analyzed with ELISA for the interleukins (IL, IL-1β, IL-6, and IL-10, monocyte chemoattractant protein-1 (MCP-1, insulin growth factor 1 (IGF-1, and C-reactive protein (CRP. Statistical analysis was with Wilcoxon signed-rank tests. Results. ET led to both a significant acute and long-term inflammatory response with a significant decrease at 30 minutes after exercise in the IL-6/IL-10 ratio (−20%; p=0.047 and a decrease of MCP-1 (−17.9%; p=0.03. Conclusion. This study demonstrates that ET affects the inflammatory response more adversely at 30 minutes after exercise compared to HIIT. However, this is compensated by a significant decrease in MCP-1 at two days associated with a reduced risk of atherosclerosis.

  18. Myeloperoxidase-deficient zebrafish show an augmented inflammatory response to challenge with Candida albicans.

    Science.gov (United States)

    Wang, Kun; Fang, Xiao; Ma, Ning; Lin, Qing; Huang, Zhibin; Liu, Wei; Xu, Mengchang; Chen, Xiaohui; Zhang, Wenqing; Zhang, Yiyue

    2015-05-01

    Myeloperoxidase is a key component of neutrophil granules involved in killing engulfed microorganisms. We obtained a zebrafish mutant (smu681) lacking Sudan black staining by large-scale screening, which was a neutrophil-replete but myeloperoxidase-deficient mutant. When infiltrated with Candida albicans, smu681 embryos and sibling embryos showed similar survival after infection. Proliferation of C. albicans was more rapid in smu681 embryos than in sibling embryos, although it was eventually suppressed. In addition, the number of neutrophils accumulating at the site of infection was significantly larger in mutant embryos than in sibling embryos, and mutant embryos showed increased expression of several inflammatory cytokines after C. albicans infection. These findings indicate that myeloperoxidase deficiency alters the inflammatory response to fungal infection.

  19. Atypical Chemokine Receptors and Their Roles in the Resolution of the Inflammatory Response

    Science.gov (United States)

    Bonecchi, Raffaella; Graham, Gerard J.

    2016-01-01

    Chemokines and their receptors are key mediators of the inflammatory process regulating leukocyte extravasation and directional migration into inflamed and infected tissues. The control of chemokine availability within inflamed tissues is necessary to attain a resolving environment and when this fails chronic inflammation ensues. Accordingly, vertebrates have adopted a number of mechanisms for removing chemokines from inflamed sites to help precipitate resolution. Over the past 15 years, it has become apparent that essential players in this process are the members of the atypical chemokine receptor (ACKR) family. Broadly speaking, this family is expressed on stromal cell types and scavenges chemokines to either limit their spatial availability or to remove them from in vivo sites. Here, we provide a brief review of these ACKRs and discuss their involvement in the resolution of inflammatory responses and the therapeutic implications of our current knowledge. PMID:27375622

  20. Study of inflammatory responses to crocidolite and basalt wool in the rat lung.

    Science.gov (United States)

    Adamis, Z; Kerényi, T; Honma, K; Jäckel, M; Tátrai, E; Ungváry, G

    2001-03-09

    The subacute effects of crocidolite and basalt wool dusts were studied by nmeans of biochemical, morphological. and histological methods 1 and .3 mo after intrabronchial instillation. The cell count, protein and phospholipid contents, and lactate dehydrogenase (LDH) activity were determined in the bronchoalveolar lavage (BAL). Both types of fibers induced a prolonged inflammatory reaction in the lung. All the parameters studied in the experimental groups were more markedly elevated after 3 mo. Relative to the control, the protein and LDH values were increased three- to fivefold, the phospholipid content twofold, and the number of free cells in the BAL exceeded the control level up to ninefold. The inflammatory responses to crocidolite and basalt wool in the lung did not differ significantly. In spite of this, basalt wool is recoinmended as an asbestos substitute, as the use of this man-nade fiber may result in a significantly lower release of dust than that from crocidolite.

  1. A new role for T cells in dampening innate inflammatory responses

    Institute of Scientific and Technical Information of China (English)

    TANG Hong; FU YangXin

    2010-01-01

    @@ The inflammatory response is an attempt by a host to protect itself against injurious stimuli and initiate the tissue healing process [1,2].Although the production of both proand anti-inflammatory mediators which occurs mainly within tissues is a systemic process, the pathophysiological events of inflammation are usually compartmentalized, being different from organ to organ, and between organs and the peripheral blood [3,4].Inflammation and consequential tissue injury vary according to the nature of the insults (e.g.burns, hemorrhages, trauma, peritonitis), the cellular composition of each tissue (e.g.the types of phagocytes or endothelial cells), the micro-environment (e.g.the localized presence of GM-CSF in the lungs, low levels of arginine in the liver, presence of endotoxins in the gut), and different modes of leukocyte recruitment.

  2. Possible Implication of Local Immune Response in Darier's Disease: An Immunohistochemical Characterization of Lesional Inflammatory Infiltrate

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    Clelia Miracco

    2010-01-01

    Full Text Available Cell-mediated immunity is considered to be normal in Darier's Disease (DD, an inherited skin disorder complicated by skin infections. To date, there are no investigations on the local inflammatory infiltrate in DD skin lesions. In this immunohistochemical study we characterized and quantified it, making comparisons with two other inflammatory skin disorders, that is, pemphigus vulgaris (PV and lichen ruber planus (LRP, and with the normal skin (NSk. We found a significant (<.05 decrease of CD1a+ Langerhans cells (LCs in DD, compared to PV, LRP, and NSk, and of CD123+ plasmacytoid dendritic cells (pDCs, compared to PV and LRP. We hypothesize that the genetic damage of keratinocytes might result in a loss of some subsets of dendritic cells and, consequently, in an impaired local immune response, which might worsen the infections that inevitably occur in this disease.

  3. Salvianolic acid B inhibits platelets-mediated inflammatory response in vascular endothelial cells.

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    Xu, Shixin; Zhong, Aiqin; Bu, Xiaokun; Ma, Huining; Li, Wei; Xu, Xiaomin; Zhang, Junping

    2015-01-01

    Salvianolic acid B (SAB) is a hydrophilic component isolated from the Chinese herb Salviae miltiorrhizae, which has been used clinically for the treatment of ischemic cardiovascular and cerebrovascular diseases. Platelets-mediated vascular inflammatory response contributes to the initiation and progression of atherosclerosis. In this paper, we focus on the modulating effects of SAB on the inflammatory reaction of endothelial cells triggered by activated platelets. Human umbilical vein endothelial cells (EA.hy926) were pretreated with SAB followed by co-culture with ADP-activated platelets. Adhesion of platelets to endothelial cells was observed by amorphological method. The activation of nuclear factor-kappa B was evaluated by NF-κB p65 nuclear translocation and the protein phosphorylation. A determination of the pro-inflammatory mediators (ICAM-1, IL-1β, IL-6, IL-8, MCP-1) mRNA and protein were also conducted. In addition, the inhibitory effects of SAB on platelets activation were also evaluated using a platelet aggregation assay and assessing the release level of soluble P-selectin. The results showed that SAB dose-dependently inhibited ADP- or α-thrombin-induced human platelets aggregation in platelet rich plasma (PRP) samples, and significantly decreased soluble P-selectin release from both agonists stimulated washed platelets. It was also found that pre-treatment with SAB reduced adhesion of ADP-activated platelets to EA.hy926 cells and inhibited NF-κB activation. In addition, SAB significantly suppressed pro-inflammatory mediators mRNA and protein in EA.hy926 cells in a dose-dependent manner. These results indicated that, in addition to its inhibitory effects on platelets activation, SAB was able to attenuate platelets-mediated inflammatory responses in endothelial cells even if the platelets had already been activated. This anti-inflammatory effect was related to the inhibition of NF-κB activation. Our findings suggest that SAB may be a potential

  4. Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2

    Energy Technology Data Exchange (ETDEWEB)

    Li, Bin [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Abdalrahman, Akram; Lai, Yimu; Janicki, Joseph S. [Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Ward, Keith W.; Meyer, Colin J. [Department of Pharmacology, Reata Pharmaceuticals, Inc., Irving, TX 75063 (United States); Wang, Xing Li [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Tang, Dongqi, E-mail: Dongqi.Tang@uscmed.sc.edu [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Cui, Taixing, E-mail: taixing.cui@uscmed.sc.edu [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States)

    2014-02-21

    Highlights: • Dh404 suppresses the expression of a selected set of pro-inflammatory cytokines in inflamed macrophages via activating Nrf2. • Dh404 activates Nrf2 while keeping Keap1 function intact in macrophages. • Dh404 minimally regulates NF-κB pathway in macrophages. - Abstract: Nuclear factor erythroid 2-related factor (Nrf2) is the major regulator of cellular defenses against various pathological stresses in a variety of organ systems, thus Nrf2 has evolved to be an attractive drug target for the treatment and/or prevention of human disease. Several synthetic oleanolic triterpenoids including dihydro-CDDO-trifluoroethyl amide (dh404) appear to be potent activators of Nrf2 and exhibit chemopreventive promises in multiple disease models. While the pharmacological efficacy of Nrf2 activators may be dependent on the nature of Nrf2 activation in specific cell types of target organs, the precise role of Nrf2 in mediating biological effects of Nrf2 activating compounds in various cell types remains to be further explored. Herein we report a unique and Nrf2-dependent anti-inflammatory profile of dh404 in inflamed macrophages. In lipopolysaccharide (LPS)-inflamed RAW264.7 macrophages, dh404 dramatically suppressed the expression of pro-inflammatory cytokines including inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1β), while minimally regulating the expression of interleulin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNFα). Dh404 potently activated Nrf2 signaling; however, it did not affect LPS-induced NF-κB activity. Dh404 did not interrupt the interaction of Nrf2 with its endogenous inhibitor Kelch-like ECH associating protein 1 (Keap1) in macrophages. Moreover, knockout of Nrf2 blocked the dh404-induced anti-inflammatory responses in LPS-inflamed macrophages. These results demonstrated that dh404 suppresses pro-inflammatory responses in macrophages via an activation

