WorldWideScience

Sample records for intestinal inflammation induced

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

    NARCIS (Netherlands)

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

    2008-01-01

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

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

    NARCIS (Netherlands)

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

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

  3. Bovine colostrum improves intestinal function following formula-induced gut inflammation in preterm pigs

    DEFF Research Database (Denmark)

    Støy, Ann Cathrine Findal; Heegaard, Peter M. H.; Thymann, Thomas

    2014-01-01

    Background & aims Only few hours of formula feeding may induce proinflammatory responses and predispose to necrotizing enterocolitis (NEC) in preterm pigs. We hypothesized that bovine colostrum, rich in bioactive factors, would improve intestinal function in preterm pigs following an initial...... exposure to formula feeding after some days of total parenteral nutrition (TPN). Methods After receiving TPN for 2 days, preterm pigs were fed formula (FORM, n = 14), bovine colostrum (COLOS, n = 6), or formula (6 h) followed by bovine colostrum (FCOLOS, n = 14). Intestinal lesions, function, and structure...... and FCOLOS pigs, relative to FORM pigs. Intestinal gene expression of serum amyloid A, IL-1β, -6 and -8, and bacterial abundance, correlated positively with NEC severity of the distal small intestine. Conclusions Bovine colostrum restores intestinal function after initial formula-induced inflammation...

  4. Tolerogenic CX3CR1+ B cells suppress food allergy-induced intestinal inflammation in mice.

    Science.gov (United States)

    Liu, Z Q; Wu, Y; Song, J P; Liu, X; Liu, Z; Zheng, P Y; Yang, P C

    2013-10-01

    B lymphocytes are an important cell population of the immune regulation; their role in the regulation of food allergy has not been fully understood yet. This study aims to investigate the role of a subpopulation of tolerogenic B cells (TolBC) in the generation of regulatory T cells (Treg) and in the suppression of food allergy-induced intestinal inflammation in mice. The intestinal mucosa-derived CD5+ CD19+ CX3CR1+ TolBCs were characterized by flow cytometry; a mouse model of intestinal T helper (Th)2 inflammation was established to assess the immune regulatory role of this subpopulation of TolBCs. A subpopulation of CD5+ CD19+ CX3CR1+ B cells was detected in the mouse intestinal mucosa. The cells also expressed transforming growth factor (TGF)-β and carried integrin alpha v beta 6 (αvβ6). Exposure to recombinant αvβ6 and anti-IgM antibody induced naive B cells to differentiate into the TGF-β-producing TolBCs. Coculturing this subpopulation of TolBCs with Th0 cells generated CD4+ CD25+ Foxp3+ Tregs. Adoptive transfer with the TolBCs markedly suppressed the food allergy-induced intestinal Th2 pattern inflammation in mice. CD5+ CD19+ CX3CR1+ TolBCs are capable of inducing Tregs in the intestine and suppress food allergy-related Th2 pattern inflammation in mice. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Titanium dioxide induced inflammation in the small intestine

    Science.gov (United States)

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

    2012-01-01

    AIM: To investigate the effects of titanium dioxide (TiO2) nanoparticles (NPTiO2) and microparticles (MPTiO2) on the inflammatory response in the small intestine of mice. METHODS: Bl 57/6 male mice received distilled water suspensions containing TiO2 (100 mg/kg body weight) as NPTiO2 (66 nm), or MPTiO2 (260 nm) by gavage for 10 d, once a day; the control group received only distilled water. At the end of the treatment the duodenum, jejunum and ileum were extracted for assessment of cytokines, inflammatory cells and titanium content. The cytokines interleukin (IL)-1b, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, IL-23, tumor necrosis factor-α (TNF-α), intracellular interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) were evaluated by enzyme-linked immunosorbent assay in segments of jejunum and ileum (mucosa and underlying muscular tissue). CD4+ and CD8+ T cells, natural killer cells, and dendritic cells were evaluated in duodenum, jejunum and ileum samples fixed in 10% formalin by immunohistochemistry. The titanium content was determined by inductively coupled plasma atomic emission spectrometry. RESULTS: We found increased levels of T CD4+ cells (cells/mm2) in duodenum: NP 1240 ± 139.4, MP 1070 ± 154.7 vs 458 ± 50.39 (P < 0.01); jejunum: NP 908.4 ± 130.3, MP 813.8 ± 103.8 vs 526.6 ± 61.43 (P < 0.05); and ileum: NP 818.60 ± 123.0, MP 640.1 ± 32.75 vs 466.9 ± 22.4 (P < 0.05). In comparison to the control group, the groups receiving TiO2 showed a statistically significant increase in the levels of the inflammatory cytokines IL-12, IL-4, IL-23, TNF-α, IFN-γ and TGF-β. The cytokine production was more pronounced in the ileum (mean ± SE): IL-12: NP 33.98 ± 11.76, MP 74.11 ± 25.65 vs 19.06 ± 3.92 (P < 0.05); IL-4: NP 17.36 ± 9.96, MP 22.94 ± 7.47 vs 2.19 ± 0.65 (P < 0.05); IL-23: NP 157.20 ± 75.80, MP 134.50 ± 38.31 vs 22.34 ± 5.81 (P < 0.05); TNFα: NP 3.71 ± 1.33, MP 5.44 ± 1.67 vs 0.99 ± 019 (P < 0.05); IFNγ: NP 15.85 ± 9

  6. Protective effect of superoxide dismutase in radiation-induced intestinal inflammation

    International Nuclear Information System (INIS)

    Molla, Meritxell; Gironella, Meritxell; Salas, Antonio; Closa, Daniel; Biete, Albert; Gimeno, Mercedes; Coronel, Pilar; Pique, Josep M.; Panes, Julian

    2005-01-01

    Purpose: To analyze the therapeutic value of Cu/Zn-superoxide dismutase (SOD1) supplementation in an experimental model of radiation-induced intestinal inflammation and explore its mechanistic effects. Methods and materials: Mice were subjected to abdominal irradiation with 10 Gy or sham irradiation and studied 24 or 72 hours after radiation. Groups of mice were treated with 0.1, 4, or 6 mg/kg/day of SOD1 or vehicle. Leukocyte-endothelial cell interactions in intestinal venules were assessed by intravital microscopy. Endothelial intercellular adhesion molecule-1 (ICAM-1) expression was determined with radiolabeled antibodies. Effects of SOD1 on histologic damage and levels of lipid hydroperoxides were also measured. Results: A significant increase in the flux of rolling leukocytes and number of firmly adherent leukocytes in intestinal venules was observed at 24 and 72 hours after irradiation. Treatment with SOD1 had no effect on leukocyte rolling but significantly and dose-dependently decreased firm leukocyte adhesion to intestinal venules. Treatment with SOD1 at doses that reduced leukocyte recruitment abrogated the increase in hydroperoxides in intestinal tissue and ICAM-1 upregulation in intestinal endothelial cells. The inflammatory score, but not a combined histology damage score, was also significantly reduced by SOD1. Conclusions: Treatment with SOD1 decreases oxidative stress and adhesion molecule upregulation in response to abdominal irradiation. This is associated with an attenuation of the radiation-induced intestinal inflammatory response

  7. Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO pathway.

    Science.gov (United States)

    Phillips, Matthew C; Dheer, Rishu; Santaolalla, Rebeca; Davies, Julie M; Burgueño, Juan; Lang, Jessica K; Toborek, Michal; Abreu, Maria T

    2018-01-15

    Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs. We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred. Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR. Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation. These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    International Nuclear Information System (INIS)

    Gremy, O.

    2006-12-01

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

  9. Introducing enteral feeding induces intestinal subclinical inflammation and respective chromatin changes in preterm pigs

    DEFF Research Database (Denmark)

    Willems, Rhea; Krych, Lukasz; Rybicki, Verena

    2015-01-01

    AIM: To analyze how enteral food introduction affects intestinal gene regulation and chromatin structure in preterm pigs. MATERIALS & METHODS: Preterm pigs were fed parenteral nutrition plus/minus slowly increasing volumes of enteral nutrition. Intestinal gene-expression and chromatin structure......; no significant differences for colostrum) with corresponding decondensed chromatin configurations. On histology this correlated with mild mucosal lesions, particularly in formula-fed pigs. In CaCo-2 cells, histone hyperacetylation led to a marked increase in TLR4 mRNA and increased IL8 expression upon...... stimulation with lipopolysaccharide (median: 7.0; interquartile range: 5.63-8.85) compared with naive cells (median 4.2; interquartile range: 2.45-6.33; p = 0.03). CONCLUSION: Enteral feeding, particular with formula, induces subclinical inflammation in the premature intestine and more open chromatin...

  10. Maternal Obesity Induces Sustained Inflammation in Both Fetal and Offspring Large Intestine of Sheep

    Science.gov (United States)

    Yan, Xu; Huang, Yan; Wang, Hui; Du, Min; Hess, Bret W.; Ford, Stephen P.; Nathanielsz, Peter W.; Zhu, Mei-Jun

    2010-01-01

    Background Both maternal obesity and inflammatory bowel diseases (IBDs) are increasing. It was hypothesized that maternal obesity induces an inflammatory response in the fetal large intestine, predisposing offspring to IBDs. Methods Nonpregnant ewes were assigned to a control (Con, 100% of National Research Council [NRC] recommendations) or obesogenic (OB, 150% of NRC) diet from 60 days before conception. The large intestine was sampled from fetuses at 135 days (term 150 days) after conception and from offspring lambs at 22.5 ± 0.5 months of age. Results Maternal obesity enhanced mRNA expression tumor necrosis factor (TNF)α, interleukin (IL)1α, IL1β, IL6, IL8, and monocyte/macrophage chemotactic protein-1 (MCP1), as well as macrophage markers, CD11b, CD14, and CD68 in fetal gut. mRNA expression of Toll-like receptor (TLR) 2 and TLR4 was increased in OB versus Con fetuses; correspondingly, inflammatory NF-κB and JNK signaling pathways were also upregulated. Both mRNA expression and protein content of transforming growth factor (TGF) β was increased. The IL-17A mRNA expression and protein content was higher in OB compared to Con samples, which was associated with fibrosis in the large intestine of OB fetuses. Similar inflammatory responses and enhanced fibrosis were detected in OB compared to Con offspring. Conclusions Maternal obesity induced inflammation and enhanced expression of proinflammatory cytokines in fetal and offspring large intestine, which correlated with increased TGFβ and IL17 expression. These data show that maternal obesity may predispose offspring gut to IBDs. PMID:21674707

  11. Soya-saponins induce intestinal inflammation and barrier dysfunction in juvenile turbot (Scophthalmus maximus).

    Science.gov (United States)

    Gu, Min; Jia, Qian; Zhang, Zhiyu; Bai, Nan; Xu, Xiaojie; Xu, Bingying

    2018-06-01

    Soybean meal-induced enteritis (SBMIE) is a well-described condition in the distal intestine (DI) of several cultured fish species, but the exact cause is still unclear. The work on Atlantic salmon and zebrafish suggested soya-saponins, as heat-stable anti-nutritional factors in soybean meal, are the major causal agents. However, this conclusion was not supported by the research on some other fish, such as gilthead sea bream and European sea bass. Our previous work proved that soybean could induce SBMIE on turbot and the present work aimed to investigate whether soya-saponins alone could cause SBMIE and the effects of soya-saponins on the intestinal barrier function in juvenile turbot. Turbots with initial weight 11.4 ± 0.02 g were fed one of four fishmeal-based diets containing graded levels of soya-saponins (0, 2.5, 7.5, 15 g kg -1 ) for 8 weeks. At the end of the trial, all fish were weighed and plasma was obtained for diamine oxidase (DAO) activity and d-lactate level analysis and DI was sampled for histological evaluation and quantification of antioxidant parameters and inflammatory marker genes. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and intestinal glutathione level were selected to evaluated intestinal antioxidant system. The distal intestinal epithelial cell (IEC) proliferation and apoptosis were investigated by proliferating cell nuclear antigen (PCNA) labelling and TdT-mediated dUTP nick end labeling (TUNEL), respectively. The results showed that soya-saponins caused significantly dose-dependent decrease in the growth performance and nutrient utilization (p soya-saponins. Significantly dose-dependent increases in severity of the inflammation concomitant with up-regulated expression of il-1β, il-8, and tnf-α, increased IEC proliferation and apoptosis, and decreases in selected antioxidant parameters were detected (p soya-saponins (p soya-saponins induced enteritis and compromised

  12. An orally active Cannabis extract with high content in cannabidiol attenuates chemical induced intestinal inflammation and hypermotility in the mouse

    OpenAIRE

    Ester Pagano; Raffaele Capasso; Fabiana Piscitelli; Barbara Romano; Olga Alessandra Parisi; Stefania Finizio; Anna Lauritano; Vincenzo Di Marzo; Angelo A Izzo; Francesca Borrelli

    2016-01-01

    Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for CBD botanical drug substance, on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was ev...

  13. Electroacupuncture Inhibits Inflammation Reaction by Upregulating Vasoactive Intestinal Peptide in Rats with Adjuvant-Induced Arthritis

    Directory of Open Access Journals (Sweden)

    Tian-Feng He

    2011-01-01

    Full Text Available Acupuncture is emerging as an alternative therapy for rheumatoid arthritis (RA. However, the molecular mechanism underlying this beneficial effect of acupuncture has not been fully understood. Here, we demonstrated that electroacupuncture at acupoints Zusanli (ST36, Xuanzhong (GB39; and Shenshu (BL23 markedly decreased the paw swelling and the histologic scores of inflammation in the synovial tissue, and reduced the body weight loss in an adjuvant-induced arthritis rat model. However, the electrical stimulation at nonacupoint did not produce any beneficial effects against the experimental arthritis. Most interestingly, the electroacupuncture treatment resulted in an enhanced immunostaining for vasoactive intestinal peptide (VIP, a potent anti-inflammatory neuropeptide, in the synovial tissue. Moreover, the VIP-immunostaining intensity was significantly negatively correlated with the scores of inflammation in the synovial tissue (r=−0.483, P=.0026. In conclusion, these findings suggest that electroacupuncture may offer therapeutic benefits for the treatment of RA, at least partially through the induction of VIP expression.

  14. Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity.

    Science.gov (United States)

    Gil-Cardoso, Katherine; Ginés, Iris; Pinent, Montserrat; Ardévol, Anna; Blay, Mayte; Terra, Ximena

    2016-12-01

    Diet-induced obesity is associated with low-grade inflammation, which, in most cases, leads to the development of metabolic disorders, primarily insulin resistance and type 2 diabetes. Although prior studies have implicated the adipose tissue as being primarily responsible for obesity-associated inflammation, the latest discoveries have correlated impairments in intestinal immune homeostasis and the mucosal barrier with increased activation of the inflammatory pathways and the development of insulin resistance. Therefore, it is essential to define the mechanisms underlying the obesity-associated gut alterations to develop therapies to prevent and treat obesity and its associated diseases. Flavonoids appear to be promising candidates among the natural preventive treatments that have been identified to date. They have been shown to protect against several diseases, including CVD and various cancers. Furthermore, they have clear anti-inflammatory properties, which have primarily been evaluated in non-intestinal models. At present, a growing body of evidence suggests that flavonoids could exert a protective role against obesity-associated pathologies by modulating inflammatory-related cellular events in the intestine and/or the composition of the microbiota populations. The present paper will review the literature to date that has described the protective effects of flavonoids on intestinal inflammation, barrier integrity and gut microbiota in studies conducted using in vivo and in vitro models.

  15. An orally active Cannabis extract with high content in cannabidiol attenuates chemical induced intestinal inflammation and hypermotility in the mouse

    Directory of Open Access Journals (Sweden)

    Ester Pagano

    2016-10-01

    Full Text Available Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD, here named CBD BDS for CBD botanical drug substance, on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS. Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage - after the inflammatory insult (curative protocol. The amounts of CBD in the colon, brain and liver after the oral treatments were measured by HPLC coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion or orally (only at one dose. In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.

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

    Energy Technology Data Exchange (ETDEWEB)

    Gremy, O

    2006-12-15

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

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

    Energy Technology Data Exchange (ETDEWEB)

    Gremy, O

    2006-12-15

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

  18. Mixed Lactobacillus plantarum Strains Inhibit Staphylococcus aureus Induced Inflammation and Ameliorate Intestinal Microflora in Mice.

    Science.gov (United States)

    Ren, Dayong; Gong, Shengjie; Shu, Jingyan; Zhu, Jianwei; Rong, Fengjun; Zhang, Zhenye; Wang, Di; Gao, Liangfeng; Qu, Tianming; Liu, Hongyan; Chen, Ping

    2017-01-01

    Objective . Staphylococcus aureus is an important pathogen that causes intestinal infection. We examined the immunomodulatory function of single and mixed Lactobacillus plantarum strains, as well as their impacts on the structure of the microbiome in mice infected with Staphylococcus aureus . The experiment was divided into three groups: protection, treatment, and control. Serum IFN- γ and IL-4 levels, as well as intestinal sIgA levels, were measured during and 1 week after infection with Staphylococcus aureus with and without Lactobacillus plantarum treatment. We used 16s rRNA tagged sequencing to analyze microbiome composition. IFN- γ /IL-4 ratio decreased significantly from infection to convalescence, especially in the mixed Lactobacillus plantarum group. In the mixed Lactobacillus plantarum group the secretion of sIgA in the intestine of mice (9.4-9.7 ug/mL) was significantly higher than in the single lactic acid bacteria group. The dominant phyla in mice are Firmicutes , Bacteroidetes , and Proteobacteria . Treatment with mixed lactic acid bacteria increased the anti-inflammatory factor and the secretion of sIgA in the intestine of mice infected with Staphylococcus aureus and inhibited inflammation.

  19. Administration of Protein kinase D1 induce an immunomodulatory effect on lipopolysaccharide-induced intestinal inflammation in a co-culture model of intestinal epithelial Caco-2 cells and RAW 264.7 macrophage cells

    DEFF Research Database (Denmark)

    Nielsen, Ditte Søvsø Gundelund; Fredborg, Marlene; Andersen, Vibeke

    2017-01-01

    the effects of human PKD1 in relation to intestinal inflammation, using a co-culture model of intestinal epithelial Caco-2 cells and RAW264.7 macrophages. An inflammatory response was induced in the macrophages by lipopolysaccharide (LPS), upregulating the expression of tumour necrosis factor alpha (TNF......-α), interleukin- (IL-) 1β, and IL-6 besides increasing the secretion of TNF-α protein. The effect of administering PKD1 to Caco-2 was evaluated in relation to both amelioration of inflammation and the ability to suppress inflammation initiation. Administration of PKD1 (10–100 ng/ml) following induction...

  20. Features of blood serum protein spectrum and cytokine spectrum of rats with chronic carrageenan-induced intestinal inflammation

    Directory of Open Access Journals (Sweden)

    A. S. Tkachenko

    2014-04-01

    Full Text Available It has been established that features of modern diet might be considered as a possible source of inflammatory diseases of gastrointestinal tract. Particular attention is paid to the role of different food additives in the development of intestinal inflammation, including the food additive E407, known as carrageenan. A model of chronic carrageenan-induced gastroenterocolitis of moderate severity has been elaborated, which allows us to study carrageenan-induced intestinal inflammation. In particular, the features of blood serum protein spectrum and cytokine spectrum in chronic carrageenan-induced intestinal inflammation are not studied. The female Wistar rats have been used for the experiment. Chronic carrageenan-induced gastroenterocolitis has been reproduced by the free access of animals to 1% solution of carrageenan in drinking water. Laboratory animals have been divided into 3 groups. Group № 1 consisted of experimental animals, who consumed food additive carrageenan during 2 weeks and group № 2 included experimental animals, who consumed food additive carrageenan during 4 weeks. Group № 3 consisted of intact healthy animals. The development of gastroenterocolitis has been proved morphologically and biochemically. Manipulations with animals have been carried out in accordance with the provisions of the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 1986. It has been established that the disease has been associated with dysproteinemia. The level of α1-globulins increased after 2 weeks of carrageenan consumption and has been normalized in animals, who consumed carrageenan during 4 weeks. The similar changes have been observed for α2-globulins level. It could be explained by production of acute phase proteins, such as α1-acid glycoprotein, C-reactive protein, fibrinogen, α2-macroglobulin, ceruloplasmin, etc. The intake of carrageenan also caused

  1. Butyrate attenuates lipopolysaccharide-induced inflammation in intestinal cells and Crohn's mucosa through modulation of antioxidant defense machinery.