  5. Cytokine profile in PFAPA syndrome suggests continuous inflammation and reduced anti-inflammatory response.

    Science.gov (United States)

    Stojanov, Silvia; Hoffmann, Florian; Kéry, Anja; Renner, Ellen D; Hartl, Dominik; Lohse, Peter; Huss, Kristina; Fraunberger, Peter; Malley, James D; Zellerer, Stephanie; Albert, Michael H; Belohradsky, Bernd H

    2006-06-01

    PFAPA syndrome is characterized by periodic episodes of high fever, aphthous stomatitis, pharyngitis, and/or cervical adenitis. It is of unknown etiology and manifests usually before 5 years of age. We determined serum and intracellular cytokine levels in six PFAPA patients (4 males, 2 females, mean age 8 years (+/- 1.2 SEM), range 4-13) during the symptom-free period as well as 6-12 hours and 18-24 hours after fever onset. Values were compared to age-matched, healthy controls. Febrile PFAPA attacks led to a significant increase in IL-6 and IFN-gamma serum concentrations compared to symptom-free periods and to controls, with IL-1beta, TNF-alpha and IL-12p70 levels being significantly higher than in controls. Lymphocytic IFN-gamma and CD8+ IL-2 production was consistently significantly elevated compared to healthy children. During the asymptomatic period, serum concentrations of IL-1beta, IL-6, TNF-alpha and IL-12p70 were significantly increased compared to controls. Intracellular TNF-alpha synthesis was not elevated at any time point. Soluble TNFRp55 levels were even lower in between febrile episodes, reaching values comparable to controls during attacks, whereas soluble TNFRp75 levels increased during attacks compared to healthy children. Anti-inflammatory IL-4 in serum was at all times lower in PFAPA patients compared to controls with no difference in levels of intracellular IL-4 and IL-10 or serum IL-10. The observed increase of pro-inflammatory mediators, even between febrile attacks, suggests a dysregulation of the immune response in PFAPA syndrome, with continuous pro-inflammatory cytokine activation and a reduced anti-inflammatory response.

  6. Characterization of the early pulmonary inflammatory response associated with PTFE fume exposure

    Science.gov (United States)

    Johnston, C. J.; Finkelstein, J. N.; Gelein, R.; Baggs, R.; Oberdorster, G.; Clarkson, T. W. (Principal Investigator)

    1996-01-01

    Heating of polytetrafluoroethylene (PTFE) has been described to release fumes containing ultrafine particles (approximately 18 nm diam). These fumes can be highly toxic in the respiratory tract inducing extensive pulmonary edema with hemorrhagic inflammation. Fischer-344 rats were exposed to PTFE fumes generated by temperatures ranging from 450 to 460 degrees C for 15 min at an exposure concentration of 5 x 10(5) particles/cm3, equivalent to approximately 50 micrograms/m3. Responses were examined 4 hr post-treatment when these rats demonstrated 60-85% neutrophils (PMNs) in their lung lavage. Increases in abundance for messages encoding the antioxidants manganese superoxide dismutase and metallothionein (MT) increased 15- and 40-fold, respectively. For messages encoding the pro- and anti-inflammatory cytokines: inducible nitric oxide synthase, interleukin 1 alpha, 1 beta, and 6 (IL-1 alpha, IL-1 beta, and IL-6), macrophage inflammatory protein-2, and tumor necrosis factor-alpha (TNF alpha) increases of 5-, 5-, 10-, 40-, 40-, and 15-fold were present. Vascular endothelial growth factor, which may play a role in the integrity of the endothelial barrier, was decreased to 20% of controls. In situ sections were hybridized with 33P cRNA probes encoding IL-6, MT, surfactant protein C, and TNF alpha. Increased mRNA abundance for MT and IL-6 was expressed around all airways and interstitial regions with MT and IL-6 demonstrating similar spatial distribution. Large numbers of activated PMNs expressed IL-6, MT, and TNF alpha. Additionally, pulmonary macrophages and epithelial cells were actively involved. These observations support the notion that PTFE fumes containing ultrafine particles initiate a severe inflammatory response at low inhaled particle mass concentrations, which is suggestive of an oxidative injury. Furthermore, PMNs may actively regulate the inflammatory process through cytokine and antioxidant expression.

  7. Xanthohumol suppresses inflammatory response to warm ischemia-reperfusion induced liver injury.

    Science.gov (United States)

    Dorn, Christoph; Massinger, Sabine; Wuzik, Andreas; Heilmann, Jörg; Hellerbrand, Claus

    2013-02-01

    Liver ischemia/reperfusion (I/R) leads to formation of reactive oxygen species (ROS), which cause hepatic injury and initiate an inflammatory response, which is a critical problem after liver surgery and transplantation. Xanthohumol, the major prenylated chalcone found in hops, has been discussed for its anti-inflammatory and ROS-scavenging properties, and thus, we aimed to investigate the effect of xanthohumol in a model of warm I/R liver injury. Xanthohumol was applied to BALB/c mice orally at a dose of 1 mg/g body weight for 5 days before I/R-injury was induced by clamping the vascular blood supply to the median and left lateral liver lobe for 1 h followed by a 6 h period of reperfusion. At this time, HPLC analysis revealed hepatic xanthohumol levels of approximately 2 μM, a concentration which has been shown to inhibit inflammatory effects in vitro. Assessment of hepatic HMOX1 expression, hepatic glutathione content and immunohistochemical analysis for proteins conjugated with the reactive aldehyde 4-hydroxynonenal indicated that I/R-induced oxidative stress was significantly inhibited in xanthohumol-fed compared to control mice. Histological analysis, TUNEL staining and determination of transaminase serum levels revealed no significant effects of xanthohumol on acute hepatocellular injury. However, at the same time point, pretreatment with xanthohumol almost completely blunted the I/R-induced AKT and NFκB activation and the expression of the proinflammatory genes IL-1alpha, IL-6, MCP-1 and ICAM-1, which are known to play a crucial role in the subacute phase of I/R-induced liver damage. In conclusion, these data indicate the potential of xanthohumol application to prevent adverse inflammatory responses to I/R-induced liver damage such as after surgical liver resection or transplantation.

  8. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Itoi, Saori; Terao, Mika, E-mail: mterao@derma.med.osaka-u.ac.jp; Murota, Hiroyuki; Katayama, Ichiro

    2013-10-18

    Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10{sup −13} M cortisol, whereas 1 × 10{sup −5} M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol

  9. NG2, a member of chondroitin sulfate proteoglycans family mediates the inflammatory response of activated microglia.

    Science.gov (United States)

    Gao, Q; Lu, J; Huo, Y; Baby, N; Ling, E A; Dheen, S T

    2010-01-20

    Activation of microglial cells, the resident immune cells of the CNS causes neurotoxicity through the release of a wide array of inflammatory mediators including proinflammatory cytokines, chemokines and reactive oxygen species. In this study, we have investigated the expression of NG2 (also known as CSPG4), one of the members of transmembrane chondroitin sulfate proteoglycans family, in microglial cells and its role on inflammatory reaction of microglia by analyzing the expression of the proinflammation cytokines (interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha)), chemokines (stromal cell-derived factor-1alpha and monocyte chemotactic protein-1) and inducible nitric oxide synthase (iNOS). NG2 expression was not detectable in microglial cells expressing OX-42 in the brains of 1-day old postnatal rat pups and adult rats; it was, however, induced in activated microglial cells in pups and adult rats injected with lipopolysaccharide (LPS). In vitro analysis further confirmed that LPS induced the expression of NG2 in primary microglial cells and this was inhibited by dexamethasone. It has been well demonstrated that LPS induces the expression of iNOS and proinflammatory cytokines in microglia. However in this study, LPS did not induce the mRNA expression of iNOS and cytokines including IL-1beta, and TNF-alpha in microglial cells transfected with CSPG4 siRNA. On the contrary, mRNA expression of chemokines such as monocyte chemoattractant protein-1 (MCP-1) and stromal cell-derived factor-1alpha (SDF-1alpha) was significantly increased in LPS-activated microglial cells after CSPG4 siRNA transfection in comparison with the control. The above results indicate that NG2 mediates the induction of iNOS and inflammatory cytokine expression, but not the chemokine expression in activated microglia.

  10. Uncoupling between inflammatory and fibrotic responses to silica: evidence from MyD88 knockout mice.

    Directory of Open Access Journals (Sweden)

    Sandra Lo Re

    Full Text Available The exact implication of innate immunity in granuloma formation and irreversible lung fibrosis remains to be determined. In this study, we examined the lung inflammatory and fibrotic responses to silica in MyD88-knockout (KO mice. In comparison to wild-type (WT mice, we found that MyD88-KO animals developed attenuated lung inflammation, neutrophil accumulation and IL-1β release in response to silica. Granuloma formation was also less pronounced in MyD88-KO mice after silica. This limited inflammatory response was not accompanied by a concomitant attenuation of lung collagen accumulation after silica. Histological analyses revealed that while pulmonary fibrosis was localized in granulomas in WT animals, it was diffusely distributed throughout the parenchyma in MyD88-KO mice. Robust collagen accumulation was also observed in mice KO for several other components of innate immunity (IL-1R, IL-1, ASC, NALP3, IL-18R, IL-33R, TRIF, and TLR2-3-4,. We additionally show that pulmonary fibrosis in MyD88-KO mice was associated with the accumulation of pro-fibrotic regulatory T lymphocytes (T regs and pro-fibrotic cytokine expression (TGF-β, IL-10 and PDGF-B, not with T helper (Th 17 cell influx. Our findings indicate that the activation of MyD88-related innate immunity is central in the establishment of particle-induced lung inflammatory and granuloma responses. The development of lung fibrosis appears uncoupled from inflammation and may be orchestrated by a T reg-associated pathway.

  11. Instillation of coarse ash particulate matter and lipopolysaccharide produces a systemic inflammatory response in mice

    Energy Technology Data Exchange (ETDEWEB)

    Finnerty, K.; Choi, J.E.; Lau, A.; Davis-Gorman, G.; Diven, C.; Seaver, N.; Linak, W.P.; Witten, M.; McDonagh, P.F. [Arizona Health Science Center, Tucson, AZ (United States)

    2007-07-01

    Coronary ischemic events increase significantly following a 'bad air' day. Ambient particulate matter (PM10) is the pollutant most strongly associated with these events. PM10 produces inflammatory injury to the lower airways. It is not clear, however, whether pulmonary inflammation translates to a systemic response. Lipopolysaccharide (LPS) is a proinflammatory molecule often associated with the coarse fraction of PM. It was hypothesized that PM > 2.5 from coal plus LPS induce pulmonary inflammation leading to a systemic inflammatory response. Mice were intratracheally instilled with saline, PM (200 {mu} g), PM+ LPS10 (PM+ 10 {mu} g LPS), or PM+ LPS100 (PM+ 100 {mu} g LPS). Eighteen hours later, histologic analysis was performed on lungs from each group. Pulmonary and systemic inflammation were assessed by measuring the proinflammatory cytokines tumor necrosis factor (TNF)-{alpha} and interleukin (IL)-6 in the pulmonary supernatant and plasma. In a follow-up study, the effects of LPS alone were assessed. Histologic analysis revealed a dose-dependent elevation in pulmonary inflammation with all treatments. Pulmonary TNF-{alpha} and IL-6 both increased significantly with PM+ LPS100 treatment. Regarding plasma, TNF-{alpha} significantly increased in both PM+ LPS10 and PM+ LPS100 treatments. For plasma IL-6, all groups tended to rise with a significant increase in the PM+ LPS100 group. The results of the follow-up study indicate that the responses to PM+ LPS were not due to LPS alone. These results suggest that coarse coal fly ash PM > 2.5 combined with LPS produced pulmonary and systemic inflammatory responses. The resulting low-level systemic inflammation may contribute to the increased severity of ischemic heart disease observed immediately following a bad air day.

  12. Training reduces catabolic and inflammatory response to a single practice in female volleyball players.

    Science.gov (United States)

    Eliakim, Alon; Portal, Shawn; Zadik, Zvi; Meckel, Yoav; Nemet, Dan

    2013-11-01

    We examined the effect of training on hormonal and inflammatory response to a single volleyball practice in elite adolescent players. Thirteen female, national team level, Israeli volleyball players (age 16.0 ± 1.4 years, Tanner stage 4-5) participated in the study. Blood samples were collected before and immediately after a typical 60 minutes of volleyball practice, before and after 7 weeks of training during the initial phase of the season. Training involved tactic and technical drills (20% of time), power and speed drills (25% of time), interval sessions (25% of time), endurance-type training (15% of time), and resistance training (15% of time). To achieve greater training responses, the study was performed during the early phase (first 7 weeks) of the volleyball season. Hormonal measurements included the anabolic hormones growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3, the catabolic hormone cortisol, the proinflammatory marker interleukin-6 (IL-6), and the anti-inflammatory marker IL-1 receptor antagonist. Training led to a significant improvement of vertical jump, anaerobic properties (peak and mean power by the Wingate Anaerobic Test), and predicted VO2max (by the 20-m shuttle run). Volleyball practice, both before and after the training intervention, was associated with a significant increase of serum lactate, GH, and IL-6. Training resulted in a significantly reduced cortisol response ([INCREMENT]cortisol: 4.2 ± 13.7 vs. -4.4 ± 12.3 ng · ml, before and after training, respectively; p volleyball practice. The results suggest that along with the improvement of power and anaerobic and aerobic characteristics, training reduces the catabolic and inflammatory response to exercise.

  13. The role of interpersonal processes in shaping inflammatory responses to social-evaluative threat.

    Science.gov (United States)

    John-Henderson, Neha A; Stellar, Jennifer E; Mendoza-Denton, Rodolfo; Francis, Darlene D

    2015-09-01

    In response to social-evaluative threat induced in the laboratory, lower (compared to higher) subjective social class of a participant predicts greater increases in the inflammatory cytokine interleukin-6 (IL-6). In spite of the interpersonal nature of social-evaluation, little work has explored whether characteristics of the evaluator shape physiological responses in this context. In the current study, in a sample of 190 college students (male=66), we explored whether one's subjective social class interacts with the perceived social class of an evaluator to predict changes in Oral Mucosal Transudate (OMT) IL-6 in response to the Trier Social Stress Test (TSST). Participants were randomly assigned to be the speaker or the evaluator. Extending past work, we found that while speakers low in subjective social class consistently respond with strong increases in IL-6 regardless of their perception of their evaluator's social class, speakers high in subjective social class responded with greater increases in IL-6 when their evaluator was perceived as high social class compared to when they were perceived as low social class. This finding highlights the importance of perceptions of the evaluator in informing inflammatory responses to a social-evaluative task.

  14. Neural mechanisms linking social status and inflammatory responses to social stress.

    Science.gov (United States)

    Muscatell, Keely A; Dedovic, Katarina; Slavich, George M; Jarcho, Michael R; Breen, Elizabeth C; Bower, Julienne E; Irwin, Michael R; Eisenberger, Naomi I

    2016-06-01

    Social stratification has important implications for health and well-being, with individuals lower in standing in a hierarchy experiencing worse outcomes than those higher up the social ladder. Separate lines of past research suggest that alterations in inflammatory processes and neural responses to threat may link lower social status with poorer outcomes. This study was designed to bridge these literatures to investigate the neurocognitive mechanisms linking subjective social status and inflammation. Thirty-one participants reported their subjective social status, and underwent a functional magnetic resonance imaging scan while they were socially evaluated. Participants also provided blood samples before and after the stressor, which were analysed for changes in inflammation. Results showed that lower subjective social status was associated with greater increases in inflammation. Neuroimaging data revealed lower subjective social status was associated with greater neural activity in the dorsomedial prefrontal cortex (DMPFC) in response to negative feedback. Finally, results indicated that activation in the DMPFC in response to negative feedback mediated the relation between social status and increases in inflammatory activity. This study provides the first evidence of a neurocognitive pathway linking subjective social status and inflammation, thus furthering our understanding of how social hierarchies shape neural and physiological responses to social interactions.

  15. Effect of volume expansion with 6% hydroxyethyl starch on perioperative hemodynamics and inflammatory factors in patients with traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    Guo-Wen Zhao; Xing-Chang Zhao; Yong-Guo Cui; De-Chao Lu; Jian-Feng Wang

    2016-01-01

    Objective:To study the effect of volume expansion with 6% hydroxyethyl starch on perioperative hemodynamics and inflammatory factors in patients with traumatic brain injury. Methods:A total of 82 cases of traumatic brain injury from January 2011 to June 2016 in our hospital were randomly divided into the observation group with injection of 6% hydroxyethyl starch and the control group with injection of compound sodium lactate, 41 cases in each group. Hemodynamics, TNF-α and IL-6 were detected in before induction of anesthesia (T0), before skull plate (T1), after skull plate 5 min (T2), 15 min (T3), 30 min (T4).Results:There were no significant differences in CVP, MAP and HR between the two groups at T0 time (P>0.05); HR of the two groups of patients were significantly increased (P0.05); The MAP of the two groups began to decrease significantly at T1, but the observation group was significantly lower than the control group (P0.05). There was no significant difference in the levels of IL-6 and TNF-α between the two groups before surgery (P>0.05); After operation, the control group of TNF- and IL-6 were significantly higher, and higher than the same period of observation group, the difference was statistically significant (P<0.05).Conclusions:Using 6% hydroxyethyl starch preloading craniocerebral trauma patients is helpful to maintain the perioperative hemodynamic stability, reduce the level of inflammatory factors, which is worthy of reference.