    Directory of Open Access Journals (Sweden)

    Ilaria Russo

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

  2. The Food Contaminants Nivalenol and Deoxynivalenol Induce Inflammation in Intestinal Epithelial Cells by Regulating Reactive Oxygen Species Release

    Directory of Open Access Journals (Sweden)

    Simona Adesso

    2017-12-01

    Full Text Available Fusarium mycotoxins are fungal metabolites whose ability to affect cereal grains as multi-contaminants is progressively increasing. The trichothecene mycotoxins nivalenol (NIV and deoxynivalenol (DON are often found in almost all agricultural commodities worldwide. They are able to affect animal and human health, including at the intestinal level. In this study, NIV, both alone and in combination with DON, induced inflammation and increased the inflammatory response induced by lipopolysaccharide (LPS plus Interferon-γ (IFN in the non-tumorigenic intestinal epithelial cell line (IEC-6. The inflammatory response induced by NIV and DON involves tumor necrosis factor-α (TNF-α production, inducible nitric oxide synthase (iNOS and cyclooxygenase-2 (COX-2 expression, nitrotyrosine formation, reactive oxygen species (ROS release, Nuclear Factor-κB (NF-κB, Nuclear factor (erythroid-derived 2-like 2 (Nrf2 and inflammasome activation. The pro-inflammatory effect was strongly induced by NIV and by the mycotoxin mixture, when compared to DON alone. Mechanistic studies indicate a pivotal role for ROS in the observed pro-inflammatory effects induced by mycotoxins. In this study, the interactions between NIV and DON point out the importance of their food co-contamination, further highlighting the risk assessment process that is of growing concern.

  3. The Food Contaminants Nivalenol and Deoxynivalenol Induce Inflammation in Intestinal Epithelial Cells by Regulating Reactive Oxygen Species Release.

    Science.gov (United States)

    Adesso, Simona; Autore, Giuseppina; Quaroni, Andrea; Popolo, Ada; Severino, Lorella; Marzocco, Stefania

    2017-12-11

    Fusarium mycotoxins are fungal metabolites whose ability to affect cereal grains as multi-contaminants is progressively increasing. The trichothecene mycotoxins nivalenol (NIV) and deoxynivalenol (DON) are often found in almost all agricultural commodities worldwide. They are able to affect animal and human health, including at the intestinal level. In this study, NIV, both alone and in combination with DON, induced inflammation and increased the inflammatory response induced by lipopolysaccharide (LPS) plus Interferon-γ (IFN) in the non-tumorigenic intestinal epithelial cell line (IEC-6). The inflammatory response induced by NIV and DON involves tumor necrosis factor-α (TNF-α) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, nitrotyrosine formation, reactive oxygen species (ROS) release, Nuclear Factor-κB (NF-κB), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inflammasome activation. The pro-inflammatory effect was strongly induced by NIV and by the mycotoxin mixture, when compared to DON alone. Mechanistic studies indicate a pivotal role for ROS in the observed pro-inflammatory effects induced by mycotoxins. In this study, the interactions between NIV and DON point out the importance of their food co-contamination, further highlighting the risk assessment process that is of growing concern.

  4. Soybean β-conglycinin induces inflammation and oxidation and causes dysfunction of intestinal digestion and absorption in fish.

    Directory of Open Access Journals (Sweden)

    Jin-Xiu Zhang

    Full Text Available β-Conglycinin has been identified as one of the major feed allergens. However, studies of β-conglycinin on fish are scarce. This study investigated the effects of β-conglycinin on the growth, digestive and absorptive ability, inflammatory response, oxidative status and gene expression of juvenile Jian carp (Cyprinus carpio var. Jian in vivo and their enterocytes in vitro. The results indicated that the specific growth rate (SGR, feed intake, and feed efficiency were reduced by β-conglycinin. In addition, activities of trypsin, chymotrypsin, lipase, creatine kinase, Na(+,K(+-ATPase and alkaline phosphatase in the intestine showed similar tendencies. The protein content of the hepatopancreas and intestines, and the weight and length of the intestines were all reduced by β-conglycinin. β-Conglycinin increased lipid and protein oxidation in the detected tissues and cells. However, β-conglycinin decreased superoxide dismutase (SOD, catalase (CAT, glutathione-S-transferase (GST, glutathione peroxidase (GPx and glutathione reductase (GR activities and glutathione (GSH content in the intestine and enterocytes. Similar antioxidant activity in the hepatopancreas was observed, except for GST. The expression of target of rapamycin (TOR gene was reduced by β-conglycinin. Furthermore, mRNA levels of interleukin-8 (IL-8, tumor necrosis factor-α (TNF-α, and transforming growth factor-β (TGF-β genes were increased by β-conglycinin. However, β-conglycinin increased CuZnSOD, MnSOD, CAT, and GPx1b gene expression. In conclusion, this study indicates that β-conglycinin induces inflammation and oxidation, and causes dysfunction of intestinal digestion and absorption in fish, and finally reduces fish growth. The results of this study provide some information to the mechanism of β-conglycinin-induced negative effects.

  5. Role of Smooth Muscle in Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Stephen M Collins

    1996-01-01

    Full Text Available The notion that smooth muscle function is altered in inflammation is prompted by clinical observations of altered motility in patients with inflammatory bowel disease (IBD. While altered motility may reflect inflammation-induced changes in intrinsic or extrinsic nerves to the gut, changes in gut hormone release and changes in muscle function, recent studies have provided in vitro evidence of altered muscle contractility in muscle resected from patients with ulcerative colitis or Crohn’s disease. In addition, the observation that smooth muscle cells are more numerous and prominent in the strictured bowel of IBD patients compared with controls suggests that inflammation may alter the growth of intestinal smooth muscle. Thus, inflammation is associated with changes in smooth muscle growth and contractility that, in turn, contribute to important symptoms of IBD including diarrhea (from altered motility and pain (via either altered motility or stricture formation. The involvement of smooth muscle in this context may be as an innocent bystander, where cells and products of the inflammatory process induce alterations in muscle contractility and growth. However, it is likely that intestinal muscle cells play a more active role in the inflammatory process via the elaboration of mediators and trophic factors, including cytokines, and via the production of collagen. The concept of muscle cells as active participants in the intestinal inflammatory process is a new concept that is under intense study. This report summarizes current knowledge as it relates to these two aspects of altered muscle function (growth and contractility in the inflamed intestine, and will focus on mechanisms underlying these changes, based on data obtained from animal models of intestinal inflammation.

  6. An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse

    OpenAIRE

    Pagano, Ester; Capasso, Raffaele; Piscitelli, Fabiana; Romano, Barbara; Parisi, Olga A.; Finizio, Stefania; Lauritano, Anna; Marzo, Vincenzo Di; Izzo, Angelo A.; Borrelli, Francesca

    2016-01-01

    Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for “CBD botanical drug substance,” on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was ...

  7. TLR2/TLR4 activation induces Tregs and suppresses intestinal inflammation caused by Fusobacterium nucleatum in vivo.

    Directory of Open Access Journals (Sweden)

    Yin-Ping Jia

    Full Text Available Toll-like receptors (TLRs 2 and 4 play critical roles in intestinal inflammation caused by Fusobacterium nucleatum (F. nucleatum infection, but the role of TLR2/TLR4 in regulation of proinflammatory cytokines remains unknown. In this study, through microarray analysis and qRT-PCR, we showed that TLR2/TLR4 are involved in the F. nucleatum-induced inflammatory signaling pathway in Caco-2 cells, C57BL/6 mice and human clinical specimens. In TLR2-/- and TLR4-/- mice, F. nucleatum infection resulted in increased colonization of the bacteria and production of the proinflammatory cytokines IL-8, IL-1β and TNF-α. In addition, the ratio of Foxp3+ CD4+ T cells in the total CD4+ T cells in TLR2-/- and TLR4-/- mice was less than that in wild-type mice, and the ratio in hybrid mice was more than that in knockout mice, which suggested that TLR2/TLR4 mediated the number of Tregs. Furthermore, it was observed that inflammatory cytokine levels were reduced in TLR2-/- mice after Treg transfer. Thus, these data indicate that TLR2/TLR4 regulate F. nucleatum-induced inflammatory cytokines through Tregs in vivo.

  8. Intestinal parasites : associations with intestinal and systemic inflammation

    NARCIS (Netherlands)

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

    2018-01-01

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

  9. An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse.

    Science.gov (United States)

    Pagano, Ester; Capasso, Raffaele; Piscitelli, Fabiana; Romano, Barbara; Parisi, Olga A; Finizio, Stefania; Lauritano, Anna; Marzo, Vincenzo Di; Izzo, Angelo A; Borrelli, Francesca

    2016-01-01

    Anecdotal and scientific evidence suggests that Cannabis use may be beneficial in inflammatory bowel disease (IBD) patients. Here, we have investigated the effect of a standardized Cannabis sativa extract with high content of cannabidiol (CBD), here named CBD BDS for "CBD botanical drug substance," on mucosal inflammation and hypermotility in mouse models of intestinal inflammation. Colitis was induced in mice by intracolonic administration of dinitrobenzenesulfonic acid (DNBS). Motility was evaluated in the experimental model of intestinal hypermotility induced by irritant croton oil. CBD BDS or pure CBD were given - either intraperitoneally or by oral gavage - after the inflammatory insult (curative protocol). The amounts of CBD in the colon, brain, and liver after the oral treatments were measured by high-performance liquid chromatography coupled to ion trap-time of flight mass spectrometry. CBD BDS, both when given intraperitoneally and by oral gavage, decreased the extent of the damage (as revealed by the decrease in the colon weight/length ratio and myeloperoxidase activity) in the DNBS model of colitis. It also reduced intestinal hypermotility (at doses lower than those required to affect transit in healthy mice) in the croton oil model of intestinal hypermotility. Under the same experimental conditions, pure CBD did not ameliorate colitis while it normalized croton oil-induced hypermotility when given intraperitoneally (in a dose-related fashion) or orally (only at one dose). In conclusion, CBD BDS, given after the inflammatory insult, attenuates injury and motility in intestinal models of inflammation. These findings sustain the rationale of combining CBD with other minor Cannabis constituents and support the clinical development of CBD BDS for IBD treatment.

  10. The POZ-ZF transcription factor Kaiso (ZBTB33 induces inflammation and progenitor cell differentiation in the murine intestine.

    Directory of Open Access Journals (Sweden)

    Roopali Chaudhary

    Full Text Available Since its discovery, several studies have implicated the POZ-ZF protein Kaiso in both developmental and tumorigenic processes. However, most of the information regarding Kaiso's function to date has been gleaned from studies in Xenopus laevis embryos and mammalian cultured cells. To examine Kaiso's role in a relevant, mammalian organ-specific context, we generated and characterized a Kaiso transgenic mouse expressing a murine Kaiso transgene under the control of the intestine-specific villin promoter. Kaiso transgenic mice were viable and fertile but pathological examination of the small intestine revealed distinct morphological changes. Kaiso transgenics (Kaiso(Tg/+ exhibited a crypt expansion phenotype that was accompanied by increased differentiation of epithelial progenitor cells into secretory cell lineages; this was evidenced by increased cell populations expressing Goblet, Paneth and enteroendocrine markers. Paradoxically however, enhanced differentiation in Kaiso(Tg/+ was accompanied by reduced proliferation, a phenotype reminiscent of Notch inhibition. Indeed, expression of the Notch signalling target HES-1 was decreased in Kaiso(Tg/+ animals. Finally, our Kaiso transgenics exhibited several hallmarks of inflammation, including increased neutrophil infiltration and activation, villi fusion and crypt hyperplasia. Interestingly, the Kaiso binding partner and emerging anti-inflammatory mediator p120(ctn is recruited to the nucleus in Kaiso(Tg/+ mice intestinal cells suggesting that Kaiso may elicit inflammation by antagonizing p120(ctn function.

  11. Innate Lymphoid Cells in Intestinal Inflammation

    Science.gov (United States)

    Geremia, Alessandra; Arancibia-Cárcamo, Carolina V.

    2017-01-01

    Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine that encompasses Crohn’s disease (CD) and ulcerative colitis. The cause of IBD is unknown, but the evidence suggests that an aberrant immune response toward the commensal bacterial flora is responsible for disease in genetically susceptible individuals. Results from animal models of colitis and human studies indicate a role for innate lymphoid cells (ILC) in the pathogenesis of chronic intestinal inflammation in IBD. ILC are a population of lymphocytes that are enriched at mucosal sites, where they play a protective role against pathogens including extracellular bacteria, helminthes, and viruses. ILC lack an antigen-specific receptor, but can respond to environmental stress signals contributing to the rapid orchestration of an early immune response. Several subsets of ILC reflecting functional characteristics of T helper subsets have been described. ILC1 express the transcription factor T-bet and are characterized by secretion of IFNγ, ILC2 are GATA3+ and secrete IL5 and IL13 and ILC3 depend on expression of RORγt and secrete IL17 and IL22. However, ILC retain a degree of plasticity depending on exposure to cytokines and environmental factors. IL23 responsive ILC have been implicated in the pathogenesis of colitis in several innate murine models through the production of IL17, IFNγ, and GM-CSF. We have previously identified IL23 responsive ILC in the human intestine and found that they accumulate in the inflamed colon and small bowel of patients with CD. Other studies have confirmed accumulation of ILC in CD with increased frequencies of IFNγ-secreting ILC1 in both the intestinal lamina propria and the epithelium. Moreover, IL23 driven IL22 producing ILC have been shown to drive bacteria-induced colitis-associated cancer in mice. Interestingly, our data show increased ILC accumulation in patients with IBD and primary sclerosing cholangitis, who carry an increased risk of

  12. Innate Lymphoid Cells in Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Alessandra Geremia

    2017-10-01

    Full Text Available Inflammatory bowel disease (IBD is a chronic inflammatory disorder of the intestine that encompasses Crohn’s disease (CD and ulcerative colitis. The cause of IBD is unknown, but the evidence suggests that an aberrant immune response toward the commensal bacterial flora is responsible for disease in genetically susceptible individuals. Results from animal models of colitis and human studies indicate a role for innate lymphoid cells (ILC in the pathogenesis of chronic intestinal inflammation in IBD. ILC are a population of lymphocytes that are enriched at mucosal sites, where they play a protective role against pathogens including extracellular bacteria, helminthes, and viruses. ILC lack an antigen-specific receptor, but can respond to environmental stress signals contributing to the rapid orchestration of an early immune response. Several subsets of ILC reflecting functional characteristics of T helper subsets have been described. ILC1 express the transcription factor T-bet and are characterized by secretion of IFNγ, ILC2 are GATA3+ and secrete IL5 and IL13 and ILC3 depend on expression of RORγt and secrete IL17 and IL22. However, ILC retain a degree of plasticity depending on exposure to cytokines and environmental factors. IL23 responsive ILC have been implicated in the pathogenesis of colitis in several innate murine models through the production of IL17, IFNγ, and GM-CSF. We have previously identified IL23 responsive ILC in the human intestine and found that they accumulate in the inflamed colon and small bowel of patients with CD. Other studies have confirmed accumulation of ILC in CD with increased frequencies of IFNγ-secreting ILC1 in both the intestinal lamina propria and the epithelium. Moreover, IL23 driven IL22 producing ILC have been shown to drive bacteria-induced colitis-associated cancer in mice. Interestingly, our data show increased ILC accumulation in patients with IBD and primary sclerosing cholangitis, who carry an

  13. Functions and Signaling Pathways of Amino Acids in Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Fang He

    2018-01-01

    Full Text Available Intestine is always exposed to external environment and intestinal microorganism; thus it is more sensitive to dysfunction and dysbiosis, leading to intestinal inflammation, such as inflammatory bowel disease (IBD, irritable bowel syndrome (IBS, and diarrhea. An increasing number of studies indicate that dietary amino acids play significant roles in preventing and treating intestinal inflammation. The review aims to summarize the functions and signaling mechanisms of amino acids in intestinal inflammation. Amino acids, including essential amino acids (EAAs, conditionally essential amino acids (CEAAs, and nonessential amino acids (NEAAs, improve the functions of intestinal barrier and expressions of anti-inflammatory cytokines and tight junction proteins but decrease oxidative stress and the apoptosis of enterocytes as well as the expressions of proinflammatory cytokines in the intestinal inflammation. The functions of amino acids are associated with various signaling pathways, including mechanistic target of rapamycin (mTOR, inducible nitric oxide synthase (iNOS, calcium-sensing receptor (CaSR, nuclear factor-kappa-B (NF-κB, mitogen-activated protein kinase (MAPK, nuclear erythroid-related factor 2 (Nrf2, general controlled nonrepressed kinase 2 (GCN2, and angiotensin-converting enzyme 2 (ACE2.

  14. Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats

    Directory of Open Access Journals (Sweden)

    Wei Zhong

    2015-10-01

    Full Text Available Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation.

  15. Expression and distribution patterns of Mas-related gene receptor subtypes A-H in the mouse intestine: inflammation-induced changes.

    Science.gov (United States)

    Avula, Leela Rani; Buckinx, Roeland; Favoreel, Herman; Cox, Eric; Adriaensen, Dirk; Van Nassauw, Luc; Timmermans, Jean-Pierre

    2013-05-01

    Mas-related gene (Mrg) receptors constitute a subfamily of G protein-coupled receptors that are implicated in nociception, and are as such considered potential targets for pain therapies. Furthermore, some Mrgs have been suggested to play roles in the regulation of inflammatory responses to non-immunological activation of mast cells and in mast cell-neuron communication. Except for MrgD, E and F, whose changed expression has been revealed during inflammation in the mouse intestine in our earlier studies, information concerning the remaining cloned mouse Mrg subtypes in the gastrointestinal tract during (patho) physiological conditions is lacking. Therefore, the present study aimed at identifying the presence and putative function of these remaining cloned Mrg subtypes (n = 19) in the (inflamed) mouse intestine. Using reverse transcriptase-PCR, quantitative-PCR and multiple immunofluorescence staining with commercial and newly custom-developed antibodies, we compared the ileum and the related dorsal root ganglia (DRG) of non-inflamed mice with those of two models of intestinal inflammation, i.e., intestinal schistosomiasis and 2,4,6-trinitrobenzene sulfonic acid-induced ileitis. In the non-inflamed ileum and DRG, the majority of the Mrg subtypes examined were sparsely expressed, showing a neuron-specific expression pattern. However, significant changes in the expression patterns of multiple Mrg subtypes were observed in the inflamed ileum; for instance, MrgA4, MrgB2and MrgB8 were expressed in a clearly increased number of enteric sensory neurons and in nerve fibers in the lamina propria, while de novo expression of MrgB10 was observed in enteric sensory neurons and in newly recruited mucosal mast cells (MMCs). The MrgB10 expressing MMCs were found to be in close contact with nerve fibers in the lamina propria. This is the first report on the expression of all cloned Mrg receptor subtypes in the (inflamed) mouse intestine. The observed changes in the expression and

  16. Natural compound methyl protodioscin protects against intestinal inflammation through modulation of intestinal immune responses

    OpenAIRE

    Zhang, Rongli; Gilbert, Shila; Yao, Xinsheng; Vallance, Jefferson; Steinbrecher, Kris; Moriggl, Richard; Zhang, Dongsheng; Eluri, Madhu; Chen, Haifeng; Cao, Huiqing; Shroyer, Noah; Denson, Lee; Han, Xiaonan

    2015-01-01

    Dioscoreaceae, a kind of yam plant, has been recommended for treatment of chronic inflammatory conditions. However, the mechanisms are poorly defined. Methyl protodioscin (MPD) is one of the main bioactive components in Dioscoreaceae. Here, we aim to determine the mechanisms by which MPD ameliorates intestinal inflammation. Surgical intestinal specimens were collected from inflammatory bowel diseases (IBD) patients to perform organ culture. Experimental colitis was induced in mice by dextran ...