  16. Clinical aspects of acute inflammatory diseases of the brain; Klinisch-neurologische Aspekte akut-entzuendlicher Hirnerkrankungen

    Energy Technology Data Exchange (ETDEWEB)

    Block, F.; Nolden-Koch, M. [RWTH Aachen (Germany). Neurologische Klinik

    2000-11-01

    Despite the progress, which has been made in diagnosis and therapy of encephalitis and bacterial meningitis, these acute inflammatory diseases of the brain still display a certain amount of morbidity and mortality. History, physical examination, analysis of serum and cerebrospinal fluid and radiological examination are the mainstay for the diagnosis of these diseases. With respect to the acute inflammatory diseases of the brain computed tomography and magnetic resonance imaging fulfil three purposes: 1. They can be used to clarify the diagnosis and to rule out other diseases. 2. They can identify the focus from which a bacterial meningitis can evolve. 3. Complications like edema, cerebral vasculitis, septic sinus thrombosis, hydrocephalus or abscess can be visualized. If the diagnosis is made early, the possible complications are recognized in good time and the appropriate therapy is started immediately, then morbidity and mortality can be kept at a minimum. (orig.) [German] Die bakterielle Meningitis und die Enzephalitis sind akut-entzuendliche Hirnerkrankungen, die trotz aller Fortschritte in der Diagnostik und Therapie mit einer nicht unerheblichen Morbiditaet und Mortalitaet behaftet sind. Die Anamnese, die koerperliche Untersuchung, die laborchemische Diagnostik von Blut und Liquor und die Bildgebung sind die wesentlichen Saeulen in der Diagnostik akut-entzuendlicher Hirnerkrankungen. Die Bildgebung, die mittels Computertomographie bzw. Kernspintomographie erfolgt, hat in diesem Zusammenhang 3 Aufgaben: 1. Sie kann dazu beitragen, die Diagnose zu sichern bzw. differentialdiagnostisch in Erwaegung zu ziehende Erkrankungen auszuschliessen oder nachzuweisen. 2. Sie kann bei der bakteriellen Meningitis entzuendliche Foci im Bereich der Nasennebenhoehlen, des Mastoids oder des Mittelohrs erkennen, die sofort operativ saniert werden muessen. 3. Komplikationen akut-entzuendlicher Hirnerkrankungen koennen bei entsprechendem klinischem Verdacht mittels Bildgebung

  17. Role of cholinergic anti-inflammatory pathway in regulating host response and its interventional strategy for inflammatory diseases

    Institute of Scientific and Technical Information of China (English)

    WANG Da-wei; ZHOU Rong-bin; YAO Yong-ming

    2009-01-01

    @@ The cholinergic anti-inflammatory pathway (CAP) is a neurophysiological mechanism that regulates the immune system. The CAP inhibits inflammation by suppressing cytokine synthesis via release of acetylcholine in organs of the reticuloendothelial system, including the lungs, spleen, liver, kidneys and gastrointestinal tract.

  18. Anti-inflammatory effects of tanshinone IIA on radiation-induced microglia BV-2 cells inflammatory response

    DEFF Research Database (Denmark)

    Dong, Xiaorong; Dong, Jihua; Zhang, Ruiguang;

    2009-01-01

    that Tanshinone II(A) exerts anti-inflammatory properties by suppressing the transcription of proinflammatory cytokine genes that might be associated with the NF-kappabeta signaling pathway. It is postulated that irradiation causes immediate cellular reaction, and that double-strand breaks trigger the molecular...

  19. Enhanced regional brain metabolic responses to benzodiazepines in cocaine abusers

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Wang, G.J.; Fowler, J.S. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1997-05-01

    While dopamine (DA) appears to be crucial for cocaine reinforcement, its involvement in cocaine addiction is much less clear. Using PET we have shown persistent reductions in striatal DA D2 receptors (which arc predominantly located on GABA cells) in cocaine abusers. This finding coupled to GABA`s role as an effector for DA led us to investigate if there were GABAergic abnormalities in cocaine abusers. In this study we measured regional brain metabolic responses to lorazepam, to indirectly assess GABA function (benzodiazepines facilitate GABAergic neurotransmission). Methods: The experimental subjects consisted of 12 active cocaine abusers and 32 age matched controls. Each subject underwent two PET FDG scans obtained within 1 week of each other. The first FDG scan was obtained after administration of placebo (3 cc of saline solution) given 40-50 minutes prior to FDG; and the second after administration of lorazepam (30 {mu}g/kg) given 40-50 minutes prior to FDG. The subjects were blind to the drugs received. Results: Lorazepam-induced sleepiness was significantly greater in abusers than in controls (p<0.001). Lorazepam-induced decreases in brain glucose metabolism were significantly larger in cocaine abusers than in controls. Whereas in controls whole brain metabolism decreased 13{+-}7 %, in cocaine abusers it decreased 21{+-}13 % (p < 0.05). Lorazepam-induced decrements in regional metabolism were significantly larger in striatum (p < 0.0 1), thalamus (p < 0.01) and cerebellum (p < 0.005) of cocaine abusers than of controls (ANOVA diagnosis by condition (placebo versus lorazepam) interaction effect). The only brain region for which the absolute metabolic changes-induced by lorazepam in cocaine abusers were equivalent to those in controls was the orbitofrontal cortex. These results document an accentuated sensitivity to benzodiazepines in cocaine abusers which is compatible with disrupted GABAergic function in these patients.

  20. Crucial role of Toll-like receptors in the zinc/nickel-induced inflammatory response in vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan (China); Liou, Saou-Hsing; Yeh, Szu-Ching; Tsai, Feng-Yuan [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli 350, Taiwan (China); Chao, How-Ran [Emerging Compounds Research Center, Department of Environmental Science and Engineering, National Pingtung University and Science and Technology, Neipu, Pingtung 912, Taiwan (China)

    2013-12-15

    Our previous studies indicated that zinc induced inflammatory response in both vascular endothelial cells and promonocytes. Here, we asked if other metals could cause the similar effect on vascular endothelial cells and tried to determine its underlying mechanism. Following screening of fifteen metals, zinc and nickel were identified with a marked proinflammatory effect, as determined by ICAM-1 and IL-8 induction, on human umbilical vein endothelial cells (HUVECs). Inhibiting protein expression of myeloid differentiation primary response protein-88 (MyD88), a Toll-like receptor (TLR) adaptor acting as a TLR-signaling transducer, significantly attenuated the zinc/nickel-induced inflammatory response, suggesting the critical roles of TLRs in the inflammatory response. Blockage of TLR-4 signaling by CLI-095, a TLR-4 inhibitor, completely inhibited the nickel-induced ICAM-1 and IL-8 expression and NFκB activation. The same CLI-095 treatment significantly blocked the zinc-induced IL-8 expression, however with no significant effect on the ICAM-1 expression and a minor inhibitory effect on the NFκB activation. The finding demonstrated the differential role of TLR-4 in regulation of the zinc/nickel-induced inflammatory response, where TLR-4 played a dominant role in NFκB activation by nickel, but not by zinc. Moreover, inhibition of NFκB by adenovirus-mediated IκBα expression and Bay 11-7025, an inhibitor of cytokine-induced IκB-α phosphorylation, significantly attenuated the zinc/nickel-induced inflammatory responses, indicating the critical of NFκB in the process. The study demonstrates the crucial role of TLRs in the zinc/nickel-induced inflammatory response in vascular endothelial cells and herein deciphers a potential important difference in NFκB activation via TLRs. The study provides a molecular basis for linkage between zinc/nickel exposure and pathogenesis of the metal-related inflammatory vascular disease. - Highlights: • Both zinc and nickel cause

  1. MAPK and pro-inflammatory mediators in the walls of brain blood vessels following cerebral ischemia

    OpenAIRE

    Maddahi, Aida

    2012-01-01

    INTRODUCTION Stroke is a serious neurological disease which may lead to death and severe disability [1, 2]. There are two major types of stroke: ischemic and hemorrhagic stroke. Both are associated with disruption of blood flow to a part of the brain with rapid depletion of cellular energy and oxygen, resulting in ionic disturbances and eventually neuronal cell death [3]. The pathologic process that develops after stroke is divided into acute (within hours), sub-acute (hours to days), ...

  2. Lung inflammatory responses and hyperinflation induced by an intratracheal exposure to lipopolysaccharide in rats.

    Science.gov (United States)

    Jansson, Anne-Helene; Eriksson, Christina; Wang, Xiangdong

    2004-01-01

    Exposure of the respiratory tract to lipopolysaccharide (LPS) induces acute local inflammation and tissue injury associated with the various deliveries of LPS. To determine potential association of local inflammatory responses with respiratory tract dysfunction, infiltration of inflammatory cells, production of inflammatory mediators, lung hyperinflation and edema were measured in Wister rats 2, 4, and 24 h after an intratracheal administration of LPS at different doses (5, 50, 500 and 5000 microg/ml/kg). Lung hyperinflation determined by an increased excised lung gas volume was significantly increased 2 and 4 h after LPS instillation and lung edema occurred from 2 h onward. Peak BAL levels of TNFalpha appeared at 2 h, MCP-1 at 4 h, and IL-6 at 2 and 4 h, while BAL levels of IL-1beta were increased during 24 h after the intratracheal instillation of LPS. Neutrophilia in BAL fluid was noted from 2 h post-challenge. Our results demonstrate a clear dose-related change in the lung weight at 4 and 24 h, in the BAL levels of MCP-1 at 4 h, and IL-6 and IL-1beta at 2 and 4 h. It seems important to understand polymorphisms of LPS-induced lung hyperinflation and inflammation. Lung hyperinflation and inflammation may be independent during the development of acute lung injury.

  3. Utility of immune response-derived biomarkers in the differential diagnosis of inflammatory disorders.

    Science.gov (United States)

    ten Oever, Jaap; Netea, Mihai G; Kullberg, Bart-Jan

    2016-01-01

    Differentiating between inflammatory disorders is difficult, but important for a rational use of antimicrobial agents. Biomarkers reflecting the host immune response may offer an attractive strategy to predict the etiology of an inflammatory process and can thus be of help in decision making. We performed a review of the literature to evaluate the diagnostic value of inflammatory biomarkers in adult patients admitted to the hospital with suspected systemic acute infections. Elevated procalcitonin (PCT) concentrations indicate a bacterial infection in febrile patients with an auto-immune disease, rather than a disease flare. CD64 expression on neutrophils can discriminate between non-infectious systemic inflammation and sepsis, and limited evidence suggests the same for decoy receptor 3. PCT is useful for both diagnosing bacterial infection complicating influenza and guiding antibiotic treatment in lower respiratory tract infections in general. In undifferentiated illnesses, increased CD35 expression on neutrophils distinguishes bacterial from viral infections. Compared to bacterial infections, invasive fungal infections are characterized by low concentrations of PCT. No biomarker predicting a specific infecting agent could be identified.

  4. Systemic Inflammatory Response and Severe Thrombocytopenia after Endovascular Thoracic Aortic Aneurysm Repair

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    Valentina Silvestrin

    2017-01-01

    Full Text Available After Endovascular repair of thoracic aortic aneurysm, a systemic inflammatory response, named postimplantation syndrome, can develop. This syndrome is characterized by fever, leukocytosis, and elevated CRP plasma levels and its pathogenetic mechanisms are still unknown. Although this syndrome generally resolves within few days, some patients develop a persisting severe inflammatory reaction leading to mild or severe complications. Here we describe the case of a male patient who developed postimplantation inflammatory syndrome and severe thrombocytopenia after endovascular repair of thoracic aortic aneurysm. Treatment with prednisone (50 mg/bid for two weeks did not improve the clinical and laboratory findings. We utilized danazol, a weak androgen that has been shown to be effective in the treatment of immune and idiopathic thrombocytopenic purpura, and after 12 days of treatment with danazol (200 mg/bid, the patient improved progressively and platelet number increased up to 53,000/μL. Patients undergoing endovascular repair of thoracic aortic aneurysm should be carefully monitored for the development of postimplantation syndrome. This clinical condition is relatively common after the endovascular repair of aortic aneurysm but is rarely observed after endovascular repair of thoracic aortic aneurysms. The different known therapeutical approaches are still empiric, with reported beneficial effects with the use of NSAID, corticosteroids, and danazol.

  5. Systemic Inflammatory Response and Severe Thrombocytopenia after Endovascular Thoracic Aortic Aneurysm Repair

    Science.gov (United States)

    Silvestrin, Valentina; Bonvini, Stefano; Antonello, Michele; Grego, Franco; Vettor, Roberto

    2017-01-01

    After Endovascular repair of thoracic aortic aneurysm, a systemic inflammatory response, named postimplantation syndrome, can develop. This syndrome is characterized by fever, leukocytosis, and elevated CRP plasma levels and its pathogenetic mechanisms are still unknown. Although this syndrome generally resolves within few days, some patients develop a persisting severe inflammatory reaction leading to mild or severe complications. Here we describe the case of a male patient who developed postimplantation inflammatory syndrome and severe thrombocytopenia after endovascular repair of thoracic aortic aneurysm. Treatment with prednisone (50 mg/bid) for two weeks did not improve the clinical and laboratory findings. We utilized danazol, a weak androgen that has been shown to be effective in the treatment of immune and idiopathic thrombocytopenic purpura, and after 12 days of treatment with danazol (200 mg/bid), the patient improved progressively and platelet number increased up to 53,000/μL. Patients undergoing endovascular repair of thoracic aortic aneurysm should be carefully monitored for the development of postimplantation syndrome. This clinical condition is relatively common after the endovascular repair of aortic aneurysm but is rarely observed after endovascular repair of thoracic aortic aneurysms. The different known therapeutical approaches are still empiric, with reported beneficial effects with the use of NSAID, corticosteroids, and danazol. PMID:28154580

  6. The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease.

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    Robert N Schuck

    Full Text Available Fatty liver disease is an emerging public health problem without effective therapies, and chronic hepatic inflammation is a key pathologic mediator in its progression. Cytochrome P450 (CYP epoxygenases metabolize arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs, which have potent anti-inflammatory effects. Although promoting the effects of EETs elicits anti-inflammatory and protective effects in the cardiovascular system, the contribution of CYP-derived EETs to the regulation of fatty liver disease-associated inflammation and injury is unknown. Using the atherogenic diet model of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH, our studies demonstrated that induction of fatty liver disease significantly and preferentially suppresses hepatic CYP epoxygenase expression and activity, and both hepatic and circulating levels of EETs in mice. Furthermore, mice with targeted disruption of Ephx2 (the gene encoding soluble epoxide hydrolase exhibited restored hepatic and circulating EET levels and a significantly attenuated induction of hepatic inflammation and injury. Collectively, these data suggest that suppression of hepatic CYP-mediated EET biosynthesis is an important pathological consequence of fatty liver disease-associated inflammation, and that the CYP epoxygenase pathway is a central regulator of the hepatic inflammatory response in NAFLD/NASH. Future studies investigating the utility of therapeutic strategies that promote the effects of CYP-derived EETs in NAFLD/NASH are warranted.

  7. Brazilin Limits Inflammatory Responses through Induction of Prosurvival Autophagy in Rheumatoid Fibroblast-Like Synoviocytes.

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    Hyunji Lee

    Full Text Available Brazilin is an active compound of Caesalpinia sappan L. (Leguminosae, which possesses pro-apoptotic and anti-inflammation potentials depending on the specific cell type. However, it is largely unknown whether autophagy is implicated in the mechanism underlying its chemotherapeutic and anti-inflammatory effects in rheumatoid arthritis (RA. Here, we show that treatment of RA fibroblast-like synoviocytes (FLS with brazilin results in enhanced level of autophagic flux, evidenced by accumulation of autophagosome and increased level of lipidated LC3 (LC3-II, which is mainly mediated by enhanced production of reactive oxygen species (ROS. Interestingly, long-term exposure of brazilin was able to restore cell survival against the cytotoxity, exclusively in RA FLS, but not in normal fibroblast. Importantly, such a restoration from brazilin-induced cytotoxity in RA FLS was completely abrogated after co-treatment with autophagy inhibitors including NH4Cl or chloroquine. Furthermore, we found that the pretreatment of RA FLS with brazilin reduced LPS- or TNF-induced NF-κB activation and the secretion of inflammatory cytokines in parallel with the enhanced autophagic flux. Such anti-NF-κB potentials of brazilin were drastically masked in RA FLS when autophagy was suppressed. These results suggest that brazilin is capable of activating autophagy exclusively in RA FLS, and such inducible autophagy promotes cell survival and limits inflammatory response.

  8. Association Between Psychological Stress and Stimulation of Inflammatory Responses in Periodontal Disease

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    Mahvash MousaviJazi

    2013-01-01

    Full Text Available Objective: Based on the evidence regarding the relationship between inflammatory processes and stress responses, the present study investigated the association between psychological stress and elevation of inflammatory mediators related to periodontal disease in adult patients.Materials and Methods: The study consisted of 50 patients including 25 patients with chronic periodontitis and 25 cases with aggressive periodontitis. Twenty-five healthy subjects without any evidence of periodontal disorder were also randomly selected as the control group. The clinical parameters including plaque index (PI, bleeding on probing (BOP, probing depth (PPD and clinical attachment loss (CAL were recorded and GCF samples were collected for analysis of GCF contents of IL-6 and IL-1β levels. The Kettle stress questionnaire was also used to determine stress severity.Results: IL-1β was significantly higher, but IL-6 was only slightly higher(marginal p-value=0.058The median score of stress was higher in aggressive periodontitis than the chronic disorder and also in the two periodontal disease groups than the healthy subjects. Among studied clinical parameters, CAL and PPD were positively correlated with the GCF IL-1β level. No significant correlations were found between clinical parameters and GCF IL-6 level. There were strong positive relationships between stress severity and in both aggressive and chronic periodontitis; however stress did not influence GCF contents of IL-6.Conclusion: Psychological stress has a pivotal role in the stimulation of inflammatory processes via IL-1β increase in aggressive and chronic periodontitis.

  9. Effects Of Different PUFA Supplementation On Inflammatory Response Markers In Young Soccer Players

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    Radoman Kristina

    2015-12-01

    Full Text Available Considering the limited knowledge regarding the effects of n-3 and n-6 PUFAs on the inflammatory response during physical activity, we aimed to evaluate the level of pro- and anti-inflammatory cytokines in young soccer players before and after a maximal physical load test at the beginning and end of a two-month training process. The study included 75 young footballers from Football School “Kragujevac,” who were followed during the two-month training programme. The subjects were divided into the following groups: 1 control group (consumed a standard diet; 2 group that consumed fish oil (2500 mg of n-3 PUFAs per day; 3 group that consumed nutritional sunflower oil (2500 mg of n-6 PUFAs daily. The maximal progressive exercise test was performed using a treadmill belt. Venous blood samples were drawn 4 times for the determination of cytokine levels (IL-6 and TNF-α: before and after the exercise load test before the two-month training programme (initial measurement and immediately before and after the exercise load test after the two-month training programme (control measurement. Supplementation with fish oil (n-3 has been associated with reduced levels of IL-6 compared with the initial values. After an acute bout of exercise, n-3 PUFAs did not show a significant effect on inflammatory marker dynamics, whereas n-6 PUFAs slightly stimulated the production of TNF-α.

  10. Effects of Thymol and Carvacrol, Constituents of Thymus vulgaris L. Essential Oil, on the Inflammatory Response

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    Fernanda Carolina Fachini-Queiroz

    2012-01-01

    Full Text Available Thyme (Thymus vulgaris L., Lamiaceae is an aromatic and medicinal plant that has been used in folk medicine, phytopharmaceutical preparations, food preservatives, and as an aromatic ingredient. The effect of Thymus vulgaris essential oil (TEO and its isolated constituents thymol and cavacrol (CVL were studied in the following experimental models: ear edema, carrageenan-induced pleurisy, and chemotaxis in vitro. In the pleurisy model, TEO, CVL, and thymol significantly inhibited inflammatory edema. However, only TEO and CVL inhibited leukocyte migration. In the in vitro chemotaxis experiment, CVL inhibited leukocyte migration, whereas thymol exerted a potent chemoattractant effect. In the ear edema model, CVL (10 mg/ear, applied topically, reduced edema formation, exerting a topical anti-inflammatory effect. Thymol did not reduce edema formation but rather presented an irritative response, probably dependent on histamine and prostanoid release. Our data suggest that the antiinflammatory effects of TEO and CVL are attributable to the inhibition of inflammatory edema and leukocyte migration.