  17. Macrophages in intestinal homeostasis and inflammation

    Science.gov (United States)

    Bain, Calum C; Mowat, Allan McI

    2014-01-01

    The intestine contains the largest pool of macrophages in the body which are essential for maintaining mucosal homeostasis in the face of the microbiota and the constant need for epithelial renewal but are also important components of protective immunity and are involved in the pathology of inflammatory bowel disease (IBD). However, defining the biological roles of intestinal macrophages has been impeded by problems in defining the phenotype and origins of different populations of myeloid cells in the mucosa. Here, we discuss how multiple parameters can be used in combination to discriminate between functionally distinct myeloid cells and discuss the roles of macrophages during homeostasis and how these may change when inflammation ensues. We also discuss the evidence that intestinal macrophages do not fit the current paradigm that tissue-resident macrophages are derived from embryonic precursors that self-renew in situ, but require constant replenishment by blood monocytes. We describe our recent work demonstrating that classical monocytes constantly enter the intestinal mucosa and how the environment dictates their subsequent fate. We believe that understanding the factors that drive intestinal macrophage development in the steady state and how these may change in response to pathogens or inflammation could provide important insights into the treatment of IBD. PMID:24942685

  18. Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance.

    Directory of Open Access Journals (Sweden)

    Raul Ramos Furtado Dias

    Full Text Available Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS or resistance (TR to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis.

  19. Toxoplasma gondii Oral Infection Induces Intestinal Inflammation and Retinochoroiditis in Mice Genetically Selected for Immune Oral Tolerance Resistance

    Science.gov (United States)

    Dias, Raul Ramos Furtado; de Carvalho, Eulógio Carlos Queiroz; Leite, Carla Cristina da Silva; Tedesco, Roberto Carlos; Calabrese, Katia da Silva; Silva, Antonio Carlos; DaMatta, Renato Augusto; de Fatima Sarro-Silva, Maria

    2014-01-01

    Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS) or resistance (TR) to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis. PMID:25437299

  20. In vitro activated CD4+ T cells from interferon-gamma (IFN-gamma)-deficient mice induce intestinal inflammation in immunodeficient hosts

    DEFF Research Database (Denmark)

    Bregenholt, S; Brimnes, J; Nissen, Mogens Holst

    1999-01-01

    To investigate the role of IFN-gamma in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4+ T cells from either wild-type (WT) or IFN-gamma-deficient (IFN-gammaKO) BALB/c mice. In vitro, the two types...... of T cells displayed comparable proliferation rates and production of tumour necrosis factor-alpha (TNF-alpha), IL-2, IL-4 and IL-10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4+ blasts induced a lethal IBD, whereas IFN-gammaKO blasts induced a less severe...... intestinal inflammation with moderate weight loss. Intracellular cytokine staining of lamina propria lymphocytes (LPL) revealed comparable fractions of CD4+ T cells positive for TNF-alpha, IL-2 and IL-10 in the two groups of transplanted SCID mice, whereas a two-to-three-fold increase in the fraction of IL-4...

  1. Giardia duodenalis infection reduces granulocyte infiltration in an in vivo model of bacterial toxin-induced colitis and attenuates inflammation in human intestinal tissue.

    Directory of Open Access Journals (Sweden)

    James A Cotton

    Full Text Available Giardia duodenalis (syn. G. intestinalis, G. lamblia is a predominant cause of waterborne diarrheal disease that may lead to post-infectious functional gastrointestinal disorders. Although Giardia-infected individuals could carry as much as 106 trophozoites per centimetre of gut, their intestinal mucosa is devoid of overt signs of inflammation. Recent studies have shown that in endemic countries where bacterial infectious diseases are common, Giardia infections can protect against the development of diarrheal disease and fever. Conversely, separate observations have indicated Giardia infections may enhance the severity of diarrheal disease from a co-infecting pathogen. Polymorphonuclear leukocytes or neutrophils (PMNs are granulocytic, innate immune cells characteristic of acute intestinal inflammatory responses against bacterial pathogens that contribute to the development of diarrheal disease following recruitment into intestinal tissues. Giardia cathepsin B cysteine proteases have been shown to attenuate PMN chemotaxis towards IL-8/CXCL8, suggesting Giardia targets PMN accumulation. However, the ability of Giardia infections to attenuate PMN accumulation in vivo and how in turn this effect may alter the host inflammatory response in the intestine has yet to be demonstrated. Herein, we report that Giardia infection attenuates granulocyte tissue infiltration induced by intra-rectal instillation of Clostridium difficile toxin A and B in an isolate-dependent manner. This attenuation of granulocyte infiltration into colonic tissues paralled decreased expression of several cytokines associated with the recruitment of PMNs. Giardia trophozoite isolates that attenuated granulocyte infiltration in vivo also decreased protein expression of cytokines released from inflamed mucosal biopsy tissues collected from patients with active Crohn's disease, including several cytokines associated with PMN recruitment. These results demonstrate for the first time

  2. Treatment with Saccharomyces boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in 5-fluorouracil-induced intestinal mucositis in mice.

    Science.gov (United States)

    Justino, Priscilla F C; Melo, Luis F M; Nogueira, Andre F; Costa, Jose V G; Silva, Luara M N; Santos, Cecila M; Mendes, Walber O; Costa, Marina R; Franco, Alvaro X; Lima, Aldo A; Ribeiro, Ronaldo A; Souza, Marcellus H L P; Soares, Pedro M G

    2014-05-01

    (control 25·21 (SEM 2·55) %, 5-FU 54·91 (SEM 3·43) % and 5-FU+S. boulardii 31·38 (SEM 2·80) %) and induced the recovery of intestinal permeability (lactulose:mannitol ratio: control 0·52 (SEM 0·03), 5-FU 1·38 (SEM 0·24) and 5-FU+S. boulardii 0·62 (SEM 0·03)). In conclusion, S. boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in intestinal mucositis induced by 5-FU.

  3. Intestinal Hedgehog signaling in tumors and inflammation

    NARCIS (Netherlands)

    Büller, N.V.J.A.

    2015-01-01

    In this thesis we investigated the role of Hedgehog signaling in tumors and inflammation. By using an inducible Indian Hedgehog (Ihh) knockout mouse we show that Ihh signals via the mesenchyme to the proliferating cells in the crypt to attenuate proliferation. Despite its anti-proliferative role in

  4. Homing of immune cells: role in homeostasis and intestinal inflammation.

    Science.gov (United States)

    Hart, Ailsa L; Ng, Siew C; Mann, Elizabeth; Al-Hassi, Hafid Omar; Bernardo, David; Knight, Stella C

    2010-11-01

    Rather like a satellite navigation system directing a vehicle to a particular destination defined by post-code, immune cells have homing molecules or "immune post-codes" enabling them to be recruited to specific organs, such as the intestine or skin. An efficient system would be designed such that the site of entry of an antigen influences the homing of effector T cells back to the appropriate organ. For example, to mount an immune response against an intestinal pathogen, T cells with a propensity to home to the gut to clear the infection would be induced. In health, there is such a sophisticated and finely tuned system in operation, enabling an appropriate balance of immune activity in different anatomical compartments. In disease states such as inflammatory bowel disease (IBD), which is characterized by intestinal inflammation and often an inflammatory process involving other organs such as skin, joints, liver, and eye, there is accumulating evidence that there is malfunction of this immune cell trafficking system. The clinical importance of dysregulated immune cell trafficking in IBD is reflected in recently proven efficacious therapies that target trafficking pathways such as natalizumab, an α4 integrin antibody, and Traficet-EN, a chemokine receptor-9 (CCR9) antagonist. Here we review the mechanisms involved in the homing of immune cells to different tissues, in particular the intestine, and focus on alterations in immune cell homing pathways in IBD. Unraveling the mechanisms underlying the immune post-code system would assist in achieving the goal of tissue-specific immunotherapy.

  5. Bovine lactoferrin regulates cell survival, apoptosis and inflammation in intestinal epithelial cells and preterm pig intestine.

    Science.gov (United States)

    Nguyen, Duc Ninh; Jiang, Pingping; Stensballe, Allan; Bendixen, Emøke; Sangild, Per T; Chatterton, Dereck E W

    2016-04-29

    Bovine lactoferrin (bLF) may modulate neonatal intestinal inflammation. Previous studies in intestinal epithelial cells (IECs) indicated that moderate bLF doses enhance proliferation whereas high doses trigger inflammation. To further elucidate cellular mechanisms, we profiled the porcine IEC proteome after stimulation with bLF at 0, 0.1, 1 and 10g/L by LC-MS-based proteomics. Key pathways were analyzed in the intestine of formula-fed preterm pigs with and without supplementation of 10g/L bLF. Levels of 123 IEC proteins were altered by bLF. Low bLF doses (0.1-1g/L) up-regulated 11 proteins associated with glycolysis, energy metabolism and protein synthesis, indicating support of cell survival. In contrast, a high bLF dose (10g/L) up-regulated three apoptosis-inducing proteins, down-regulated five anti-apoptotic and proliferation-inducing proteins and 15 proteins related to energy and amino acid metabolism, and altered three proteins enhancing the hypoxia inducible factor-1 (HIF-1) pathway. In the preterm pig intestine, bLF at 10g/L decreased villus height/crypt depth ratio and up-regulated the Bax/Bcl-2 ratio and HIF-1α, indicating elevated intestinal apoptosis and inflammation. In conclusion, bLF dose-dependently affects IECs via metabolic, apoptotic and inflammatory pathways. It is important to select an appropriate dose when feeding neonates with bLF to avoid detrimental effects exerted by excessive doses. The present work elucidates dose-dependent effects of bLF on the proteomic changes of IECs in vitro supplemented with data from a preterm pig study confirming detrimental effects of enteral feeding with the highest dose of bLF (10g/L). The study contributes to further understanding on mechanisms that bLF, as an important milk protein, can regulate the homeostasis of the immature intestine. Results from this study urge neonatologists to carefully consider the dose of bLF to supplement into infant formula used for preterm neonates. Copyright © 2016 Elsevier B

  6. Muscadine Grape (Vitis rotundifolia) or Wine Phytochemicals Reduce Intestinal Inflammation in Mice with Dextran Sulfate Sodium-Induced Colitis.

    Science.gov (United States)

    Li, Ruiqi; Kim, Min-Hyun; Sandhu, Amandeep K; Gao, Chi; Gu, Liwei

    2017-02-01

    The objective of this study was to determine the anti-inflammatory effects of phytochemical extracts from muscadine grapes or wine on dextran sulfate sodium (DSS)-induced colitis in mice and to investigate cellular mechanisms. Two groups of C57BL/6J mice were gavaged with muscadine grape phytochemicals (MGP) or muscadine wine phytochemicals (MWP), respectively, for 14 days. Acute colitis was induced by 3% DSS in drinking water for 7 days. An additional two groups of mice served as healthy and disease controls. Results indicated that MGP or MWP significantly prevented weight loss, reduced disease activity index, and preserved colonic length compared to the colitis group (p ≤ 0.05). MGP or MWP significantly decreased myeloperoxidase activity as well as the levels of IL-1β, IL-6, and TNF-α in colon (p ≤ 0.05). MGP or MWP caused down-regulation of the NF-κB pathway by inhibiting the phosphorylation and degradation of IκB in a dose-dependent manner. These findings suggest that phytochemicals from muscadine grape or wine mitigate ulcerative colitis via attenuation of pro-inflammatory cytokine production and modulation of the NF-κB pathway.

  7. Fecal markers of intestinal inflammation and intestinal permeability are elevated in Parkinson's disease.

    Science.gov (United States)

    Schwiertz, Andreas; Spiegel, Jörg; Dillmann, Ulrich; Grundmann, David; Bürmann, Jan; Faßbender, Klaus; Schäfer, Karl-Herbert; Unger, Marcus M

    2018-02-12

    Intestinal inflammation and increased intestinal permeability (both possibly fueled by dysbiosis) have been suggested to be implicated in the multifactorial pathogenesis of Parkinson's disease (PD). The objective of the current study was to investigate whether fecal markers of inflammation and impaired intestinal barrier function corroborate this pathogenic aspect of PD. In a case-control study, we quantitatively analyzed established fecal markers of intestinal inflammation (calprotectin and lactoferrin) and fecal markers of intestinal permeability (alpha-1-antitrypsin and zonulin) in PD patients (n = 34) and controls (n = 28, group-matched for age) by enzyme-linked immunosorbent assay. The study design controlled for potential confounding factors. Calprotectin, a fecal marker of intestinal inflammation, and two fecal markers of increased intestinal permeability (alpha-1-antitrypsin and zonulin) were significantly elevated in PD patients compared to age-matched controls. Lactoferrin, as a second fecal marker of intestinal inflammation, showed a non-significant trend towards elevated concentrations in PD patients. None of the four fecal markers correlated with disease severity, PD subtype, dopaminergic therapy, or presence of constipation. Fecal markers reflecting intestinal inflammation and increased intestinal permeability have been primarily investigated in inflammatory bowel disease so far. Our data indicate that calprotectin, alpha-1-antitrypsin and zonulin could be useful non-invasive markers in PD as well. Even though these markers are not disease-specific, they corroborate the hypothesis of an intestinal inflammation as contributing factor in the pathogenesis of PD. Further investigations are needed to determine whether calprotectin, alpha-1-antitrypsin and zonulin can be used to define PD subgroups and to monitor the effect of interventions in PD. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Opposite effect of oxidative stress on inducible nitric oxide synthase and haem oxygenase-1 expression in intestinal inflammation: anti-inflammatory effect of carbon monoxide

    NARCIS (Netherlands)

    Dijkstra, Gerard; Blokzijl, Hans; Bok, Lisette; Homan, Manon; van Goor, Harry; Faber, Klaas Nico; Jansen, Peter L. M.; Moshage, Han

    2004-01-01

    Inducible nitric oxide synthase (iNOS) is expressed in intestinal epithelial cells (IEC) of patients with active inflammatory bowel disease (IBD) and in IEC of endotoxaemic rats. The induction of iNOS in IEC is an element of the NF-kappaB-mediated survival pathway. Haem oxygenase-1 (HO-1) is an

  9. The role of CDX2 in intestinal homeostasis and inflammation

    DEFF Research Database (Denmark)

    Coskun, Mehmet; Troelsen, Jesper Thorvald; Nielsen, Ole Haagen

    2011-01-01

    a causal role in a large number of diseases and developmental disorders. Inflammatory bowel disease (IBD) is characterized by a chronically inflamed mucosa caused by dysregulation of the intestinal immune homeostasis. The aetiology of IBD is thought to be a combination of genetic and environmental factors......, including luminal bacteria. The Caudal-related homeobox transcription factor 2 (CDX2) is critical in early intestinal differentiation and has been implicated as a master regulator of the intestinal homeostasis and permeability in adults. When expressed, CDX2 modulates a diverse set of processes including...... of the intestinal homeostasis and further to reveal its potential role in inflammation....

  10. Zinc treatment ameliorates diarrhea and intestinal inflammation in undernourished rats.

    Science.gov (United States)

    de Queiroz, Camila A A; Fonseca, Said Gonçalves C; Frota, Priscila B; Figueiredo, Italo L; Aragão, Karoline S; Magalhães, Carlos Emanuel C; de Carvalho, Cibele B M; Lima, Aldo Ângelo M; Ribeiro, Ronaldo A; Guerrant, Richard L; Moore, Sean R; Oriá, Reinaldo B

    2014-08-05

    WHO guidelines recommend zinc supplementation as a key adjunct therapy for childhood diarrhea in developing countries, however zinc's anti-diarrheal effects remain only partially understood. Recently, it has been recognized that low-grade inflammation may influence stunting. In this study, we examined whether oral zinc supplementation could improve weight, intestinal inflammation, and diarrhea in undernourished weanling rats. Rats were undernourished using a northeastern Brazil regional diet (RBD) for two weeks, followed by oral gavage with a saturated lactose solution (30 g/kg) in the last 7 days to induce osmotic diarrhea. Animals were checked for diarrhea daily after lactose intake. Blood was drawn in order to measure serum zinc levels by atomic absorption spectroscopy. Rats were euthanized to harvest jejunal tissue for histology and cytokine profiles by ELISA. In a subset of animals, spleen samples were harvested under aseptic conditions to quantify bacterial translocation. Oral zinc supplementation increased serum zinc levels following lactose-induced osmotic diarrhea. In undernourished rats, zinc improved weight gain following osmotic diarrhea and significantly reduced diarrheal scores by the third day of lactose intake (p diarrhea and undernutrition and support the use of zinc to prevent the vicious cycle of malnutrition and diarrhea.

  11. JAK/STAT-1 Signaling Is Required for Reserve Intestinal Stem Cell Activation during Intestinal Regeneration Following Acute Inflammation

    Directory of Open Access Journals (Sweden)

    Camilla A. Richmond

    2018-01-01

    Full Text Available The intestinal epithelium serves as an essential barrier to the outside world and is maintained by functionally distinct populations of rapidly cycling intestinal stem cells (CBC ISCs and slowly cycling, reserve ISCs (r-ISCs. Because disruptions in the epithelial barrier can result from pathological activation of the immune system, we sought to investigate the impact of inflammation on ISC behavior during the regenerative response. In a murine model of αCD3 antibody-induced small-intestinal inflammation, r-ISCs proved highly resistant to injury, while CBC ISCs underwent apoptosis. Moreover, r-ISCs were induced to proliferate and functionally contribute to intestinal regeneration. Further analysis revealed that the inflammatory cytokines interferon gamma and tumor necrosis factor alpha led to r-ISC activation in enteroid culture, which could be blocked by the JAK/STAT inhibitor, tofacitinib. These results highlight an important role for r-ISCs in response to acute intestinal inflammation and show that JAK/STAT-1 signaling is required for the r-ISC regenerative response.

  12. Inflammasome in Intestinal Inflammation and Cancer

    Directory of Open Access Journals (Sweden)

    Tiago Nunes

    2013-01-01

    Full Text Available The activation of specific cytosolic pathogen recognition receptors, the nucleotide-binding-oligomerization-domain- (NOD- like receptors (NLRs, leads to the assembly of the inflammasome, a multimeric complex platform that activates caspase-1. The caspase-1 pathway leads to the upregulation of important cytokines from the interleukin (IL-1 family, IL-1β, and IL-18, with subsequent activation of the innate immune response. In this review, we discuss the molecular structure, the mechanisms behind the inflammasome activation, and its possible role in the pathogenesis of inflammatory bowel diseases and intestinal cancer. Here, we show that the available data points towards the importance of the inflammasome in the innate intestinal immune response, being the complex involved in the maintenance of intestinal homeostasis, correct intestinal barrier function and efficient elimination of invading pathogens.