  11. Dextromethorphan Efficiently Increases Bactericidal Activity, Attenuates Inflammatory Responses, and Prevents Group A Streptococcal Sepsis▿ †

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    Li, Ming-Han; Luo, Yueh-Hsia; Lin, Chiou-Feng; Chang, Yu-Tzu; Lu, Shiou-Ling; Kuo, Chih-Feng; Hong, Jau-Shyong; Lin, Yee-Shin

    2011-01-01

    Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild throat and skin infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), a dextrorotatory morphinan and a widely used antitussive drug, has recently been reported to possess anti-inflammatory properties. In this study, we investigated the potential protective effect of DM in GAS infection using an air pouch infection mouse model. Our results showed that DM treatment increased the survival rate of GAS-infected mice. Bacterial numbers in the air pouch were lower in mice treated with DM than in those infected with GAS alone. The bacterial elimination efficacy was associated with increased cell viability and bactericidal activity of air-pouch-infiltrating cells. Moreover, DM treatment prevented bacterial dissemination in the blood and reduced serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-1β and the chemokines monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and RANTES. In addition, GAS-induced mouse liver injury was reduced by DM treatment. Taken together, DM can increase bacterial killing and reduce inflammatory responses to prevent sepsis in GAS infection. The consideration of DM as an adjunct treatment in combination with antibiotics against bacterial infection warrants further study. PMID:21199930

  12. Obesity and coronary microvascular disease - implications for adipose tissue-mediated remote inflammatory response.

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    Bagi, Zsolt; Broskova, Zuzana; Feher, Attila

    2014-05-01

    It is believed that obesity has detrimental effects on the coronary circulation. These include immediate changes in coronary arterial vasomotor responsiveness and the development of occlusive large coronary artery disease. Despite its critical role in regulating myocardial perfusion, the altered behavior of coronary resistance arteries, which gives rise to coronary microvascular disease (CMD) is poorly understood in obesity. A chronic, low-grade vascular inflammation has been long considered as one of the main underlying pathology behind CMD. The expanded adipose tissue and the infiltrating macrophages are the major sources of pro-inflammatory mediators that have been implicated in causing inadequate myocardial perfusion and, in a long term, development of heart failure in obese patients. Much less is known the mechanisms regulating the release of these cytokines into the circulation that enable them to exert their remote effects in the coronary microcirculation. This mini review aims to examine recent studies describing alterations in the vasomotor function of coronary resistance arteries and the role of adipose tissue-derived pro-inflammatory cytokines and adipokines in contributing to CMD in obesity. We provide examples of regulatory mechanisms by which adipokines are released from adipose tissue to exert their remote inflammatory effects on coronary microvessels. We identify some of the important challenges and opportunities going forward.

  13. Crocetin Inhibits Lipopolysaccharide-Induced Inflammatory Response in Human Umbilical Vein Endothelial Cells

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    Lei Song

    2016-11-01

    Full Text Available Background/Aim: Crocetin is a readily bioavailable and bioactive compound extracted from Saffron. Previous studies indicated its various biomedical properties including antioxidant and anti-coagulation potencies. However, its effect on inflammation, notably within the cardiovascular system, has not been investigated yet. In the present study, we utilized human umbilical vein endothelial cell (HUVEC to elucidate the effect of Crocetin on vascular inflammation. Methods: Cell viability and toxicity were evaluated by MTT and Lactate dehydrogenase (LDH assay, respectively. Pro-inflammatory chemokine Monocyte Chemoattractant Protein-1 (MCP-1 and Interleukin-8 (IL-8 expressions were determined by RT-PCR and ELISA. With fluorescence labeled U937 cells, we examined immune cell adhesion to the inflamed HUVEC in vitro, which was further confirmed by the H&E staining in the murine subcutaneous endothelium in vivo. Results: Upon Lipopolysaccharide (LPS-induced inflammatory response in HUVECs, Crocetin ameliorated cell cytotoxicity, suppressed MCP-1 and IL-8 expressions through blocking NF-κB p65 signaling transduction. Moreover, Crocetin inhibited immune cells adhesion and infiltration to inflamed endothelium, which is a key step in inflammatory vascular injury. Conclusions: These findings suggest that Crocetin, a natural herb extract, is a potent suppressor of vascular endothelial inflammation.

  14. Mutation of cysteine 46 in IKK-beta increases inflammatory responses

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    Jiang, Zhi Hong; Jiang, Shui Ping; Liu, Yan; Wang, Ting Yu; Yao, Xiao Jun; Su, Xiao Hui; Yan, Feng Gen; Liu, Juan; Leung, Elaine Lai-Han; Yi, Xiao Qin; Wong, Yuen Fan; Zhou, Hua; Liu, Liang

    2015-01-01

    Activation of IκB kinase β (IKK-β) and nuclear factor (NF)-κB signaling contributes to cancer pathogenesis and inflammatory disease; therefore, the IKK-β−NF-κB signaling pathway is a potential therapeutic target. Current drug design strategies focus on blocking NF-κB signaling by binding to specific cysteine residues on IKK-β. However, mutations in IKK-β have been found in patients who may eventually develop drug resistance. For these patients, a new generation of IKK-β inhibitors are required to provide novel treatment options. We demonstrate in vitro that cysteine-46 (Cys-46) is an essential residue for IKK-β kinase activity. We then validate the role of Cys-46 in the pathogenesis of inflammation using delayed-type hypersensitivity (DTH) and an IKK-βC46A transgenic mouse model. We show that a novel IKK-β inhibitor, dihydromyricetin (DMY), has anti-inflammatory effects on WT DTH mice but not IKK-βC46A transgenic mice. These findings reveal the role of Cys-46 in the promotion of inflammatory responses, and suggest that Cys-46 is a novel drug-binding site for the inhibition of IKK-β. PMID:26378659

  15. Cold stress aggravates inflammatory responses in an LPS-induced mouse model of acute lung injury

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    Joo, Su-Yeon; Park, Mi-Ju; Kim, Kyun-Ha; Choi, Hee-Jung; Chung, Tae-Wook; Kim, Yong Jin; Kim, Joung Hee; Kim, Keuk-Jun; Joo, Myungsoo; Ha, Ki-Tae

    2016-08-01

    Although the relationship between environmental cold temperature and susceptibility to respiratory infection is generally accepted, the effect of ambient cold temperature on host reactivity in lung inflammation has not been fully studied. To examine the function of ambient cold temperature on lung inflammation, mice were exposed to 4 °C for 8 h each day for 14 days. In the lungs of mice exposed to cold stress, inflammatory cells in bronchoalveolar lavage (BAL) fluid and lung tissues were slightly increased by about twofold. However, the structures of pulmonary epithelial cells were kept within normal limits. Next, we examined the effect of cold stress on the inflammatory responses in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. The infiltration of neutrophils and inflammation of lung tissue determined by histology were significantly increased by exposure to ambient cold temperature. In addition, the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-17, and monokine induced by gamma interferon (MIG) was elevated by exposure to cold stress. Therefore, we suggest that cold stress is a factor that exacerbates lung inflammation including ALI. To our knowledge, this is the first report on the relationship between cold stress and severity of lung inflammation.

  16. SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells.

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    Li, Yanxiang; Wang, Ping; Yang, Xiaofeng; Wang, Weirong; Zhang, Jiye; He, Yanhao; Zhang, Wei; Jing, Ting; Wang, Bo; Lin, Rong

    2016-09-01

    Emerging evidence has indicated that vascular endothelial cells (ECs) not only form the barrier between blood and the vessel wall but also serve as conditional innate immune cells. Our previous study found that SIRT1, a class III histone deacetylase, inhibits the inflammatory response in ECs. Recent studies revealed that SIRT1 also participates in the modulation of immune responses. Although the NLRP3 inflammasome is known to be a crucial component of the innate immune system, there is no direct evidence demonstrating the anti-inflammatory effect of SIRT1 on ECs through the NLRP3 inflammasome. In this study, we observed that lipopolysaccharide (LPS) and adenosine triphosphate (ATP) triggered the activation of NLRP3 inflammasome in human umbilical vein ECs (HUVECs). Moreover, SIRT1 expression was reduced in HUVECs stimulated with LPS and ATP. SIRT1 activator inhibited the expression of monocyte chemotactic protein-1 (MCP-1) and C-reactive protein (CRP), whereas SIRT1 knockdown resulted in significant increases in MCP-1 and CRP levels in HUVECs stimulated with LPS and ATP. Importantly, the lack of SIRT1 enhanced NLRP3 inflammasome activation and subsequent caspase-1 cleavage. On the other hand, NLRP3 siRNA blocked the activation of the NLRP3 inflammasome in HUVECs stimulated with LPS plus ATP. Further study revealed that NLRP3 inflammasome blockade significantly reduced MCP-1 and CRP production in HUVECs. In vivo studies indicated that implantation of the periarterial carotid collar inhibited arterial SIRT1 expression in rabbits. Meanwhile, treatment with a SIRT1 activator decreased the expression levels of MCP-1 and CRP in collared arteries and the interleukin (IL)-1β level in serum. Taken together, these findings indicate that NLRP3 inflammasome activation promoted endothelial inflammation and that SIRT1 inhibits the inflammatory response partly through regulation of the NLRP3 inflammasome in ECs.