  13. Determination of Intestine Inflammation Markers in Diagnostic Search in Children with Intestinal Diseases

    Directory of Open Access Journals (Sweden)

    N.V. Pavlenko

    2016-08-01

    Full Text Available Introduction. Prevalence of bowel diseases in children is the second, trailing only the diseases of gastroduodenal zone and growing in recent years. Actual one is the problem of differential diagnosis of functional and inflammatory intestinal diseases using non-invasive methods on the prehospital stage and as a screening. Objective. Comparative analysis of fecal markers of the bowel inflammation (lactoferrine and calprotectine with endoscopy and morphology of intestinal mucosa in children. Matherials and methods. 49 children aged 6–18 years were examined. All patients underwent endoscopic and morphological study of the intestine, coprotest, determination of fecal markers of bowel inflammation (lactoferrin and calprotectine. Results. It is shown that in young children, the intestinal mucosa mainly hadn’t endoscopic changes, coprotest and morphological examination didn’t reveal the signs of inflammation, fecal intestinal inflammation markers were negative (p < 0.05. In the group of older children, moderate or marked catarrhal changes were found endoscopically, coprotest results were typical of inflammation in the intestines, it was morphologically proved the presence of chronic inflammation of the mucous membrane of the colon with signs of atrophy, the results of lactoferrin and calprotectine determination were positive (p < 0.05. Conclusion. The findings suggest that the evaluation of calprotectine and lactoferrin can be used in pediatric patients because of its non-invasiveness as diagnostic screening for the selection of patients for the further endoscopic examination and diagnostic search.

  14. Epithelial Cell Inflammasomes in Intestinal Immunity and Inflammation

    Directory of Open Access Journals (Sweden)

    Andrea C. Lei-Leston

    2017-09-01

    Full Text Available Pattern recognition receptors (PRR, such as NOD-like receptors (NLRs, sense conserved microbial signatures, and host danger signals leading to the coordination of appropriate immune responses. Upon activation, a subset of NLR initiate the assembly of a multimeric protein complex known as the inflammasome, which processes pro-inflammatory cytokines and mediates a specialized form of cell death known as pyroptosis. The identification of inflammasome-associated genes as inflammatory bowel disease susceptibility genes implicates a role for the inflammasome in intestinal inflammation. Despite the fact that the functional importance of inflammasomes within immune cells has been well established, the contribution of inflammasome expression in non-hematopoietic cells remains comparatively understudied. Given that intestinal epithelial cells (IEC act as a barrier between the host and the intestinal microbiota, inflammasome expression by these cells is likely important for intestinal immune homeostasis. Accumulating evidence suggests that the inflammasome plays a key role in shaping epithelial responses at the host–lumen interface with many inflammasome components highly expressed by IEC. Recent studies have exposed functional roles of IEC inflammasomes in mucosal immune defense, inflammation, and tumorigenesis. In this review, we present the main features of the predominant inflammasomes and their effector mechanisms contributing to intestinal homeostasis and inflammation. We also discuss existing controversies in the field and open questions related to their implications in disease. A comprehensive understanding of the molecular basis of intestinal inflammasome signaling could hold therapeutic potential for clinical translation.

  15. Intestinal inflammation in TNBS sensitized rats as a model of chronic inflammatory bowel disease

    Directory of Open Access Journals (Sweden)

    N. Selve

    1992-01-01

    Full Text Available An enteritis, based on a delayed-type hypersensitivity reaction, was induced in TNBS (2,4,4-trinitrobenzenesulphonic acid sensitized rats by multiple intrajejunal challenge with TNBS via an implanted catheter. This treatment induced chronic inflammation of the distal small intestine characterized by intense hyperaemia, oedema and gut wall thickening as assessed by macroscopic scoring and weighing a defined part of the dissected intestine. Histologically, the inflammatory response included mucosal and submucosal cell infiltration by lymphocytes and histiocytes, transmural granulomatous inflammation with multinucleated cells and activated mesenteric lymph nodes. Ex vivo stimulated release of the inflammatory mediator LTB4 in the dissected part of the intestine was increased following TNBS treatment. Drug treatment with sulphasalazine or 5-aminosalicylic acid improved the enteritis score and attenuated TNBS induced oedema formation and LTB4 production. The applicability and relevance of this new model are discussed with respect to drug development and basic research of inflammatory bowel diseases.

  16. Zinc treatment ameliorates diarrhea and intestinal inflammation in undernourished rats

    OpenAIRE

    de Queiroz, Camila AA; Fonseca, Said Gonçalves C; Frota, Priscila B; Figueiredo, Ítalo L; Aragão, Karoline S; Magalhães, Carlos Emanuel C; de Carvalho, Cibele BM; Lima, Aldo Ângelo M; Ribeiro, Ronaldo A; Guerrant, Richard L; Moore, Sean R; Oriá, Reinaldo B

    2014-01-01

    Background WHO guidelines recommend zinc supplementation as a key adjunct therapy for childhood diarrhea in developing countries, however zinc’s anti-diarrheal effects remain only partially understood. Recently, it has been recognized that low-grade inflammation may influence stunting. In this study, we examined whether oral zinc supplementation could improve weight, intestinal inflammation, and diarrhea in undernourished weanling rats. Methods Rats were undernourished using a northeastern Br...

  17. Protein hydrolysate from canned sardine and brewing by-products improves TNF-α-induced inflammation in an intestinal-endothelial co-culture cell model.

    Science.gov (United States)

    Vieira, Elsa F; Van Camp, John; Ferreira, Isabel M P L V O; Grootaert, Charlotte

    2017-07-17

    The anti-inflammatory activity of sardine protein hydrolysates (SPH) obtained by hydrolysis with proteases from brewing yeast surplus was ascertained. For this purpose, a digested and desalted SPH fraction with molecular weight lower than 10 kDa was investigated using an endothelial cell line (EA.hy926) as such and in a co-culture model with an intestinal cell line (Caco-2). Effects of SPH <10 kDa on nitric oxide (NO) production, reactive oxygen species (ROS) inhibition and secretion of monocyte chemoattractant protein 1 (MCP-1), vascular endothelial growth factor (VEGF), chemokine IL-8 (IL-8) and intercellular adhesion molecule-1 (ICAM-1) were evaluated in TNF-α-treated and untreated cells. Upon TNF-α treatment, levels of NO, MCP-1, VEGF, IL-8, ICAM-1 and endothelial ROS were significantly increased in both mono- and co-culture models. Treatment with SPH <10 kDa (2.0 mg peptides/mL) significantly decreased all the inflammation markers when compared to TNF-α-treated control. This protective effect was more pronounced in the co-culture model, suggesting that SPH <10 kDa Caco-2 cells metabolites produced in the course of intestinal absorption may provide a more relevant protective effect against endothelial dysfunction. Additionally, indirect cross-talk between two cell types was established, suggesting that SPH <10 kDa may also bind to receptors on the Caco-2 cells, thereby triggering a pathway to secrete the pro-inflammatory compounds. Overall, these in vitro screening results, in which intestinal digestion, absorption and endothelial bioactivity are simulated, show the potential of SPH to be used as a functional food with anti-inflammatory properties.

  18. Human-derived probiotic Lactobacillus reuteri strains differentially reduce intestinal inflammation.

    Science.gov (United States)

    Liu, Yuying; Fatheree, Nicole Y; Mangalat, Nisha; Rhoads, Jon Marc

    2010-11-01

    Lactobacillus reuteri (L. reuteri) is a probiotic that inhibits the severity of enteric infections and modulates the immune system. Human-derived L. reuteri strains DSM17938, ATCC PTA4659, ATCC PTA 5289, and ATCC PTA 6475 have demonstrated strain-specific immunomodulation in cultured monocytoid cells, but information about how these strains affect inflammation in intestinal epithelium is limited. We determined the effects of the four different L. reuteri strains on lipopolysaccharide (LPS)-induced inflammation in small intestinal epithelial cells and in the ileum of newborn rats. IPEC-J2 cells (derived from the jejunal epithelium of a neonatal piglet) and IEC-6 cells (derived from the rat crypt) were treated with L. reuteri. Newborn rat pups were gavaged cow milk formula supplemented with L. reuteri strains in the presence or absence of LPS. Protein and mRNA levels of cytokines and histological changes were measured. We demonstrate that even though one L. reuteri strain (DSM 17938) did not inhibit LPS-induced IL-8 production in cultured intestinal cells, all strains significantly reduced intestinal mucosal levels of KC/GRO (∼IL-8) and IFN-γ when newborn rat pups were fed formula containing LPS ± L. reuteri. Intestinal histological damage produced by LPS plus cow milk formula was also significantly reduced by all four strains. Cow milk formula feeding (without LPS) produced mild gut inflammation, evidenced by elevated mucosal IFN-γ and IL-13 levels, a process that could be suppressed by strain 17938. Other cytokines and chemokines were variably affected by the different strains, and there was no toxic effect of L. reuteri on intestinal cells or mucosa. In conclusion, L. reuteri strains differentially modulate LPS-induced inflammation. Probiotic interactions with both epithelial and nonepithelial cells in vivo must be instrumental in modulating intrinsic anti-inflammatory effects in the intestine. We suggest that the terms anti- and proinflammatory be used only

  19. Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation.

    Directory of Open Access Journals (Sweden)

    Xinhua Chen

    Full Text Available Saccharomyces boulardii (Sb can protect against intestinal injury and tumor formation, but how this probiotic yeast controls protective mucosal host responses is unclear. Angiogenesis is an integral process of inflammatory responses in inflammatory bowel diseases (IBD and required for mucosal remodeling during restitution. The aim of this study was to determine whether Sb alters VEGFR (vascular endothelial growth factor receptor signaling, a central regulator of angiogenesis.HUVEC were used to examine the effects of Sb on signaling and on capillary tube formation (using the ECMatrix™ system. The effects of Sb on VEGF-mediated angiogenesis were examined in vivo using an adenovirus expressing VEGF-A(164 in the ears of adult nude mice (NuNu. The effects of Sb on blood vessel volume branching and density in DSS-induced colitis was quantified using VESsel GENeration (VESGEN software.1 Sb treatment attenuated weight-loss (p<0.01 and histological damage (p<0.01 in DSS colitis. VESGEN analysis of angiogenesis showed significantly increased blood vessel density and volume in DSS-treated mice compared to control. Sb treatment significantly reduced the neo-vascularization associated with acute DSS colitis and accelerated mucosal recovery restoration of the lamina propria capillary network to a normal morphology. 2 Sb inhibited VEGF-induced angiogenesis in vivo in the mouse ear model. 3 Sb also significantly inhibited angiogenesis in vitro in the capillary tube assay in a dose-dependent manner (p<0.01. 4 In HUVEC, Sb reduced basal VEGFR-2 phosphorylation, VEGFR-2 phosphorylation in response to VEGF as well as activation of the downstream kinases PLCγ and Erk1/2.Our findings indicate that the probiotic yeast S boulardii can modulate angiogenesis to limit intestinal inflammation and promote mucosal tissue repair by regulating VEGFR signaling.

  20. Lymphatic deletion of calcitonin receptor–like receptor exacerbates intestinal inflammation

    Science.gov (United States)

    Davis, Reema B.; Kechele, Daniel O.; Blakeney, Elizabeth S.; Pawlak, John B.

    2017-01-01

    Lymphatics play a critical role in maintaining gastrointestinal homeostasis and in the absorption of dietary lipids, yet their roles in intestinal inflammation remain elusive. Given the increasing prevalence of inflammatory bowel disease, we investigated whether lymphatic vessels contribute to, or may be causative of, disease progression. We generated a mouse model with temporal and spatial deletion of the key lymphangiogenic receptor for the adrenomedullin peptide, calcitonin receptor–like receptor (Calcrl), and found that the loss of lymphatic Calcrl was sufficient to induce intestinal lymphangiectasia, characterized by dilated lacteals and protein-losing enteropathy. Upon indomethacin challenge, Calcrlfl/fl/Prox1-CreERT2 mice demonstrated persistent inflammation and failure to recover and thrive. The epithelium and crypts of Calcrlfl/fl/Prox1-CreERT2 mice exhibited exacerbated hallmarks of disease progression, and the lacteals demonstrated an inability to absorb lipids. Furthermore, we identified Calcrl/adrenomedullin signaling as an essential upstream regulator of the Notch pathway, previously shown to be critical for intestinal lacteal maintenance and junctional integrity. In conclusion, lymphatic insufficiency and lymphangiectasia caused by loss of lymphatic Calcrl exacerbates intestinal recovery following mucosal injury and underscores the importance of lymphatic function in promoting recovery from intestinal inflammation. PMID:28352669

  1. Fecal lipocalin 2, a sensitive and broadly dynamic non-invasive biomarker for intestinal inflammation.

    Science.gov (United States)

    Chassaing, Benoit; Srinivasan, Gayathri; Delgado, Maria A; Young, Andrew N; Gewirtz, Andrew T; Vijay-Kumar, Matam

    2012-01-01

    Inflammation has classically been defined histopathologically, especially by the presence of immune cell infiltrates. However, more recent studies suggest a role for "low-grade" inflammation in a variety of disorders ranging from metabolic syndrome to cancer, which is defined by modest elevations in pro-inflammatory gene expression. Consequently, there is a need for cost-effective, non-invasive biomarkers that, ideally, would have the sensitivity to detect low-grade inflammation and have a dynamic range broad enough to reflect classic robust intestinal inflammation. Herein, we report that, for assessment of intestinal inflammation, fecal lipocalin 2 (Lcn-2), measured by ELISA, serves this purpose. Specifically, using a well-characterized mouse model of DSS colitis, we observed that fecal Lcn-2 and intestinal expression of pro-inflammatory cytokines (IL-1β, CXCL1, TNFα) are modestly but significantly induced by very low concentrations of DSS (0.25 and 0.5%), and become markedly elevated at higher concentrations of DSS (1.0 and 4.0%). As expected, careful histopathologic analysis noted only modest immune infiltrates at low DSS concentration and robust colitis at higher DSS concentrations. In accordance, increased levels of the neutrophil product myeloperoxidase (MPO) was only detected in mice given 1.0 and 4.0% DSS. In addition, fecal Lcn-2 marks the severity of spontaneous colitis development in IL-10 deficient mice. Unlike histopathology, MPO, and q-RT-PCR, the assay of fecal Lcn-2 requires only a stool sample, permits measurement over time, and can detect inflammation as early as 1 day following DSS administration. Thus, assay of fecal Lcn-2 by ELISA can function as a non-invasive, sensitive, dynamic, stable and cost-effective means to monitor intestinal inflammation in mice.

  2. [Saccharomyces boulardii reduced intestinal inflammation in mice model of 2,4,6-trinitrobencene sulfonic acid induced colitis: based on microarray].

    Science.gov (United States)

    Lee, Sang Kil; Kim, Hyo Jong; Chi, Sung Gil

    2010-01-01

    Saccharomyces boulardii has been reported to be beneficial in the treatment of inflammatory bowel disease. The aim of this work was to evaluate the effect of S. boulardii in a mice model of 2,4,6-trinitrobencene sulfonic acid (TNBS) induced colitis and analyze the expression of genes in S. boulardii treated mice by microarray. BALB/c mice received TNBS or TNBS and S. boulardii treatment for 4 days. Microarray was performed on total mRNA form colon, and histologic evaluation was also performed. In mice treated with S. boulardii, the histological appearance and mortality rate were significantly restored compared with rats receiving only TNBS. Among 330 genes which were altered by both S. boulardii and TNBS (>2 folds), 193 genes were down-regulated by S. boulardii in microarray. Most of genes which were down-regulated by S. bouardii were functionally classified as inflammatory and immune response related genes. S. boulardii may reduce colonic inflammation along with regulation of inflammatory and immune responsive genes in TNBS-induced colitis.

  3. Lychee (Litchi chinensis Sonn.) Pulp Phenolic Extract Provides Protection against Alcoholic Liver Injury in Mice by Alleviating Intestinal Microbiota Dysbiosis, Intestinal Barrier Dysfunction, and Liver Inflammation.

    Science.gov (United States)

    Xiao, Juan; Zhang, Ruifen; Zhou, Qiuyun; Liu, Lei; Huang, Fei; Deng, Yuanyuan; Ma, Yongxuan; Wei, Zhencheng; Tang, Xiaojun; Zhang, Mingwei

    2017-11-08

    Liver injury is the most common consequence of alcohol abuse, which is promoted by the inflammatory response triggered by gut-derived endotoxins produced as a consequence of intestinal microbiota dysbiosis and barrier dysfunction. The aim of this study was to investigate whether modulation of intestinal microbiota and barrier function, and liver inflammation contributes to the hepatoprotective effect of lychee pulp phenolic extract (LPPE) in alcohol-fed mice. Mice were treated with an ethanol-containing liquid diet alone or in combination with LPPE for 8 weeks. LPPE supplementation alleviated ethanol-induced liver injury and downregulated key markers of inflammation. Moreover, LPPE supplementation reversed the ethanol-induced alteration of intestinal microbiota composition and increased the expression of intestinal tight junction proteins, mucus protecting proteins, and antimicrobial proteins. Furthermore, in addition to decreasing serum endotoxin level, LPPE supplementation suppressed CD14 and toll-like receptor 4 expression, and repressed the activation of nuclear factor-κB p65 in the liver. These data suggest that intestinal microbiota dysbiosis, intestinal barrier dysfunction, and liver inflammation are improved by LPPE, and therefore, the intake of LPPE or Litchi pulp may be an effective strategy to alleviate the susceptibility to alcohol-induced hepatic diseases.

  4. Kaiso overexpression promotes intestinal inflammation and potentiates intestinal tumorigenesis in Apc(Min/+) mice.

    Science.gov (United States)

    Pierre, Christina C; Longo, Joseph; Mavor, Meaghan; Milosavljevic, Snezana B; Chaudhary, Roopali; Gilbreath, Ebony; Yates, Clayton; Daniel, Juliet M

    2015-09-01

    Constitutive Wnt/β-catenin signaling is a key contributor to colorectal cancer (CRC). Although inactivation of the tumor suppressor adenomatous polyposis coli (APC) is recognized as an early event in CRC development, it is the accumulation of multiple subsequent oncogenic insults facilitates malignant transformation. One potential contributor to colorectal carcinogenesis is the POZ-ZF transcription factor Kaiso, whose depletion extends lifespan and delays polyp onset in the widely used Apc(Min/+) mouse model of intestinal cancer. These findings suggested that Kaiso potentiates intestinal tumorigenesis, but this was paradoxical as Kaiso was previously implicated as a negative regulator of Wnt/β-catenin signaling. To resolve Kaiso's role in intestinal tumorigenesis and canonical Wnt signaling, we generated a transgenic mouse model (Kaiso(Tg/+)) expressing an intestinal-specific myc-tagged Kaiso transgene. We then mated Kaiso(Tg/+) and Apc(Min/+) mice to generate Kaiso(Tg/+):Apc(Min/+) mice for further characterization. Kaiso(Tg/+):Apc(Min/+) mice exhibited reduced lifespan and increased polyp multiplicity compared to Apc(Min/+) mice. Consistent with this murine phenotype, we found increased Kaiso expression in human CRC tissue, supporting a role for Kaiso in human CRC. Interestingly, Wnt target gene expression was increased in Kaiso(Tg/+):Apc(Min/+) mice, suggesting that Kaiso's function as a negative regulator of canonical Wnt signaling, as seen in Xenopus, is not maintained in this context. Notably, Kaiso(Tg/+):Apc(Min/+) mice exhibited increased inflammation and activation of NFκB signaling compared to their Apc(Min/+) counterparts. This phenotype was consistent with our previous report that Kaiso(Tg/+) mice exhibit chronic intestinal inflammation. Together our findings highlight a role for Kaiso in promoting Wnt signaling, inflammation and tumorigenesis in the mammalian intestine. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. VESGEN Mapping of Bioactive Protection against Intestinal Inflammation: Application to Human Spaceflight and ISS Experiments

    Science.gov (United States)

    Parsons-Wingerter, P. A.; Chen, X.; Kelly, C. P.; Reinecker, H. C.

    2011-01-01

    Challenges to successful space exploration and colonization include adverse physiological reactions to micro gravity and space radiation factors. Constant remodeling of the microvasculature is critical for tissue preservation, wound healing, and recovery after ischemia. Regulation of the vascular system in the intestine is particularly important to enable nutrient absorption while maintaining barrier function and mucosal defense against micro biota. Although tremendous progress has been made in understanding the molecular circuits regulating neovascularization, our knowledge of the adaptations of the vascular system to environmental challenges in the intestine remains incomplete. This is in part because of the lack of methods to observe and quantify the complex processes associated with vascular responses in vivo. Developed by GRC as a mature beta version, pre-release research software, VESsel GENeration Analysis (VESGEN) maps and quantifies the fractal-based complexity of vascular branching for novel insights into the cytokine, transgenic and therapeutic regulation of angiogenesis, lymphangiogenesis and microvascular remodeling. Here we demonstrate that VESGEN can be used to characterize the dynamic vascular responses to acute intestinal inflammation and mucosal recovery from in vivo confocal microscopic 3D image series. We induced transient intestinal inflammation in mice by DSS treatment and investigated whether the ability of the pro biotic yeast Saccharomyces boulardii (Sb) to protect against intestinal inflammation was due to regulation of vascular remodeling. A primary characteristic of inflammation is excessive neovascularization (angiogenesis) resulting in fragile vessels prone to bleeding. Morphological parameters for triplicate specimens revealed that Sb treatment greatly reduced the inflammatory response of vascular networks by an average of 78%. This resulted from Sb inhibition of vascular endothelial growth factor receptor signaling, a major

  6. Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation.

    Science.gov (United States)

    Brasseit, Jennifer; Kwong Chung, Cheong K C; Noti, Mario; Zysset, Daniel; Hoheisel-Dickgreber, Nina; Genitsch, Vera; Corazza, Nadia; Mueller, Christoph

    2018-01-01

    Aberrant interferon gamma (IFNγ) expression is associated with the pathogenesis of numerous autoimmune- and inflammatory disorders, including inflammatory bowel diseases (IBD). However, the requirement of IFNγ for the pathogenesis of chronic intestinal inflammation remains controversial. The aim of this study was thus to investigate the role of IFNγ in experimental mouse models of innate and adaptive immune cell-mediated intestinal inflammation using genetically and microbiota-stabilized hosts. While we find that IFNγ drives acute intestinal inflammation in the anti-CD40 colitis model in an innate lymphoid cell (ILC)-dependent manner, IFNγ secreted by both transferred CD4 T cells and/or cells of the lymphopenic Rag1 -/- recipient mice was dispensable for CD4 T cell-mediated colitis. In the absence of IFNγ, intestinal inflammation in CD4 T cell recipient mice was associated with enhanced IL17 responses; consequently, targeting IL17 signaling in IFNγ-deficient mice reduced T cell-mediated colitis. Intriguingly, in contrast to the anti-CD40 model of colitis, depletion of ILC in the Rag1 -/- recipients of colitogenic CD4 T cells did not prevent induction of colonic inflammation. Together, our findings demonstrate that IFNγ represents an essential, or a redundant, pro-inflammatory cytokine for the induction of intestinal inflammation, depending on the experimental mouse model used and on the nature of the critical disease inducing immune cell populations involved.

  7. Candida utilis and Chlorella vulgaris counteract intestinal inflammation in Atlantic salmon (Salmo salar L..

    Directory of Open Access Journals (Sweden)

    Fabian Grammes

    Full Text Available Intestinal inflammation, caused by impaired intestinal homeostasis, is a serious condition in both animals and humans. The use of conventional extracted soybean meal (SBM in diets for Atlantic salmon and several other fish species is known to induce enteropathy in the distal intestine, a condition often referred to as SBM induced enteropathy (SBMIE. In the present study, we investigated the potential of different microbial ingredients to alleviate SBMIE in Atlantic salmon, as a model of feed-induced inflammation. The dietary treatments consisted of a negative control based on fish meal (FM, a positive control based on 20% SBM, and four experimental diets combining 20% SBM with either one of the three yeasts Candida utilis (CU, Kluyveromyces marxianus (KM, Saccharomyces cerevisiae (SC or the microalgae Chlorella vulgaris (CV. Histopathological examination of the distal intestine showed that all fish fed the SC or SBM diets developed characteristic signs of SBMIE, while those fed the FM, CV or CU diets showed a healthy intestine. Fish fed the KM diet showed intermediate signs of SBMIE. Corroborating results were obtained when measuring the relative length of PCNA positive cells in the crypts of the distal intestine. Gene set enrichment analysis revealed decreased expression of amino acid, fat and drug metabolism pathways as well as increased expression of the pathways for NOD-like receptor signalling and chemokine signalling in both the SC and SBM groups while CV and CU were similar to FM and KM was intermediate. Gene expression of antimicrobial peptides was reduced in the groups showing SBMIE. The characterisation of microbial communities using PCR-DGGE showed a relative increased abundance of Firmicutes bacteria in fish fed the SC or SBM diets. Overall, our results show that both CU and CV were highly effective to counteract SBMIE, while KM had less effect and SC had no functional effects.

  8. [Alteration of intestinal permeability: the missing link between gut microbiota modifications and inflammation in obesity?].

    Science.gov (United States)

    Genser, Laurent; Poitou, Christine; Brot-Laroche, Édith; Rousset, Monique; Vaillant, Jean-Christophe; Clément, Karine; Thenet, Sophie; Leturque, Armelle

    2016-05-01

    The increasing incidence of obesity and associated metabolic complications is a worldwide public health issue. The role of the gut in the pathophysiology of obesity, with an important part for microbiota, is becoming obvious. In rodent models of diet-induced obesity, the modifications of gut microbiota are associated with an alteration of the intestinal permeability increasing the passage of food or bacterial antigens, which contribute to low-grade inflammation and insulin resistance. In human obesity, intestinal permeability modification, and its role in the crosstalk between gut microbiota changes and inflammation at systemic and tissular levels, are still poorly documented. Hence, further characterization of the triggering mechanisms of such inflammatory responses in obese subjects could enable the development of personalized intervention strategies that will help to reduce the risk of obesity-associated diseases. © 2016 médecine/sciences – Inserm.

  9. Salmonella enterica serovar Typhimurium exploits inflammation to modify swine intestinal microbiota.

    Directory of Open Access Journals (Sweden)

    Rosanna eDrumo

    2016-01-01

    Full Text Available Salmonella enterica serovar Typhimurium is an important zoonotic gastrointestinal pathogen responsible for foodborne disease worldwide. It is a successful enteric pathogen because it has developed virulence strategies allowing it to survive in a highly inflamed intestinal environment exploiting inflammation to overcome colonization resistance provided by intestinal microbiota. In this study, we used piglets featuring an intact microbiota, which naturally develop gastroenteritis, as model for salmonellosis. We compared the effects on the intestinal microbiota induced by a wild type and an attenuated S. Typhimurium in order to evaluate whether the modifications are correlated with the virulence of the strain. This study showed that Salmonella alters microbiota in a virulence-dependent manner. We found that the wild type S. Typhimurium induced inflammation and a reduction of specific protecting microbiota species (SCFA-producing bacteria normally involved in providing a barrier against pathogens. Both these effects could contribute to impair colonization resistance, increasing the host susceptibility to wild type S. Typhimurium colonization. In contrast, the attenuated S. Typhimurium, which is characterized by a reduced ability to colonize the intestine, and by a very mild inflammatory response, was unable to successfully sustain competition with the microbiota.

  10. Gp96 Peptide Antagonist gp96-II Confers Therapeutic Effects in Murine Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Claudia A. Nold-Petry

    2017-12-01

    Full Text Available BackgroundThe expression of heat shock protein gp96 is strongly correlated with the degree of tissue inflammation in ulcerative colitis and Crohn’s disease, thereby leading us to the hypothesis that inhibition of expression via gp96-II peptide prevents intestinal inflammation.MethodsWe employed daily injections of gp96-II peptide in two murine models of intestinal inflammation, the first resulting from five daily injections of IL-12/IL-18, the second via a single intrarectal application of TNBS (2,4,6-trinitrobenzenesulfonic acid. We also assessed the effectiveness of gp96-II peptide in murine and human primary cell culture.ResultsIn the IL-12/IL-18 model, all gp96-II peptide-treated animals survived until day 5, whereas 80% of placebo-injected animals died. gp96-II peptide reduced IL-12/IL-18-induced plasma IFNγ by 89%, IL-1β by 63%, IL-6 by 43% and tumor necrosis factor (TNF by 70% compared to controls. The clinical assessment Disease Activity Index of intestinal inflammation severity was found to be significantly lower in the gp96-II-treated animals when compared to vehicle-injected mice. gp96-II peptide treatment in the TNBS model limited weight loss to 5% on day 7 compared with prednisolone treatment, whereas placebo-treated animals suffered a 20% weight loss. Histological disease severity was reduced equally by prednisolone (by 40% and gp96-II peptide (35%. Mice treated with either gp96-II peptide or prednisolone exhibited improved endoscopic scores compared with vehicle-treated control mice: vascularity, fibrin, granularity, and translucency scores were reduced by up to 49% by prednisolone and by up to 30% by gp96-II peptide. In vitro, gp96-II peptide reduced TLR2-, TLR4- and IL-12/IL-18-induced cytokine expression in murine splenocytes, with declines in constitutive IL-6 (54%, lipopolysaccharide-induced TNF (48%, IL-6 (81% and in Staphylococcus epidermidis-induced TNF (67% and IL-6 (81%, as well as IL-12/IL-18-induced IFNγ (75%. gp

  11. Milk diets influence doxorubicin-induced intestinal toxicity in piglets

    DEFF Research Database (Denmark)

    Shen, R. L.; Pontoppidan, P. E.; Rathe, M.

    2016-01-01

    Chemotherapy-induced gastrointestinal (GI) toxicity is a common adverse effect of cancer treatment. We used preweaned piglets as models to test our hypothesis that the immunomodulatory and GI trophic effects of bovine colostrum would reduce the severity of GI complications associated with doxorub......Chemotherapy-induced gastrointestinal (GI) toxicity is a common adverse effect of cancer treatment. We used preweaned piglets as models to test our hypothesis that the immunomodulatory and GI trophic effects of bovine colostrum would reduce the severity of GI complications associated...... to assess markers of small intestinal function and inflammation. All DOX-treated animals developed diarrhea, growth deficits, and leukopenia. However, the intestines of DOX-Colos pigs had lower intestinal permeability, longer intestinal villi with higher activities of brush border enzymes, and lower tissue...

  12. Histamine H2 Receptor-Mediated Suppression of Intestinal Inflammation by Probiotic Lactobacillus reuteri.

    Science.gov (United States)

    Gao, Chunxu; Major, Angela; Rendon, David; Lugo, Monica; Jackson, Vanessa; Shi, Zhongcheng; Mori-Akiyama, Yuko; Versalovic, James

    2015-12-15

    Probiotics and commensal intestinal microbes suppress mammalian cytokine production and intestinal inflammation in various experimental model systems. Limited information exists regarding potential mechanisms of probiotic-mediated immunomodulation in vivo. In this report, we demonstrate that specific probiotic strains of Lactobacillus reuteri suppress intestinal inflammation in a trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model. Only strains that possess the hdc gene cluster, including the histidine decarboxylase and histidine-histamine antiporter genes, can suppress colitis and mucosal cytokine (interleukin-6 [IL-6] and IL-1β in the colon) gene expression. Suppression of acute colitis in mice was documented by diminished weight loss, colonic injury, serum amyloid A (SAA) protein concentrations, and reduced uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG) in the colon by positron emission tomography (PET). The ability of probiotic L. reuteri to suppress colitis depends on the presence of a bacterial histidine decarboxylase gene(s) in the intestinal microbiome, consumption of a histidine-containing diet, and signaling via the histamine H2 receptor (H2R). Collectively, luminal conversion of l-histidine to histamine by hdc(+) L. reuteri activates H2R, and H2R signaling results in suppression of acute inflammation within the mouse colon. Probiotics are microorganisms that when administered in adequate amounts confer beneficial effects on the host. Supplementation with probiotic strains was shown to suppress intestinal inflammation in patients with inflammatory bowel disease and in rodent colitis models. However, the mechanisms of probiosis are not clear. Our current studies suggest that supplementation with hdc(+) L. reuteri, which can convert l-histidine to histamine in the gut, resulted in suppression of colonic inflammation. These findings link luminal conversion of dietary components (amino acid metabolism) by gut microbes and probiotic

  13. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine.

    Science.gov (United States)

    Pagel, René; Bär, Florian; Schröder, Torsten; Sünderhauf, Annika; Künstner, Axel; Ibrahim, Saleh M; Autenrieth, Stella E; Kalies, Kathrin; König, Peter; Tsang, Anthony H; Bettenworth, Dominik; Divanovic, Senad; Lehnert, Hendrik; Fellermann, Klaus; Oster, Henrik; Derer, Stefanie; Sina, Christian

    2017-11-01

    Endogenous circadian clocks regulate 24-h rhythms of physiology and behavior. Circadian rhythm disruption (CRD) is suggested as a risk factor for inflammatory bowel disease. However, the underlying molecular mechanisms remain unknown. Intestinal biopsies from Per1/2 mutant and wild-type (WT) mice were investigated by electron microscopy, immunohistochemistry, and bromodeoxyuridine pulse-chase experiments. TNF-α was injected intraperitoneally, with or without necrostatin-1, into Per1/2 mice or rhythmic and externally desynchronized WT mice to study intestinal epithelial cell death. Experimental chronic colitis was induced by oral administration of dextran sodium sulfate. In vitro , caspase activity was assayed in Per1/2-specific small interfering RNA-transfected cells. Wee1 was overexpressed to study antiapoptosis and the cell cycle. Genetic ablation of circadian clock function or environmental CRD in mice increased susceptibility to severe intestinal inflammation and epithelial dysregulation, accompanied by excessive necroptotic cell death and a reduced number of secretory epithelial cells. Receptor-interacting serine/threonine-protein kinase (RIP)-3-mediated intestinal necroptosis was linked to increased mitotic cell cycle arrest via Per1/2-controlled Wee1, resulting in increased antiapoptosis via cellular inhibitor of apoptosis-2. Together, our data suggest that circadian rhythm stability is pivotal for the maintenance of mucosal barrier function. CRD increases intestinal necroptosis, thus rendering the gut epithelium more susceptible to inflammatory processes.-Pagel, R., Bär, F., Schröder, T., Sünderhauf, A., Künstner, A., Ibrahim, S. M., Autenrieth, S. E., Kalies, K., König, P., Tsang, A. H., Bettenworth, D., Divanovic, S., Lehnert, H., Fellermann, K., Oster, H., Derer, S., Sina, C. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine. © FASEB.

  14. The Effect of DA-6034 on Intestinal Permeability in an Indomethacin-Induced Small Intestinal Injury Model.

    Science.gov (United States)

    Kwak, Dong Shin; Lee, Oh Young; Lee, Kang Nyeong; Jun, Dae Won; Lee, Hang Lak; Yoon, Byung Chul; Choi, Ho Soon

    2016-05-23

    DA-6034 has anti-inflammatory activities and exhibits cytoprotective effects in acute gastric injury models. However, explanations for the protective effects of DA-6034 on intestinal permeability are limited. This study sought to investigate the effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model and its protective effect against small intestinal injury. Rats in the treatment group received DA-6034 from days 0 to 2 and indomethacin from days 1 to 2. Rats in the control group received indomethacin from days 1 to 2. On the fourth day, the small intestines were examined to compare the severity of inflammation. Intestinal permeability was evaluated by using fluorescein isothiocyanate-labeled dextran. Western blotting was performed to confirm the association between DA-6034 and the extracellular signal-regulated kinase (ERK) pathway. The inflammation scores in the treatment group were lower than those in the control group, but the difference was statistically insignificant. Hemorrhagic lesions in the treatment group were broader than those in the control group, but the difference was statistically insignificant. Intestinal permeability was lower in the treatment group than in the control group. DA-6034 enhanced extracellular signal-regulated kinase expression, and intestinal permeability was negatively correlated with ERK expression. DA-6034 may decrease intestinal permeability in an indomethacin-induced intestinal injury model via the ERK pathway.

  15. Macrophages and dendritic cells emerge in the liver during intestinal inflammation and predispose the liver to inflammation.

    Directory of Open Access Journals (Sweden)

    Yohei Mikami

    Full Text Available The liver is a physiological site of immune tolerance, the breakdown of which induces immunity. Liver antigen-presenting cells may be involved in both immune tolerance and activation. Although inflammatory diseases of the liver are frequently associated with inflammatory bowel diseases, the underlying immunological mechanisms remain to be elucidated. Here we report two murine models of inflammatory bowel disease: RAG-2(-/- mice adoptively transferred with CD4(+CD45RB(high T cells; and IL-10(-/- mice, accompanied by the infiltration of mononuclear cells in the liver. Notably, CD11b(-CD11c(lowPDCA-1(+ plasmacytoid dendritic cells (DCs abundantly residing in the liver of normal wild-type mice disappeared in colitic CD4(+CD45RB(high T cell-transferred RAG-2(-/- mice and IL-10(-/- mice in parallel with the emergence of macrophages (Mφs and conventional DCs (cDCs. Furthermore, liver Mφ/cDCs emerging during intestinal inflammation not only promote the proliferation of naïve CD4(+ T cells, but also instruct them to differentiate into IFN-γ-producing Th1 cells in vitro. The emergence of pathological Mφ/cDCs in the liver also occurred in a model of acute dextran sulfate sodium (DSS-induced colitis under specific pathogen-free conditions, but was canceled in germ-free conditions. Last, the Mφ/cDCs that emerged in acute DSS colitis significantly exacerbated Fas-mediated hepatitis. Collectively, intestinal inflammation skews the composition of antigen-presenting cells in the liver through signaling from commensal bacteria and predisposes the liver to inflammation.

  16. Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy.

    Science.gov (United States)

    Willemze, Rose A; Luyer, Misha D; Buurman, Wim A; de Jonge, Wouter J

    2015-06-01

    Studies in neuroscience and immunology have clarified much of the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems. As with other organs, intestinal immune responses and the development of immunity seems to be modulated by neural reflexes. Sympathetic immune modulation and reflexes are well described, and in the past decade the parasympathetic efferent vagus nerve has been added to this immune-regulation network. This system, designated 'the inflammatory reflex', comprises an afferent arm that senses inflammation and an efferent arm that inhibits innate immune responses. Intervention in this system as an innovative principle is currently being tested in pioneering trials of vagus nerve stimulation using implantable devices to treat IBD. Patients benefit from this treatment, but some of the working mechanisms remain to be established, for instance, treatment is effective despite the vagus nerve not always directly innervating the inflamed tissue. In this Review, we will focus on the direct neuronal regulatory mechanisms of immunity in the intestine, taking into account current advances regarding the innervation of the spleen and lymphoid organs, with a focus on the potential for treatment in IBD and other gastrointestinal pathologies.