  17. Expression patterns and action analysis of genes associated with inflammatory responses during rat liver regeneration

    Institute of Scientific and Technical Information of China (English)

    Heng-Yi Shao; Li-Feng Zhao; Cun-Shuan Xu

    2007-01-01

    AIM: To study the relationship between inflammatory response and liver regeneration (LR) at transcriptional level.METHODS: After partial hepatectomy (PH) of rats,the genes associated with inflammatory response were obtained according to the databases, and the gene expression changes during LR were checked by the Rat Genome 230 2.0 array.RESULTS: Two hundred and thirty-nine genes were associated with liver regeneration. The initial and total expressing gene numbers found in initiation phase (0.5-4 h after PH), G0/G1 transition (4-6 h after PH),cell proliferation (6-66 h after PH), cell differentiation and structure-function reconstruction (66-168 h after PH) of liver regeneration were 107, 34, 126, 6 and 107,92, 233, 145 respectively, showing that the associated genes were mainly triggered at the beginning of liver regeneration, and worked at different phases. According to their expression similarity, these genes were classified into 5 groups: only up-regulated, predominantly up-,only down-, predominantly down-, up- and down-,involving 92, 25, 77, 14 and 31 genes, respectively. The total times of their up- and down-regulated expression were 975 and 494, respectively, demonstrating that the expressions of the majority of genes were increased,and that of a few genes were decreased. Their time relevance was classified into 13 groups, showing that the cellular physiological and biochemical activities were staggered during liver regeneration. According to gene expression patterns, they were classified into 33 types,suggesting that the activities were diverse and complex during liver regeneration.CONCLUSION: Inflammatory response is closely associated with liver regeneration, in which 239 LRassociated genes play an important role.

  18. The human metapneumovirus matrix protein stimulates the inflammatory immune response in vitro.

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    Audrey Bagnaud-Baule

    Full Text Available Each year, during winter months, human Metapneumovirus (hMPV is associated with epidemics of bronchiolitis resulting in the hospitalization of many infants. Bronchiolitis is an acute illness of the lower respiratory tract with a consequent inflammation of the bronchioles. The rapid onset of inflammation suggests the innate immune response may have a role to play in the pathogenesis of this hMPV infection. Since, the matrix protein is one of the most abundant proteins in the Paramyxoviridae family virion, we hypothesized that the inflammatory modulation observed in hMPV infected patients may be partly associated with the matrix protein (M-hMPV response. By western blot analysis, we detected a soluble form of M-hMPV released from hMPV infected cell as well as from M-hMPV transfected HEK 293T cells suggesting that M-hMPV may be directly in contact with antigen presenting cells (APCs during the course of infection. Moreover, flow cytometry and confocal microscopy allowed determining that M-hMPV was taken up by dendritic cells (moDCs and macrophages inducing their activation. Furthermore, these moDCs enter into a maturation process inducing the secretion of a broad range of inflammatory cytokines when exposed to M-hMPV. Additionally, M-hMPV activated DCs were shown to stimulate IL-2 and IFN-γ production by allogeneic T lymphocytes. This M-hMPV-mediated activation and antigen presentation of APCs may in part explain the marked inflammatory immune response observed in pathology induced by hMPV in patients.

  19. Cardiopulmonary Bypass Down-Regulates NOD Signaling and Inflammatory Response in Children with Congenital Heart Disease

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    Li, Yi Ping; Huang, Shungen; Zhou, Huiting; Xie, Yi; Pan, Jian; Li, Yanhong; Wang, Jiang Huai; Wang, Jian

    2016-01-01

    In the present study, we aimed to examine the impact of cardiopulmonary bypass (CPB) on expression and function of NOD1 and NOD2 in children with congenital heart disease (CHD), in an attempt to clarify whether NOD1 and NOD2 signaling is involved in the modulation of host innate immunity against postoperative infection in pediatric CHD patients. Peripheral blood samples were collected from pediatric CHD patients at five different time points: before CPB, immediately after CPB, and 1, 3, and 7 days after CPB. Real-time PCR, Western blot, and ELISA were performed to measure the expression of NOD1 and NOD2, their downstream signaling pathways, and inflammatory cytokines at various time points. Proinflammatory cytokine IL-6 and TNF-α levels in response to stimulation with either the NOD1 agonist Tri-DAP or the NOD2 agonist MDP were significantly reduced after CPB compared with those before CPB, which is consistent with a suppressed inflammatory response postoperatively. The expression of phosphorylated RIP2 and activation of the downstream signaling pathways NF-κB p65 and MAPK p38 upon Tri-DAP or MDP stimulation in PBMCs were substantially inhibited after CPB. The mRNA level of NOD1 and protein levels of NOD1 and NOD2 were also markedly decreased after CPB. Our results demonstrated that NOD-mediated signaling pathways were substantially inhibited after CPB, which correlates with the suppressed inflammatory response and may account, at least in part, for the increased risk of postoperative infection in pediatric CHD patients. PMID:27622570

  20. Effects of different esophageal carcinoma resection on the lung function, inflammatory factor production and stress response

    Institute of Scientific and Technical Information of China (English)

    Guo-Cai Zhang; Fu-Chun Zeng

    2016-01-01

    Objective:To investigate the influence of thoracic minimally invasive laparoscopic surgery and conventional thoracotomy on lung function, inflammatory factor and stress response for esophageal cancer patients.Methods:In this study, 288 cases of esophageal cancer patients were collected in our hospital from January 2011 to January 2016. Patients were randomly divided into observation group (n=144) and control group (n=144), the observation group received thoracic minimally invasive laparoscopic surgery and control group underwent conventional open surgery. The levels of inflammatory cytokines indicators [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, IL-10] and stress response [white blood cell count (WBC), three free triiodothyronine (FT3), free thyroxine (FT4), C-reactive protein (CRP), cortisol] were detected 1 d, 3 d and 5 d after surgery. Lung function [percent predicted vital capacity (VC%), percentage of predicted forced expiratory volume (FEV%), forced expiratory volume in 1 second percentage of predicted value (FEV1%), FVC% predicted percentage (FVC%), accounted for the maximum ventilation per minute, percentage of predicted value (MVV%)] of patients in two groups were measured 1 month after surgery.Results:Compared with the control group, VC and FVC in the observation group were significantly higher 1 month after surgery; the levels of TNF-α in patients of observation group were significantly lower than the control group 1 d, 3 d and 5 d after surgery; the levels IL-6, IL-8 and IL-10 in patients of observation group were significantly lower than the control group 1 d and 3 d after surgery but not on Day5. No significant difference was found in WBC, FT3, FT4, CRP and cortisol levels between the two groups.Conclusion:Compared with conventional thoracotomy, thoracic minimally invasive laparoscopic surgery can effectively reduce surgical trauma and inhibit the release of inflammatory factors, bring less effect on lung function and improve the

  1. Apoptosis and pro-inflammatory cytokine response of mast cells induced by influenza A viruses.

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    Bo Liu

    Full Text Available The pathogenesis of the influenza A virus has been investigated heavily, and both the inflammatory response and apoptosis have been found to have a definitive role in this process. The results of studies performed by the present and other groups have indicated that mast cells may play a role in the severity of the disease. To further investigate cellular responses to influenza A virus infection, apoptosis and inflammatory response were studied in mouse mastocytoma cell line P815. This is the first study to demonstrate that H1N1 (A/WSN/33, H5N1 (A/Chicken/Henan/1/04, and H7N2 (A/Chicken/Hebei/2/02 influenza viruses can induce mast cell apoptosis. They were found to do this mainly through the mitochondria/cytochrome c-mediated intrinsic pathway, and the activation of caspase 8-mediated extrinsic pathway was here found to be weak. Two pro-apoptotic Bcl-2 homology domain 3 (BH3 -only molecules Bim and Puma appeared to be involved in the apoptotic pathways. When virus-induced apoptosis was inhibited in P815 cells using pan-caspase (Z-VAD-fmk and caspase-9 (Z-LEHD-fmk inhibitors, the replication of these three subtypes of viruses was suppressed and the secretions of pro-inflammatory cytokines and chemokines, including IL-6, IL-18, TNF-α, and MCP-1, decreased. The results of this study may further understanding of the role of mast cells in host defense and pathogenesis of influenza virus. They may also facilitate the development of novel therapeutic aids against influenza virus infection.

  2. Oleanolic acid controls allergic and inflammatory responses in experimental allergic conjunctivitis.

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    Claudia Córdova

    Full Text Available Pollen is the most common aeroallergen to cause seasonal conjunctivitis. The result of allergen exposure is a strong Th2-mediated response along with conjunctival mast cell degranulation and eosinophilic infiltration. Oleanolic acid (OA is natural a triterpene that displays strong anti-inflammatory and immunomodulatory properties being an active anti-allergic molecule on hypersensitivity reaction models. However, its effect on inflammatory ocular disorders including conjunctivitis, has not yet been addressed. Hence, using a Ragweed pollen (RWP-specific allergic conjunctivitis (EAC mouse model we study here whether OA could modify responses associated to allergic processes. We found that OA treatment restricted mast cell degranulation and infiltration of eosinophils in conjunctival tissue and decreased allergen-specific Igs levels in EAC mice. Th2-type cytokines, secreted phospholipase A2 type-IIA (sPLA2-IIA, and chemokines levels were also significantly diminished in the conjunctiva and serum of OA-treated EAC mice. Moreover, OA treatment also suppressed RWP-specific T-cell proliferation. In vitro studies, on relevant cells of the allergic process, revealed that OA reduced the proliferative and migratory response, as well as the synthesis of proinflammatory mediators on EoL-1 eosinophils and RBL-2H3 mast cells exposed to allergic and/or crucial inflammatory stimuli such as RWP, sPLA2-IIA or eotaxin. Taken together, these findings demonstrate the beneficial activity of OA in ocular allergic processes and may provide a new intervention strategy and potential therapy for allergic diseases.