  17. Mechanisms involved in alleviation of intestinal inflammation by bifidobacterium breve soluble factors.

    Directory of Open Access Journals (Sweden)

    Elise Heuvelin

    Full Text Available OBJECTIVES: Soluble factors released by Bifidobacterium breve C50 (Bb alleviate the secretion of pro-inflammatory cytokines by immune cells, but their effect on intestinal epithelium remains elusive. To decipher the mechanisms accounting for the cross-talk between bacteria/soluble factors and intestinal epithelium, we measured the capacity of the bacteria, its conditioned medium (Bb-CM and other Gram(+ commensal bacteria to dampen inflammatory chemokine secretion. METHODS: TNFalpha-induced chemokine (CXCL8 secretion and alteration of NF-kappaB and AP-1 signalling pathways by Bb were studied by EMSA, confocal microscopy and western blotting. Anti-inflammatory capacity was also tested in vivo in a model of TNBS-induced colitis in mice. RESULTS: Bb and Bb-CM, but not other commensal bacteria, induced a time and dose-dependent inhibition of CXCL8 secretion by epithelial cells driven by both AP-1 and NF-kappaB transcription pathways and implying decreased phosphorylation of p38-MAPK and IkappaB-alpha molecules. In TNBS-induced colitis in mice, Bb-CM decreased the colitis score and inflammatory cytokine expression, an effect reproduced by dendritic cell conditioning with Bb-CM. CONCLUSIONS: Bb and secreted soluble factors contribute positively to intestinal homeostasis by attenuating chemokine production. The results indicate that Bb down regulate inflammation at the epithelial level by inhibiting phosphorylations involved in inflammatory processes and by protective conditioning of dendritic cells.

  18. Propolis from Different Geographic Origins Suppress Intestinal Inflammation in a Model of DSS-Induced Colitis is Associated with Decreased Bacteroides spp. in the Gut.

    Science.gov (United States)

    Wang, Kai; Jin, Xiaolu; Li, Qiangqiang; Sawaya, Alexandra Christine Helena Frankland; Leu, Richard K Le; Conlon, Michael A; Wu, Liming; Hu, Fuliang

    2018-06-11

    Dietary supplementation with polyphenol-rich propolis can protect against experimentally-induced colitis. We examined whether different polyphenol compositions of Chinese propolis (CP) and Brazilian propolis (BP) influences their ability to protect against dextran sulfate sodium (DSS)-induced colitis in rats. HPLC-DAD/Q-TOF-MS analysis confirmed that polyphenol compositions of CP and BP were dissimilar. Rats were given CP or BP by gavage (300 mg/kg body weight) throughout the study, starting 1 week prior to DSS treatment for 1 week followed by 3 d without DSS. CP and BP significantly reduced the colitis disease activity index relative to controls not receiving propolis, prevented significant DSS-induced colonic tissue damage and increased resistance to DSS-induced colonic oxidative stress as shown by reduced malonaldehyde levels and increased T-AOC levels. CP and BP significantly reduced DSS-induced colonic apoptosis. Colonic inflammatory markers IL-1β, IL-6 and MCP-1 were suppressed by CP and BP, whereas only BP induced expression of TGF-β. CP, not BP, increased the diversity and richness of gut microbiota populations. Both forms of propolis significantly reduced populations of Bacteroides spp. Despite the dissimilar polyphenol compositions of CP and BP, their ability to protect against DSS-induced colitis is similar. Nevertheless, some different physiological impacts were observed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Effect of microalgae on intestinal inflammation triggered by soybean meal and bacterial infection in zebrafish.

    Directory of Open Access Journals (Sweden)

    Karina Bravo-Tello

    Full Text Available Soybean meal has been used in many commercial diets for farm fish; despite this component inducing intestinal inflammation. On the other hand, microalgae have increasingly been used as dietary supplements in fish feed. Nevertheless, the vast quantity of microalgae species means that many remain under- or unstudied, thus limiting wide scale commercial application. In this work, we evaluated the effects to zebrafish (Danio rerio of including Tetraselmis sp (Ts; Phaeodactylum tricornutum (Pt; Chlorella sp (Ch; Nannochloropsis oculata (No; or Nannochloropsis gaditana (Ng as additives in a soybean meal-based diet on intestinal inflammation and survival after Edwardsiella tarda infection. In larvae fed a soybean meal diet supplemented with Ts, Pt, Ch, or Ng, the quantity of neutrophils present in the intestine drastically decreased as compared to larvae fed only the soybean meal diet. Likewise, Ts or Ch supplements in soybean meal or fishmeal increased zebrafish survival by more than 20% after being challenged. In the case of Ts, the observed effect correlated with an increased number of neutrophils present at the infection site. These results suggest that the inclusion of Ts or Ch in fish diets could allow the use of SBM and at the same time improve performance against pathogen.

  20. Diagnosis of edema and inflammation in human intestines using ultrawideband radar

    Science.gov (United States)

    Smith, Sonny; Narayanan, Ram M.; Messaris, Evangelos

    2015-05-01

    Human intestines are vital organs, which are often subjected to chronic issues. In particular, Crohn's disease is a bowel aliment resulting in inflammation along the lining of one's digestive tract. Moreover, such an inflammatory condition causes changes in the thickness of the intestines; and we posit induce changes in the dielectric properties detectable by radar. This detection hinges on the increase in fluid content in the afflicted area, which is described by effective medium approximations (EMA). In this paper, we consider one of the constitutive parameters (i.e. relative permittivity) of different human tissues and introduce a simple numerical, electromagnetic multilayer model. We observe how the increase in water content in one layer can be approximated to predict the effective permittivity of that layer. Moreover, we note trends in how such an accumulation can influence the total effective reflection coefficient of the multiple layers.

  1. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.

    Directory of Open Access Journals (Sweden)

    Bärbel Stecher

    2007-10-01

    Full Text Available Most mucosal surfaces of the mammalian body are colonized by microbial communities ("microbiota". A high density of commensal microbiota inhabits the intestine and shields from infection ("colonization resistance". The virulence strategies allowing enteropathogenic bacteria to successfully compete with the microbiota and overcome colonization resistance are poorly understood. Here, we investigated manipulation of the intestinal microbiota by the enteropathogenic bacterium Salmonella enterica subspecies 1 serovar Typhimurium (S. Tm in a mouse colitis model: we found that inflammatory host responses induced by S. Tm changed microbiota composition and suppressed its growth. In contrast to wild-type S. Tm, an avirulent invGsseD mutant failing to trigger colitis was outcompeted by the microbiota. This competitive defect was reverted if inflammation was provided concomitantly by mixed infection with wild-type S. Tm or in mice (IL10(-/-, VILLIN-HA(CL4-CD8 with inflammatory bowel disease. Thus, inflammation is necessary and sufficient for overcoming colonization resistance. This reveals a new concept in infectious disease: in contrast to current thinking, inflammation is not always detrimental for the pathogen. Triggering the host's immune defence can shift the balance between the protective microbiota and the pathogen in favour of the pathogen.

  2. The Role of Carrageenan and Carboxymethylcellulose in the Development of Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Johan Van Limbergen

    2017-05-01

    Full Text Available Although the exact pathophysiology remains unknown, the development of inflammatory bowel disease (IBD is influenced by the interplay between genetics, the immune system, and environmental factors such as diet. The commonly used food additives, carrageenan and carboxymethylcellulose (CMC, are used to develop intestinal inflammation in animal models. These food additives are excluded from current dietary approaches to induce disease remission in Crohn’s disease such as exclusive enteral nutrition (EEN using a polymeric formula. By reviewing the existing scientific literature, this review aims to discuss the role that carrageenan and CMC may play in the development of IBD. Animal studies consistently report that carrageenan and CMC induce histopathological features that are typical of IBD while altering the microbiome, disrupting the intestinal epithelial barrier, inhibiting proteins that provide protection against microorganisms, and stimulating the elaboration of pro-inflammatory cytokines. Similar trials directly assessing the influence of carrageenan and CMC in humans are of course unethical to conduct, but recent studies of human epithelial cells and the human microbiome support the findings from animal studies. Carrageenan and CMC may trigger or magnify an inflammatory response in the human intestine but are unlikely to be identified as the sole environmental factor involved in the development of IBD or in disease recurrence after treatment. However, the widespread use of carrageenan and CMC in foods consumed by the pediatric population in a “Western” diet is on the rise alongside a corresponding increase in IBD incidence, and questions are being raised about the safety of frequent usage of these food additives. Therefore, further research is warranted to elucidate the role of carrageenan and CMC in intestinal inflammation, which may help identify novel nutritional strategies that hinder the development of the disease or prevent

  3. Reishi Protein LZ-8 Induces FOXP3+ Treg Expansion via a CD45-Dependent Signaling Pathway and Alleviates Acute Intestinal Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Hsien-Yeh Hsu

    2013-01-01

    Full Text Available LZ-8, an immunomodulatory protein isolated from Ganoderma lucidum (also known as Ling-Zhi or Reishi, has been shown to promote cell proliferation and IL-2 production in T cells. In this study, we show that LZ-8 induces the expansion of both murine and human CD4+ T cells into FOXP3+ regulatory T (Treg cells. LZ-8 treatment was found to stimulate a 4-fold and a 10-fold expansion in the Treg populations of murine and human primary CD4+ T cells, respectively. In addition, the expression of CTLA-4 and IL-10 was induced in LZ-8-treated CD4+ T cells. Using neutralizing antibodies and gene-deficient T-cell lines, we also found that LZ-8 promotes Treg expansion through a CD45-mediated signaling pathway and that the CD18-dependent induction of IL-2 was involved in Treg formation and IL-10 production. The suppressive activity of LZ-8 was confirmed using a murine model of DSS-induced colitis; the disease was alleviated by the adoptive transfer of LZ-8-treated CD4+ T cells. In conclusion, a new regulatory function for LZ-8 was identified, and the molecular mechanisms underlying this function were elucidated.

  4. Lactococcus lactis carrying the pValac eukaryotic expression vector coding for IL-4 reduces chemically-induced intestinal inflammation by increasing the levels of IL-10-producing regulatory cells.

    Science.gov (United States)

    Souza, Bianca Mendes; Preisser, Tatiane Melo; Pereira, Vanessa Bastos; Zurita-Turk, Meritxell; de Castro, Camila Prósperi; da Cunha, Vanessa Pecini; de Oliveira, Rafael Pires; Gomes-Santos, Ana Cristina; de Faria, Ana Maria Caetano; Machado, Denise Carmona Cara; Chatel, Jean-Marc; Azevedo, Vasco Ariston de Carvalho; Langella, Philippe; Miyoshi, Anderson

    2016-08-30

    Inflammatory bowel diseases are characterized by chronic intestinal inflammation that leads to severe destruction of the intestinal mucosa. Therefore, the understanding of their aetiology as well as the development of new medicines is an important step for the treatment of such diseases. Consequently, the development of Lactococcus lactis strains capable of delivering a eukaryotic expression vector encoding the interleukin 4 (IL-4) of Mus musculus would represent a new strategy for the elaboration of a more effective alternative therapy against Crohn's disease. The murine IL-4 ORF was cloned into the eukaryotic expression vector pValac::dts. The resulting plasmid-pValac::dts::IL-4-was transfected into CHO cells so that its functionality could be evaluated in vitro. With fluorescent confocal microscopy, flow cytometry and ELISA, it was observed that pValac::dts::IL-4-transfected cells produced IL-4, while non-transfected cells and cells transfected with the empty vector did not. Then, pValac::dts::IL-4 was inserted into L. lactis MG1363 FnBPA(+) in order to evaluate the therapeutic potential of the recombinant strain against TNBS-induced colitis. Intragastric administration of L. lactis MG1363 FnBPA(+) (pValac::dts::IL-4) was able to decrease the severity of colitis, with animals showing decreased levels of IL-12, IL-6 and MPO activity; and increased levels of IL-4 and IL-10. Finally, LP-isolated cells from mice administered TNBS were immunophenotyped so that the main IL-4 and IL-10 producers were identified. Mice administered the recombinant strain presented significantly higher percentages of F4/80(+)MHCII(+)Ly6C(-)IL-4(+), F4/80(+)MHCII(+)Ly6C(-)IL-10(+), F4/80(+)MHCII(+)Ly6C(-)CD206(+)CD124(+)IL-10(+) and CD4(+)Foxp3(+)IL10(+) cells compared to the other groups. This study shows that L. lactis MG1363 FnBPA(+) (pValac::dts::IL-4) is a good candidate to maintain the anti-inflammatory and proinflammatory balance in the gastrointestinal tract, increasing the levels

  5. L-cysteine protects intestinal integrity, attenuates intestinal inflammation and oxidant stress, and modulates NF-κB and Nrf2 pathways in weaned piglets after LPS challenge.

    Science.gov (United States)

    Song, Ze he; Tong, Guo; Xiao, Kan; Jiao, Le fei; Ke, Ya lu; Hu, Cai hong

    2016-04-01

    In this study we investigated whetherL-cysteine (L-cys) could alleviate LPS-induced intestinal disruption and its underlying mechanism. Piglets fed with anL-cys-supplemented diet had higher average daily gain.L-cys alleviated LPS-induced structural and functional disruption of intestine in weanling piglets, as demonstrated by higher villus height, villus height (VH) to crypt depth (CD) ratio, and transepithelial electrical resistance (TER) and lower FITC-dextran 4 (FD4) kDa flux in jejunum and ileum. Supplementation withL-cys up-regulated occludin and claudin-1 expression, reduced caspase-3 activity and enhanced proliferating cell nuclear antigen expression of jejunum and ileum relative to LPS group. Additionally,L-cys suppressed the LPS-induced intestinal inflammation and oxidative stress, as demonstrated by down-regulated TNF-α, IL-6 and IL-8 mRNA levels, increased catalase, superoxide dismutase, glutathione peroxidase activity, glutathione (GSH) contents and the ratio of GSH and oxidized glutathione in jejunum and ileum. Finally, a diet supplemented withL-cys inhibited NF-κB(p65) nuclear translocation and elevated NF erythroid 2-related factor 2 (Nrf2) translocation compared with the LPS group. Collectively, our results indicated the protective function ofL-cys on intestinal mucosa barrier may closely associated with its anti-inflammation, antioxidant and regulating effect on the NF-κB and Nrf2 signaling pathways. © The Author(s) 2016.

  6. Persistent Salmonella enterica serovar Typhimurium Infection Increases the Susceptibility of Mice to Develop Intestinal Inflammation

    Directory of Open Access Journals (Sweden)

    Bárbara M. Schultz

    2018-05-01

    Full Text Available Chronic intestinal inflammations are triggered by genetic and environmental components. However, it remains unclear how specific changes in the microbiota, host immunity, or pathogen exposure could promote the onset and exacerbation of these diseases. Here, we evaluated whether Salmonella enterica serovar Typhimurium (S. Typhimurium infection increases the susceptibility to develop intestinal inflammation in mice. Two mouse models were used to evaluate the impact of S. Typhimurium infection: the chemical induction of colitis by dextran sulfate sodium (DSS and interleukin (IL-10−/− mice, which develop spontaneous intestinal inflammation. We observed that S. Typhimurium infection makes DSS-treated and IL-10−/− mice more susceptible to develop intestinal inflammation. Importantly, this increased susceptibility is associated to the ability of S. Typhimurium to persist in liver and spleen of infected mice, which depends on the virulence proteins secreted by Salmonella Pathogenicity Island 2-encoded type three secretion system (TTSS-2. Although immunization with a live attenuated vaccine resulted in a moderate reduction of the IL-10−/− mice susceptibility to develop intestinal inflammation due to previous S. Typhimurium infection, it did not prevent bacterial persistence. Our results suggest that persistent S. Typhimurium infection may increase the susceptibility of mice to develop inflammation in the intestine, which could be associated with virulence proteins secreted by TTSS-2.

  7. The tumor necrosis factor family member TNFSF14 (LIGHT) is required for resolution of intestinal inflammation in mice.

    Science.gov (United States)

    Krause, Petra; Zahner, Sonja P; Kim, Gisen; Shaikh, Raziyah B; Steinberg, Marcos W; Kronenberg, Mitchell

    2014-06-01

    The pathogenesis of inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response. Expression of the tumor necrosis factor (TNF) superfamily member 14 (TNFSF14, also known as LIGHT [homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes]) on T cells is involved in their activation; transgenic expression of LIGHT on T cells in mice promotes inflammation in multiple organs, including intestine. We investigated the roles for LIGHT in recovery from intestinal inflammation in mice. We studied the role of LIGHT in intestinal inflammation using Tnfsf14(-/-) and wild-type mice. Colitis was induced by transfer of CD4(+)CD45RB(high) T cells into Rag1(-/-) or Tnfsf14(-/-)Rag1(-/-) mice, or by administration of dextran sulfate sodium to Tnfsf14(-/-) or wild-type C57BL/6J mice. Mice were weighed, colon tissues were collected and measured, and histology analyses were performed. We measured infiltrating cell populations and expression of cytokines, chemokines, and LIGHT. After administration of dextran sulfate sodium, Tnfsf14(-/-) mice developed more severe colitis than controls, based on their reduced survival, accelerated loss of body weight, and histologic scores. LIGHT protected mice from colitis via the lymphotoxin β receptor and was expressed mainly by myeloid cells in the colon. Colons of Tnfsf14(-/-) mice also had increased accumulation of innate immune cells and higher levels of cytokines than colons from control mice. LIGHT, therefore, appears to regulate inflammation in the colon. Tnfsf14(-/-) mice develop more severe colitis than control mice. LIGHT signals through the lymphotoxin β receptor in the colon to regulate the innate immune response and mediate recovery from intestinal inflammation. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  8. Tumor Necrosis Factor Induces Developmental Stage-Dependent Structural Changes in the Immature Small Intestine

    Directory of Open Access Journals (Sweden)

    Kathryn S. Brown

    2014-01-01

    Full Text Available Background. Premature infants are commonly subject to intestinal inflammation. Since the human small intestine does not reach maturity until term gestation, premature infants have a unique challenge, as either acute or chronic inflammation may alter the normal development of the intestinal tract. Tumor necrosis factor (TNF has been shown to acutely alter goblet cell numbers and villus length in adult mice. In this study we tested the effects of TNF on villus architecture and epithelial cells at different stages of development of the immature small intestine. Methods. To examine the effects of TNF-induced inflammation, we injected acute, brief, or chronic exposures of TNF in neonatal and juvenile mice. Results. TNF induced significant villus blunting through a TNF receptor-1 (TNFR1 mediated mechanism, leading to loss of villus area. This response to TNFR1 signaling was altered during intestinal development, despite constant TNFR1 protein expression. Acute TNF-mediated signaling also significantly decreased Paneth cells. Conclusions. Taken together, the morphologic changes caused by TNF provide insight as to the effects of inflammation on the developing intestinal tract. Additionally, they suggest a mechanism which, coupled with an immature immune system, may help to explain the unique susceptibility of the immature intestine to inflammatory diseases such as NEC.