  3. Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease

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    Rocío Prieto-Pérez

    2016-02-01

    Full Text Available Tumor necrosis factor (TNF alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD. Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th 17 pathway.

  4. Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.

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    Prieto-Pérez, Rocío; Almoguera, Berta; Cabaleiro, Teresa; Hakonarson, Hakon; Abad-Santos, Francisco

    2016-02-06

    Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathway.

  5. Loneliness and stress-related inflammatory and neuroendocrine responses in older men and women.

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    Hackett, Ruth A; Hamer, Mark; Endrighi, Romano; Brydon, Lena; Steptoe, Andrew

    2012-11-01

    Loneliness is a predictor of mortality and increased cardiovascular morbidity. Inflammation is a potential pathway through which loneliness might impact health. The aim of the study was to investigate the relationship between loneliness and inflammatory interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra) and monocyte chemotactic protein-1 (MCP-1) responses to standardized mental stress. A secondary purpose was to evaluate whether individual variations in cortisol responses influenced the hypothesised relationship between loneliness and inflammation. Saliva samples and blood were taken from 524 healthy middle-aged men and women from the Whitehall II cohort at baseline, immediately after the stress tasks and 45min later. Loneliness was measured using the revised UCLA loneliness scale. Greater loneliness was associated with larger IL-6 (p=0.044) and IL-1Ra (p=0.006) responses to psychological stress and higher MCP-1 (ploneliness in women, with the odds of being a cortisol responder decreasing with increased loneliness independently of covariates (p=0.008). The impact of loneliness on health in women may be mediated in part through dysregulation of inflammatory and neuroendocrine systems.

  6. Immunoglobulin G–mediated Inflammatory Responses Develop Normally in Complement-deficient Mice

    Science.gov (United States)

    Sylvestre, Diana; Clynes, Raphael; Ma, Minga; Warren, Henry; Carroll, Michael C.; Ravetch, Jeffrey V.

    1996-01-01

    The role of complement in immunoglobulin G–triggered inflammation was studied in mice genetically deficient in complement components C3 and C4. Using the reverse passive Arthus reaction and experimental models of immune hemolytic anemia and immune thrombocytopenia, we show that these mice have types II and III inflammatory responses that are indistinguishable from those of wild-type animals. Complement-deficient and wild-type animals exhibit comparable levels of erythrophagocytosis and platelet clearance in response to cytotoxic anti–red blood cell and antiplatelet antibodies. Furthermore, in the reverse passive Arthus reaction, soluble immune complexes induce equivalent levels of hemmorhage, edema, and neutrophillic infiltration in complement-deficient and wild-type animals. In contrast, mice that are genetically deficient in the expression of Fc receptors exhibit grossly diminished reactions by both cytotoxic antibodies and soluble immune complexes. These studies provide strong evidence that the activation of cell-based FcγR receptors, but not complement, are required for antibody-triggered murine inflammatory responses. PMID:8976192

  7. Activated systemic inflammatory response at diagnosis reduces lymph node count in colonic carcinoma

    Institute of Scientific and Technical Information of China (English)

    Rory P Kennelly; Brenda Murphy; John O Larkin; Brian J Mehigan; Paul H McCormick

    2016-01-01

    AIM: To investigate a link between lymph node yield and systemic inflammatory response in colon cancer. METHODS: A prospectively maintained database was interrogated. All patients undergoing curative colonic resection were included. Neutrophil lymphocyte ratio(NLR) and albumin were used as markers of SIR. In keeping with previously studies, NLR ≥ 4, albumin < 35 was used as cut off points for SIR. Statistical analysis was performed using 2 sample t-test and χ~2 tests where appropriate.RESULTS: Three hundred and two patients were included for analysis. One hundred and ninety-five patients had NLR < 4 and 107 had NLR ≥ 4. There was no difference in age or sex between groups. Patients with NLR of ≥ 4 had lower mean lymph node yields than patients with NLR < 4 [17.6 ± 7.1 vs 19.2 ± 7.9(P = 0.036)]. More patients with an elevated NLR had node positive disease and an increased lymph node ratio(≥ 0.25, P = 0.044). CONCLUSION: Prognosis in colon cancer is intimately linked to the patient’s immune response. Assuming standardised surgical technique and sub specialty pathology, lymph node count is reduced when systemic inflammatory response is activated.

  8. Recovery after an Ironman triathlon: sustained inflammatory responses and muscular stress.

    Science.gov (United States)

    Neubauer, Oliver; König, Daniel; Wagner, Karl-Heinz

    2008-10-01

    Ultra-endurance exercise, such as an Ironman triathlon, induces muscle damage and a systemic inflammatory response. As the resolution of recovery in these parameters is poorly documented, we investigated indices of muscle damage and systemic inflammation in response to an Ironman triathlon and monitored these parameters 19 days into recovery. Blood was sampled from 42 well-trained male triathletes 2 days before, immediately after, and 1, 5 and 19 days after an Ironman triathlon. Blood samples were analyzed for hematological profile, and plasma values of myeloperoxidase (MPO), polymorphonuclear (PMN) elastase, cortisol, testosterone, creatine kinase (CK) activity, myoglobin, interleukin (IL)-6, IL-10 and high-sensitive C-reactive protein (hs-CRP). Immediately post-race there were significant (P triathlon were noted. This study indicates that the pronounced initial systemic inflammatory response induced by an Ironman triathlon declines rapidly. However, a low-grade systemic inflammation persisted until at least 5 days post-race, possibly reflecting incomplete muscle recovery.

  9. 3D culture broadly regulates tumor cell hypoxia response and angiogenesis via pro-inflammatory pathways.

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    DelNero, Peter; Lane, Maureen; Verbridge, Scott S; Kwee, Brian; Kermani, Pouneh; Hempstead, Barbara; Stroock, Abraham; Fischbach, Claudia

    2015-07-01

    Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation.

  10. Characterization of the inflammatory response to four commercial bone graft substitutes using a murine biocompatibility model

    Directory of Open Access Journals (Sweden)

    Markel DC

    2012-01-01

    Full Text Available David C Markel1, S Trent Guthrie2, Bin Wu3, Zheng Song4, Paul H Wooley41Department of Orthopaedics, Providence Hospital and Medical Centers, Southfield, MI, 2Henry Ford Hospital, Detroit, MI, 3Department of Biomedical Engineering, Wayne State University, Detroit, MI, 4Orthopaedic Research Institute, Wichita, KS, USAAbstract: Bone grafting is utilized in nearly all orthopedic subspecialties and in most anatomic regions. Bone graft substitutes have the potential to offer similar efficacy as autogenous grafts without the morbidity of harvest. Several studies have noted the efficacy of new-generation bone substitute products, but few studies have evaluated their safety. This study characterizes and quantifies the inflammatory reaction to four different commercially available bone graft substitutes, which were examined using the in vivo murine air pouch biocompatibility model. One coralline hydroxyapatite product was chosen as an example of a purely osteoconductive material. Three demineralized bone matrix products were chosen to represent products that are both osteoconductive and osteoinductive. Samples were implanted in a murine air pouch and harvested after 14 days in situ. Pouch fluid was extracted, mRNA isolated, and reverse transcription polymerase chain reactions carried out to detect interleukin-1 gene expression as a marker for inflammation. In addition, multiple histological characteristics were examined to quantify cellular responses to the implanted materials. All bone graft substitutes induced a significant inflammatory response compared with negative controls. Histology and polymerase chain reaction data indicated that the level of inflammatory reaction was elevated in materials with a higher demineralized bone matrix to carrier proportion. The hydroxyapatite product generated a low inflammatory reaction. In conclusion, this study used an in vivo model of biocompatibility to demonstrate that a significant inflammatory reaction occurs

  11. Diminazene aceturate (Berenil modulates the host cellular and inflammatory responses to Trypanosoma congolense infection.

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    Shiby Kuriakose

    Full Text Available BACKGROUND: Trypanosoma congolense are extracellular and intravascular blood parasites that cause debilitating acute or chronic disease in cattle and other domestic animals. Diminazene aceturate (Berenil has been widely used as a chemotherapeutic agent for trypanosomiasis in livestock since 1955. As in livestock, treatment of infected highly susceptible BALB/c mice with Berenil leads to rapid control of parasitemia and survival from an otherwise lethal infection. The molecular and biochemical mechanisms of action of Berenil are still not very well defined and its effect on the host immune system has remained relatively unstudied. Here, we investigated whether Berenil has, in addition to its trypanolytic effect, a modulatory effect on the host immune response to Trypanosoma congolense. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c and C57BL/6 mice were infected intraperitoneally with T. congolense, treated with Berenil and the expression of CD25 and FoxP3 on splenic cells was assessed directly ex vivo. In addition, serum levels and spontaneous and LPS-induced production of pro-inflammatory cytokines by splenic and hepatic CD11b⁺ cells were determined by ELISA. Berenil treatment significantly reduced the percentages of CD25⁺ cells, a concomitant reduction in the percentage of regulatory (CD4⁺Foxp3⁺ T cells and a striking reduction in serum levels of disease exacerbating pro-inflammatory cytokines including IL-6, IL-12, TNF and IFN-γ. Furthermore, Berenil treatment significantly suppressed spontaneous and LPS-induced production of inflammatory cytokines by splenic and liver macrophages and significantly ameliorated LPS-induced septic shock and the associated cytokine storm. CONCLUSIONS/SIGNIFICANCE: Collectively, these results provide evidence that in addition to its direct trypanolytic effect, Berenil also modulates the host immune response to the parasite in a manner that dampen excessive immune activation and production of pathology