  9. An innately dangerous balancing act: intestinal homeostasis, inflammation, and colitis-associated cancer

    Science.gov (United States)

    2010-01-01

    Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses to the intestinal microbiota, and by chronic intestinal inflammation. Several recent studies demonstrate the importance of innate microbial recognition by immune and nonimmune cells in the gut. Paradoxically, either diminished or exacerbated innate immune signaling may trigger the breakdown of intestinal homeostasis, leading to IBD and colitis-associated cancer (CAC). This dichotomy may reflect divergent functional roles for immune sensing in intestinal epithelial cells and leukocytes, which may vary with distinct disease mechanisms. PMID:20679404

  10. Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in rats

    NARCIS (Netherlands)

    Schoots, Ivo G.; Levi, Marcel; van Vliet, Arlène K.; Maas, Adrie M.; Roossink, E. H. Paulina; van Gulik, Thomas M.

    2004-01-01

    Objective: To examine whether administration of activated protein C or antithrombin reduces local splanchnic derangement of coagulation and inflammation and attenuates intestinal dysfunction and injury following intestinal ischemia/reperfusion. Design: Randomized prospective animal study. Setting:

  11. Retinoic acid signalling is required for the pathogenicity of effector CD4+ T cells during the development of intestinal inflammation

    DEFF Research Database (Denmark)

    Rivollier, Aymeric Marie Christian; Pool, Lieneke; Frising, Ulrika

    The vitamin A metabolite retinoic acid (RA) seems to be a double-edge sword in CD4+ T cell biology, sustaining the development of foxp3+ Treg cells, but also being essential for the stability of the Th1 lineage. Here we explored the role of RA signalling in CD4+ T cells during the development...... of intestinal inflammation in the T cell transfer colitis model. RA signalling-deficient CD4+ T cells are less potent at inducing intestinal inflammation compared to their RA signalling-proficient counterparts and exhibit a differentiation skewing towards more IL-17+ and foxp3+ cells, while their capacity......-deficient and –proficient Tregs are equally competent to inhibit colitis development. Together our results indicate that RA, through its receptor RARα, negatively regulates the early expansion of CD4+ T cells during colitis and is necessary for the generation of colitogenic Th1/Th17 cells, while it is dispensable...

  12. A role for interleukin-33 in T(H)2-polarized intestinal inflammation?

    DEFF Research Database (Denmark)

    Seidelin, J B; Rogler, G; Nielsen, O H

    2011-01-01

    Interleukin 33 (IL-33) is a recently discovered cytokine member of the IL-1 superfamily that is widely expressed in fixed tissue cells, including endothelial and epithelial cells. IL-33 induces helper T cells, mast cells, eosinophils, and basophils to produce type-2 cytokines through binding...... to the ST2/IL-1 receptor accessory protein complex. Recent studies have shown IL-33 to be upregulated in intestinal parasite infection and in epithelial cells and myofibroblasts in ulcerative colitis (UC). The findings point to a role for IL-33 in directing the T(H)2-type immune responses in these types...... of mucosal inflammation. As the IL-33/ST2 receptor axis can be manipulated by various blocking antibodies, this could be a potential therapeutic target in the future treatment of UC....

  13. Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism

    Science.gov (United States)

    Yan, Fang; Cao, Hanwei; Cover, Timothy L.; Washington, M. Kay; Shi, Yan; Liu, LinShu; Chaturvedi, Rupesh; Peek, Richard M.; Wilson, Keith T.; Polk, D. Brent

    2011-01-01

    Probiotic bacteria can potentially have beneficial effects on the clinical course of several intestinal disorders, but our understanding of probiotic action is limited. We have identified a probiotic bacteria–derived soluble protein, p40, from Lactobacillus rhamnosus GG (LGG), which prevents cytokine-induced apoptosis in intestinal epithelial cells. In the current study, we analyzed the mechanisms by which p40 regulates cellular responses in intestinal epithelial cells and p40’s effects on experimental colitis using mouse models. We show that the recombinant p40 protein activated EGFR, leading to Akt activation. Activation of EGFR by p40 was required for inhibition of cytokine-induced apoptosis in intestinal epithelial cells in vitro and ex vivo. Furthermore, we developed a pectin/zein hydrogel bead system to specifically deliver p40 to the mouse colon, which activated EGFR in colon epithelial cells. Administration of p40-containing beads reduced intestinal epithelial apoptosis and disruption of barrier function in the colon epithelium in an EGFR-dependent manner, thereby preventing and treating DSS-induced intestinal injury and acute colitis. Furthermore, p40 activation of EGFR was required for ameliorating colon epithelial cell apoptosis and chronic inflammation in oxazolone-induced colitis. These data define what we believe to be a previously unrecognized mechanism of probiotic-derived soluble proteins in protecting the intestine from injury and inflammation. PMID:21606592

  14. Increased Intestinal Inflammation and Digestive Dysfunction in Preterm Pigs with Severe Necrotizing Enterocolitis

    DEFF Research Database (Denmark)

    Støy, Ann Cathrine Findal; Heegaard, Peter M. H.; Skovgaard, Kerstin

    2017-01-01

    The risk factors for necrotizing enterocolitis (NEC) are well known, but the factors involved in the different NEC presentations remain unclear. We hypothesized that digestive dysfunction and intestinal inflammation are mainly affected by severe NEC lesions. In 48 preterm pigs, the association...... between the macroscopic NEC score (range 1-6) and the expression of 48 genes related to inflammation, morphological, and digestive parameters in the distal small intestine was investigated. Only severe NEC cases (score of 5-6) were associated with the upregulation of genes involved in inflammation (CCL2...... and decreased hydrolase activity. A severe inflammatory response and digestive dysfunction are associated mainly with severe NEC. Still, it remains difficult to separate the initial causes of NEC and the later intestinal consequences of NEC in both infants and experimental models....

  15. Orally administered Taenia solium Calreticulin prevents experimental intestinal inflammation and is associated with a type 2 immune response.

    Directory of Open Access Journals (Sweden)

    Fela Mendlovic

    Full Text Available Intestinal helminth antigens are inducers of type 2 responses and can elicit regulatory immune responses, resulting in dampened inflammation. Several platyhelminth proteins with anti-inflammatory activity have been reported. We have identified, cloned and expressed the Taenia solium calreticulin (rTsCRT and shown that it predominantly induces a type 2 response characterized by IgG1, IL-4 and IL-5 production in mice. Here, we report the rTsCRT anti-inflammatory activity in a well-known experimental colitis murine model. Mice were orally immunized with purified rTsCRT and colitis was induced with trinitrobenzene sulfonic acid (TNBS. Clinical signs of disease, macroscopic and microscopic tissue inflammation, cytokine production and micronuclei formation, as a marker of genotoxicity, were measured in order to assess the effect of rTsCRT immunization on experimentally induced colitis. rTsCRT administration prior to TNBS instillation significantly reduced the inflammatory parameters, including the acute phase cytokines TNF-α, IL-1β and IL-6. Dampened inflammation was associated with increased local expression of IL-13 and systemic IL-10 and TGF-β production. Genotoxic damage produced by the inflammatory response was also precluded. Our results show that oral treatment with rTsCRT prevents excessive TNBS-induced inflammation in mice and suggest that rTsCRT has immunomodulatory properties associated with the expression of type 2 and regulatory cytokines commonly observed in other helminths.

  16. Neural reflex pathways in intestinal inflammation: hypotheses to viable therapy

    NARCIS (Netherlands)

    Willemze, Rose A.; Luyer, Misha D.; Buurman, Wim A.; de Jonge, Wouter J.

    2015-01-01

    Studies in neuroscience and immunology have clarified much of the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems. As with other organs, intestinal immune responses and the development of immunity seems to be modulated by neural reflexes.

  17. Ventilator and viral induced inflammation

    NARCIS (Netherlands)

    Hennus, M.P.

    2013-01-01

    This thesis expands current knowledge on ventilator induced lung injury and provides insights on the immunological effects of mechanical ventilation during viral respiratory infections. The experimental studies in the first part of this thesis improve our understanding of how mechanical ventilation

  18. Deletion of Foxp3+ regulatory T cells in genetically targeted mice supports development of intestinal inflammation

    Directory of Open Access Journals (Sweden)

    Boehm Franziska

    2012-07-01

    Full Text Available Abstract Background Mice lacking Foxp3+ regulatory T (Treg cells develop severe tissue inflammation in lung, skin, and liver with premature death, whereas the intestine remains uninflamed. This study aims to demonstrate the importance of Foxp3+ Treg for the activation of T cells and the development of intestinal inflammation. Methods Foxp3-GFP-DTR (human diphtheria toxin receptor C57BL/6 mice allow elimination of Foxp3+ Treg by treatment with Dx (diphtheria toxin. The influence of Foxp3+ Treg on intestinal inflammation was tested using the CD4+ T-cell transfer colitis model in Rag−/− C57BL/6 mice and the acute DSS-colitis model. Results Continuous depletion of Foxp3+ Treg in Foxp3-GFP-DTR mice led to dramatic weight loss and death of mice by day 28. After 10 days of depletion of Foxp3+ Treg, isolated CD4+ T-cells were activated and produced extensive amounts of IFN-γ, IL-13, and IL-17A. Transfer of total CD4+ T-cells isolated from Foxp3-GFP-DTR mice did not result in any changes of intestinal homeostasis in Rag−/− C57BL/6 mice. However, administration of DTx between days 14 and 18 after T-cell reconstitution, lead to elimination of Foxp3+ Treg and to immediate weight loss due to intestinal inflammation. This pro-inflammatory effect of Foxp3+ Treg depletion consecutively increased inflammatory cytokine production. Further, the depletion of Foxp3+ Treg from Foxp3-GFP-DTR mice increased the severity of acute dSS-colitis accompanied by 80% lethality of Treg-depleted mice. CD4+ effector T-cells from Foxp3+ Treg-depleted mice produced significantly more pro-inflammatory cytokines. Conclusion Intermittent depletion of Foxp3+ Treg aggravates intestinal inflammatory responses demonstrating the importance of Foxp3+ Treg for the balance at the mucosal surface of the intestine.

  19. Validation study of villous atrophy and small intestinal inflammation in Swedish biopsy registers

    Directory of Open Access Journals (Sweden)

    Montgomery Scott M

    2009-03-01

    Full Text Available Abstract Background Small intestinal biopsy with villous atrophy (VA is the gold standard for the diagnosis of celiac disease (CD. We validated VA (Marsh 3 and small intestinal inflammation without VA (Marsh 1+2 in Swedish regional biopsy registers. Methods All pathology departments in Sweden (n = 28 were searched to identify individuals with VA or duodenal/jejunal inflammation. The validation consisted of blinded examination of biopsy samples, manual review of biopsy reports, web surveys, and patient chart reviews of 121 individuals with VA and 39 with inflammation. Results We identified 29,148 individuals with VA and 13,446 individuals with inflammation. In a blinded examination, Swedish pathologists correctly classified 90% of biopsies with VA. Manual screening of 1,534 biopsy reports (performed by co-author JFL and a research assistant found that comorbidity other than CD was rare. IBD was the most common comorbidity and occurred in 0.3% of biopsies with VA (1.6% in inflammation. Among 114 patients with VA and available data, 108 (95% had a clinical diagnosis of CD. 79% of the validated individuals with VA and 64% of those with inflammation had documented gastrointestinal symptoms prior to biopsy. 88% of the validated individuals with VA had positive CD serology before their first biopsy. 172/180 (96% of Swedish gastroenterologists and 68/68 (100% of pediatricians perform a small intestinal biopsy in at least 9 out of 10 individuals prior to diagnosis of CD. Conclusion Regional biopsy data are feasible to identify individuals with CD and small-intestinal inflammation. The specificity of CD is high in villous atrophy.

  20. Fækal calprotectin er en klinisk anvendelig markør for intestinal inflammation

    DEFF Research Database (Denmark)

    Theede, Klaus; Kiszka-Kanowitz, Marianne; Nordgaard-Lassen, Inge

    2014-01-01

    Faecal calprotectin is a biomarker for inflammation in the intestinal mucosa. Faecal calprotectin has the ability to detect inflammatory causes of gastrointestinal symptoms and to distinguish these from irritable bowel syndrome. The test is very sensitive but not specific to any particular...

  1. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation.

    Science.gov (United States)

    Liu, Bo; Gulati, Ajay S; Cantillana, Viviana; Henry, Stanley C; Schmidt, Elyse A; Daniell, Xiaoju; Grossniklaus, Emily; Schoenborn, Alexi A; Sartor, R Balfour; Taylor, Gregory A

    2013-10-15

    Crohn's disease (CD) is a chronic, immune-mediated, inflammatory disorder of the intestine that has been linked to numerous susceptibility genes, including the immunity-related GTPase (IRG) M (IRGM). IRGs comprise a family of proteins known to confer resistance to intracellular infections through various mechanisms, including regulation of phagosome processing, cell motility, and autophagy. However, despite its association with CD, the role of IRGM and other IRGs in regulating intestinal inflammation is unclear. We investigated the involvement of Irgm1, an ortholog of IRGM, in the genesis of murine intestinal inflammation. After dextran sodium sulfate exposure, Irgm1-deficient [Irgm1 knockout (KO)] mice showed increased acute inflammation in the colon and ileum, with worsened clinical responses. Marked alterations of Paneth cell location and granule morphology were present in Irgm1 KO mice, even without dextran sodium sulfate exposure, and were associated with impaired mitophagy and autophagy in Irgm1 KO intestinal cells (including Paneth cells). This was manifested by frequent tubular and swollen mitochondria and increased LC3-positive autophagic structures. Interestingly, these LC3-positive structures often contained Paneth cell granules. These results suggest that Irgm1 modulates acute inflammatory responses in the mouse intestine, putatively through the regulation of gut autophagic processes, that may be pivotal for proper Paneth cell functioning.

  2. Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

    Science.gov (United States)

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

    2016-09-23

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

  3. Crosstalk between Inflammation and ROCK/MLCK Signaling Pathways in Gastrointestinal Disorders with Intestinal Hyperpermeability

    Directory of Open Access Journals (Sweden)

    Lijun Du

    2016-01-01

    Full Text Available The barrier function of the intestine is essential for maintaining the normal homeostasis of the gut and mucosal immune system. Abnormalities in intestinal barrier function expressed by increased intestinal permeability have long been observed in various gastrointestinal disorders such as Crohn’s disease (CD, ulcerative colitis (UC, celiac disease, and irritable bowel syndrome (IBS. Imbalance of metabolizing junction proteins and mucosal inflammation contributes to intestinal hyperpermeability. Emerging studies exploring in vitro and in vivo model system demonstrate that Rho-associated coiled-coil containing protein kinase- (ROCK- and myosin light chain kinase- (MLCK- mediated pathways are involved in the regulation of intestinal permeability. With this perspective, we aim to summarize the current state of knowledge regarding the role of inflammation and ROCK-/MLCK-mediated pathways leading to intestinal hyperpermeability in gastrointestinal disorders. In the near future, it may be possible to specifically target these specific pathways to develop novel therapies for gastrointestinal disorders associated with increased gut permeability.

  4. Disrupted intestinal microbiota and intestinal inflammation in children with cystic fibrosis and its restoration with Lactobacillus GG: a randomised clinical trial.

    Directory of Open Access Journals (Sweden)

    Eugenia Bruzzese

    Full Text Available Intestinal inflammation is a hallmark of cystic fibrosis (CF. Administration of probiotics can reduce intestinal inflammation and the incidence of pulmonary exacerbations. We investigated the composition of intestinal microbiota in children with CF and analyzed its relationship with intestinal inflammation. We also investigated the microflora structure before and after Lactobacillus GG (LGG administration in children with CF with and without antibiotic treatment.The intestinal microbiota were analyzed by denaturing gradient gel electrophoresis (DGGE, real-time polymerase chain reaction (RT-PCR, and fluorescence in situ hybridization (FISH. Intestinal inflammation was assessed by measuring fecal calprotectin (CLP and rectal nitric oxide (rNO production in children with CF as compared with healthy controls. We then carried out a small double-blind randomized clinical trial with LGG.Twenty-two children with CF children were enrolled in the study (median age, 7 years; range, 2-9 years. Fecal CLP and rNO levels were higher in children with CF than in healthy controls (184±146 µg/g vs. 52±46 µg/g; 18±15 vs. 2.6±1.2 µmol/L NO2 (-, respectively; P<0.01. Compared with healthy controls, children with CF had significantly different intestinal microbial core structures. The levels of Eubacterium rectale, Bacteroides uniformis, Bacteroides vulgatus, Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Faecalibacterium prausnitzii were reduced in children with CF. A similar but more extreme pattern was observed in children with CF who were taking antibiotics. LGG administration reduced fecal CLP and partially restored intestinal microbiota. There was a significant correlation between reduced microbial richness and intestinal inflammation.CF causes qualitative and quantitative changes in intestinal microbiota, which may represent a novel therapeutic target in the treatment of CF. Administration of probiotics restored gut microbiota, supporting

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

    Directory of Open Access Journals (Sweden)

    Karin ede Punder

    2015-05-01

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

  6. Mitochondrial ROS Production Protects the Intestine from Inflammation through Functional M2 Macrophage Polarization

    Directory of Open Access Journals (Sweden)

    Laura Formentini

    2017-05-01

    Full Text Available Mitochondria are signaling hubs in cellular physiology that play a role in inflammatory diseases. We found that partial inhibition of the mitochondrial ATP synthase in the intestine of transgenic mice triggers an anti-inflammatory response through NFκB activation mediated by mitochondrial mtROS. This shielding phenotype is revealed when mice are challenged by DSS-induced colitis, which, in control animals, triggers inflammation, recruitment of M1 pro-inflammatory macrophages, and the activation of the pro-oncogenic STAT3 and Akt/mTOR pathways. In contrast, transgenic mice can polarize macrophages to the M2 anti-inflammatory phenotype. Using the mitochondria-targeted antioxidant MitoQ to quench mtROS in vivo, we observe decreased NFκB activation, preventing its cellular protective effects. These findings stress the relevance of mitochondrial signaling to the innate immune system and emphasize the potential role of the ATP synthase as a therapeutic target in inflammatory and other related diseases.

  7. Astragalus membranaceus Extract Attenuates Inflammation and Oxidative Stress in Intestinal Epithelial Cells via NF-κB Activation and Nrf2 Response

    Directory of Open Access Journals (Sweden)

    Simona Adesso

    2018-03-01

    Full Text Available Astragalus membranaceus, dried root extract, also known as Astragali radix, is used in traditional Chinese medicine as a tonic remedy. Moreover, it has been reported that Astragalus membranaceus could attenuate intestinal inflammation; however, the underlying mechanism for its anti-inflammatory activity in intestinal epithelial cells (IECs remains unclear. In this study, we evaluated Astragalus membranaceus extract (5–100 µg/mL in a model of inflammation and oxidative stress for IECs. We showed that Astragalus membranaceus extract reduced the inflammatory response induced by lipopolysaccharide from E. coli (LPS plus interferon-γ (IFN, decreasing tumor necrosis factor-α (TNF-α release, cycloxygenase-2 (COX-2 and inducible nitric oxide synthase (iNOS expression, nitrotyrosine formation, nuclear factor-κB (NF-κB activation, and reactive oxygen species (ROS release in the non-tumorigenic intestinal epithelial cell line (IEC-6. The antioxidant potential of Astragalus membranaceus extract was also evaluated in a model of hydrogen peroxide (H2O2-induced oxidative stress in IEC-6, indicating that this extract reduced ROS release and increased nuclear factor (erythroid-derived 2-like 2 (Nrf2 activation and the expression of antioxidant cytoprotective factors in these cells. The results contributed to clarify the mechanisms involved in Astragalus membranaceus extract-reduced inflammation and highlighted the potential use of this extract as an anti-inflammatory and antioxidant remedy for intestinal diseases.

  8. Inflammation Induces TDP-43 Mislocalization and Aggregation.

    Directory of Open Access Journals (Sweden)

    Ana Sofia Correia

    Full Text Available TAR DNA-binding protein 43 (TDP-43 is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD. Here we report that lipopolysaccharide (LPS-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

  9. Nopal feeding reduces adiposity, intestinal inflammation and shifts the cecal microbiota and metabolism in high-fat fed rats.

    Directory of Open Access Journals (Sweden)

    Sofia Moran-Ramos

    Full Text Available Nopal is a cactus plant widely consumed in Mexico that has been used in traditional medicine to aid in the treatment of type-2 diabetes. We previously showed that chronic consumption of dehydrated nopal ameliorated hepatic steatosis in obese (fa/fa rats; however, description of the effects on other tissues is sparse. The aim of the present study was to investigate the effects of nopal cladode consumption on intestinal physiology, microbial community structure, adipose tissue, and serum biochemistry in diet-induced obese rats. Rats were fed either a normal fat (NF diet or a HF diet containing 4% of dietary fiber from either nopal or cellulose for 6 weeks. Consumption of nopal counteracted HF-induced adiposity and adipocyte hypertrophy, and induced profound changes in intestinal physiology. Nopal consumption reduced biomarkers of intestinal inflammation (mRNA expression of IL-6 and oxidative stress (ROS, modfied gut microbiota composition, increasing microbial diversity and cecal fermentation (SCFA, and altered the serum metabolome. Interestingly, metabolomic analysis of dehydrated nopal revealed a high choline content, which appeared to generate high levels of serum betaine, that correlated negatively with hepatic triglyceride (TAG levels. A parallel decrease in some of the taxa associated with the production of trimethylamine, suggest an increase in choline absorption and bioavailability with transformation to betaine. The latter may partially explain the previously observed effect of nopal on the development of hepatic steatosis. In conclusion, this study provides new evidence on the effects of nopal consumption on normal and HF-diet induced changes in the intestine, the liver and systemic metabolism.

  10. Nopal feeding reduces adiposity, intestinal inflammation and shifts the cecal microbiota and metabolism in high-fat fed rats.

    Science.gov (United States)

    Moran-Ramos, Sofia; He, Xuan; Chin, Elizabeth L; Tovar, Armando R; Torres, Nimbe; Slupsky, Carolyn M; Raybould, Helen E

    2017-01-01

    Nopal is a cactus plant widely consumed in Mexico that has been used in traditional medicine to aid in the treatment of type-2 diabetes. We previously showed that chronic consumption of dehydrated nopal ameliorated hepatic steatosis in obese (fa/fa) rats; however, description of the effects on other tissues is sparse. The aim of the present study was to investigate the effects of nopal cladode consumption on intestinal physiology, microbial community structure, adipose tissue, and serum biochemistry in diet-induced obese rats. Rats were fed either a normal fat (NF) diet or a HF diet containing 4% of dietary fiber from either nopal or cellulose for 6 weeks. Consumption of nopal counteracted HF-induced adiposity and adipocyte hypertrophy, and induced profound changes in intestinal physiology. Nopal consumption reduced biomarkers of intestinal inflammation (mRNA expression of IL-6) and oxidative stress (ROS), modfied gut microbiota composition, increasing microbial diversity and cecal fermentation (SCFA), and altered the serum metabolome. Interestingly, metabolomic analysis of dehydrated nopal revealed a high choline content, which appeared to generate high levels of serum betaine, that correlated negatively with hepatic triglyceride (TAG) levels. A parallel decrease in some of the taxa associated with the production of trimethylamine, suggest an increase in choline absorption and bioavailability with transformation to betaine. The latter may partially explain the previously observed effect of nopal on the development of hepatic steatosis. In conclusion, this study provides new evidence on the effects of nopal consumption on normal and HF-diet induced changes in the intestine, the liver and systemic metabolism.

  11. Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation.

    Science.gov (United States)

    Koboziev, Iurii; Karlsson, Fridrik; Grisham, Matthew B

    2010-10-01

    The etiologies of the inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis) have not been fully elucidated. However, there is very good evidence implicating T cell and T cell trafficking to the gut and its associated lymphoid tissue as important components in disease pathogenesis. The objective of this review is to provide an overview of the mechanisms involved in naive and effector T cell trafficking to the gut-associated lymphoid tissue (GALT; Peyer's patches, isolated lymphoid follicles), mesenteric lymph nodes and intestine in response to commensal enteric antigens under physiological conditions as well as during the induction of chronic gut inflammation. In addition, recent data suggests that the GALT may not be required for enteric antigen-driven intestinal inflammation in certain mouse models of IBD. These new data suggest a possible paradigm shift in our understanding of how and where naive T cells become activated to yield disease-producing effector cells. © 2010 New York Academy of Sciences.

  12. The macrophage system in the intestinal muscularis externa during inflammation: an immunohistochemical and quantitative study of osteopetrotic mice

    DEFF Research Database (Denmark)

    Mikkelsen, Hanne Birte; Larsen, Jytte Overgaard; Hadberg, Hanne

    2008-01-01

    Intestinal inflammation results in disturbed intestinal motility in humans as well as in animal models. This altered function of smooth muscle cells and/or the enteric nervous system may be caused by activation of macrophages in muscularis externa and a thereby following release of cytokines and ...

  13. Intestinal fibrosis is reduced by early elimination of inflammation in a mouse model of IBD: impact of a "Top-Down" approach to intestinal fibrosis in mice.

    Science.gov (United States)

    Johnson, Laura A; Luke, Amy; Sauder, Kay; Moons, David S; Horowitz, Jeffrey C; Higgins, Peter D R

    2012-03-01

    The natural history of Crohn's disease follows a path of progression from an inflammatory to a fibrostenosing disease, with most patients requiring surgical resection of fibrotic strictures. Potent antiinflammatory therapies reduce inflammation but do not appear to alter the natural history of intestinal fibrosis. The aim of this study was to determine the relationship between intestinal inflammation and fibrogenesis and the impact of a very early "top-down" interventional approach on fibrosis in vivo. In this study we removed the inflammatory stimulus from the Salmonella typhimurium mouse model of intestinal fibrosis by eradicating the S. typhimurium infection with levofloxacin at sequential timepoints during the infection. We evaluated the effect of this elimination of the inflammatory stimulus on the natural history of inflammation and fibrosis as determined by gross pathology, histopathology, mRNA expression, and protein expression. Fibrogenesis is preceded by inflammation. Delayed eradication of the inflammatory stimulus by antibiotic treatment represses inflammation without preventing fibrosis. Early intervention significantly ameliorates but does not completely prevent subsequent fibrosis. This study demonstrates that intestinal fibrosis develops despite removal of an inflammatory stimulus and elimination of inflammation. Early intervention ameliorates but does not abolish subsequent fibrosis, suggesting that fibrosis, once initiated, is self-propagating, suggesting that a very early top-down interventional approach may have the most impact on fibrostenosing disease. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

  14. Effects of propofol on damage of rat intestinal epithelial cells induced by heat stress and lipopolysaccharides

    Energy Technology Data Exchange (ETDEWEB)

    Tang, J.; Jiang, Y. [Southern Medical University, Nanfang Hospital, Department of Anesthesia, Guangzhou, China, Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou (China); Tang, Y.; Chen, B. [Guangzhou General Hospital of Guangzhou Military Command, Department of Intensive Care Unit, Guangzhou, China, Department of Intensive Care Unit, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou (China); Sun, X. [Laboratory of Traditional Chinese Medicine Syndrome, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou (China); Su, L.; Liu, Z. [Guangzhou General Hospital of Guangzhou Military Command, Department of Intensive Care Unit, Guangzhou, China, Department of Intensive Care Unit, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou (China)

    2013-06-25

    Gut-derived endotoxin and pathogenic bacteria have been proposed as important causative factors of morbidity and death during heat stroke. However, it is still unclear what kind of damage is induced by heat stress. In this study, the rat intestinal epithelial cell line (IEC-6) was treated with heat stress or a combination of heat stress and lipopolysaccharide (LPS). In addition, propofol, which plays an important role in anti-inflammation and organ protection, was applied to study its effects on cellular viability and apoptosis. Heat stress, LPS, or heat stress combined with LPS stimulation can all cause intestinal epithelial cell damage, including early apoptosis and subsequent necrosis. However, propofol can alleviate injuries caused by heat stress, LPS, or the combination of heat stress and LPS. Interestingly, propofol can only mitigate LPS-induced intestinal epithelial cell apoptosis, and has no protective role in heat-stress-induced apoptosis. This study developed a model that can mimic the intestinal heat stress environment. It demonstrates the effects on intestinal epithelial cell damage, and indicated that propofol could be used as a therapeutic drug for the treatment of heat-stress-induced intestinal injuries.

  15. Effects of propofol on damage of rat intestinal epithelial cells induced by heat stress and lipopolysaccharides

    International Nuclear Information System (INIS)

    Tang, J.; Jiang, Y.; Tang, Y.; Chen, B.; Sun, X.; Su, L.; Liu, Z.

    2013-01-01

    Gut-derived endotoxin and pathogenic bacteria have been proposed as important causative factors of morbidity and death during heat stroke. However, it is still unclear what kind of damage is induced by heat stress. In this study, the rat intestinal epithelial cell line (IEC-6) was treated with heat stress or a combination of heat stress and lipopolysaccharide (LPS). In addition, propofol, which plays an important role in anti-inflammation and organ protection, was applied to study its effects on cellular viability and apoptosis. Heat stress, LPS, or heat stress combined with LPS stimulation can all cause intestinal epithelial cell damage, including early apoptosis and subsequent necrosis. However, propofol can alleviate injuries caused by heat stress, LPS, or the combination of heat stress and LPS. Interestingly, propofol can only mitigate LPS-induced intestinal epithelial cell apoptosis, and has no protective role in heat-stress-induced apoptosis. This study developed a model that can mimic the intestinal heat stress environment. It demonstrates the effects on intestinal epithelial cell damage, and indicated that propofol could be used as a therapeutic drug for the treatment of heat-stress-induced intestinal injuries

  16. Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice

    Directory of Open Access Journals (Sweden)

    Allison R. Rogala

    2018-02-01

    Full Text Available Crohn's disease (CD represents a chronic inflammatory disorder of the intestinal tract. Several susceptibility genes have been linked to CD, though their precise role in the pathogenesis of this disorder remains unclear. Immunity-related GTPase M (IRGM is an established risk allele in CD. We have shown previously that conventionally raised (CV mice lacking the IRGM ortholog, Irgm1 exhibit abnormal Paneth cells (PCs and increased susceptibility to intestinal injury. In the present study, we sought to utilize this model system to determine if environmental conditions impact these phenotypes, as is thought to be the case in human CD. To accomplish this, wild-type and Irgm1−/− mice were rederived into specific pathogen-free (SPF and germ-free (GF conditions. We next assessed how these differential housing environments influenced intestinal injury patterns, and epithelial cell morphology and function in wild-type and Irgm1−/− mice. Remarkably, in contrast to CV mice, SPF Irgm1−/− mice showed only a slight increase in susceptibility to dextran sodium sulfate-induced inflammation. SPF Irgm1−/− mice also displayed minimal abnormalities in PC number and morphology, and in antimicrobial peptide expression. Goblet cell numbers and epithelial proliferation were also unaffected by Irgm1 in SPF conditions. No microbial differences were observed between wild-type and Irgm1−/− mice, but gut bacterial communities differed profoundly between CV and SPF mice. Specifically, Helicobacter sequences were significantly increased in CV mice; however, inoculating SPF Irgm1−/− mice with Helicobacter hepaticus was not sufficient to transmit a pro-inflammatory phenotype. In summary, our findings suggest the impact of Irgm1-deficiency on susceptibility to intestinal inflammation and epithelial function is critically dependent on environmental influences. This work establishes the importance of Irgm1−/− mice as a model to elucidate host

  17. Mucosal innate immune cells regulate both gut homeostasis and intestinal inflammation.

    Science.gov (United States)

    Kurashima, Yosuke; Goto, Yoshiyuki; Kiyono, Hiroshi

    2013-12-01

    Continuous exposure of intestinal mucosal surfaces to diverse microorganisms and their metabolites reflects the biological necessity for a multifaceted, integrated epithelial and immune cell-mediated regulatory system. The development and function of the host cells responsible for the barrier function of the intestinal surface (e.g., M cells, Paneth cells, goblet cells, and columnar epithelial cells) are strictly regulated through both positive and negative stimulation by the luminal microbiota. Stimulation by damage-associated molecular patterns and commensal bacteria-derived microbe-associated molecular patterns provokes the assembly of inflammasomes, which are involved in maintaining the integrity of the intestinal epithelium. Mucosal immune cells located beneath the epithelium play critical roles in regulating both the mucosal barrier and the relative composition of the luminal microbiota. Innate lymphoid cells and mast cells, in particular, orchestrate the mucosal regulatory system to create a mutually beneficial environment for both the host and the microbiota. Disruption of mucosal homeostasis causes intestinal inflammation such as that seen in inflammatory bowel disease. Here, we review the recent research on the biological interplay among the luminal microbiota, epithelial cells, and mucosal innate immune cells in both healthy and pathological conditions. © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Mast cells play no role in the pathogenesis of postoperative ileus induced by intestinal manipulation.

    Science.gov (United States)

    Gomez-Pinilla, Pedro J; Farro, Giovanna; Di Giovangiulio, Martina; Stakenborg, Nathalie; Némethova, Andrea; de Vries, Annick; Liston, Adrian; Feyerabend, Thorsten B; Rodewald, Hans-Reimer; Rodewald, Hans-Reimwer; Boeckxstaens, Guy E; Matteoli, Gianluca

    2014-01-01

    Intestinal manipulation (IM) during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI). However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC) resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3(Cre/+) , devoid of mast cells but with intact Kit signaling. The role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. Kit(W-sh/W-sh) and Cpa3(Cre/+) mice, and by use of the mast cell stabilizer cromolyn. Kit(W-sh/W-sh) mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3(Cre/+) mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3(Cre/+) mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3(+/+) ). Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI. Here, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast cell inhibitors as a therapeutic approach to shorten POI.

  19. Mast cells play no role in the pathogenesis of postoperative ileus induced by intestinal manipulation.

    Directory of Open Access Journals (Sweden)

    Pedro J Gomez-Pinilla

    Full Text Available INTRODUCTION: Intestinal manipulation (IM during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI. However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3(Cre/+ , devoid of mast cells but with intact Kit signaling. DESIGN: The role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. Kit(W-sh/W-sh and Cpa3(Cre/+ mice, and by use of the mast cell stabilizer cromolyn. RESULTS: Kit(W-sh/W-sh mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3(Cre/+ mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3(Cre/+ mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3(+/+ . Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI. CONCLUSIONS: Here, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast

  20. Retinoic acid signalling is required for the efficient differentiation of CD4+ T cells into pathogenic effector cells during the development of intestinal inflammation

    DEFF Research Database (Denmark)

    Rivollier, Aymeric Marie Christian; Pool, Lieneke; Frising, Ulrika

    Epidemiological studies of vitamin A-deficient populations have illustrated the importance of the vitamin A metabolite retinoic acid (RA) in mucosal immune responses. However, RA seems to be a double-edge sword in CD4+ T cell biology. While it sustains the development of foxp3+ regulatory T cells......, it was also very recently reported to be essential for the stability of the Th1 lineage and to prevent transition to a Th17 program. Here we explored the role of RA signalling in CD4+ T cells during the development of intestinal inflammation in the T cell transfer colitis model. We found that RA signalling......-deficient CD4+ T cells are less potent at inducing intestinal inflammation compared to their RA signalling-competent counterparts and exhibit a differentiation skewing towards more IFNγ- IL-17+, IL-17+IFNγ+ and foxp3+ cells, while their capacity to differentiate into IL-17-IFNγ+ Th1 cells is compromised...

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

    NARCIS (Netherlands)

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

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

  2. Somatostatin does not attenuate intestinal injury in dextran sodium sulphate-induced subacute colitis

    Directory of Open Access Journals (Sweden)

    J. D. van Bergeijk

    1998-01-01

    Full Text Available From several in vitro and in vivo studies involvement of som atostatin (SMS in intestinal inflammation emerge. Acute colitis induced in rats is attenuated by the long-acting SMS analogue octreotide. We studied the potential beneficial effect of SMS on non-acute experimental colitis. BALB/c mice received either saline, SMS-14 (36 or 120 μg daily or octreotide (3 μg daily subcutaneously delivered by implant osmotic pumps. A non-acute colitis was induced by administration of dextran sodium sulphate (DSS 10% in drinking water during 7 days. DSS evoked a mild, superficial pancolitis, most characterized by mucosal ulceration and submucosal influx of neutrophils. Neither SMS-14 nor octreotide reduced mucosal inflammatory score or macroscopical disease activity, although reduction of intestinal levels of interleukin1 β (IL-1 β, IL-6 and IL-10 during DSS was augmented both by SMS and octreotide. A slight increase of neutrophil influx was seen during SMS administration in animals not exposed to DSS. In conclusion, SMS or its long-acting analogue did not reduce intestinal inflammation in non-acute DSS-induced colitis. According to the cytokine profile observed, SMS-14 and octreotide further diminished the reduction of intestinal macrophage and Th2 lymphocyte activity.

  3. G Protein-coupled pH-sensing Receptor OGR1 Is a Regulator of Intestinal Inflammation.

    Science.gov (United States)

    de Vallière, Cheryl; Wang, Yu; Eloranta, Jyrki J; Vidal, Solange; Clay, Ieuan; Spalinger, Marianne R; Tcymbarevich, Irina; Terhalle, Anne; Ludwig, Marie-Gabrielle; Suply, Thomas; Fried, Michael; Kullak-Ublick, Gerd A; Frey-Wagner, Isabelle; Scharl, Michael; Seuwen, Klaus; Wagner, Carsten A; Rogler, Gerhard

    2015-06-01

    A novel family of proton-sensing G protein-coupled receptors, including OGR1, GPR4, and TDAG8, was identified to be important for physiological pH homeostasis and inflammation. Thus, we determined the function of proton-sensing OGR1 in the intestinal mucosa. OGR1 expression in colonic tissues was investigated in controls and patients with IBD. Expression of OGR1 upon cell activation was studied in the Mono Mac 6 (MM6) cell line and primary human and murine monocytes by real-time PCR. Ogr1 knockout mice were crossbred with Il-10 deficient mice and studied for more than 200 days. Microarray profiling was performed using Ogr1 and Ogr1 (WT) residential peritoneal macrophages. Patients with IBD expressed higher levels of OGR1 in the mucosa than non-IBD controls. Treatment of MM6 cells with TNF, led to significant upregulation of OGR1 expression, which could be reversed by the presence of NF-κB inhibitors. Kaplan-Meier survival analysis showed a significantly delayed onset and progression of rectal prolapse in female Ogr1/Il-10 mice. These mice displayed significantly less rectal prolapses. Upregulation of gene expression, mediated by OGR1, in response to extracellular acidification in mouse macrophages was enriched for inflammation and immune response, actin cytoskeleton, and cell-adhesion gene pathways. OGR1 expression is induced in cells of human macrophage lineage and primary human monocytes by TNF. NF-κB inhibition reverses the induction of OGR1 expression by TNF. OGR1 deficiency protects from spontaneous inflammation in the Il-10 knockout model. Our data indicate a pathophysiological role for pH-sensing receptor OGR1 during the pathogenesis of mucosal inflammation.

  4. Human milk oligosaccharide effects on intestinal function and inflammation after preterm birth in pigs

    DEFF Research Database (Denmark)

    Rasmussen, Stine O.; Martin, Lena; Østergaard, Mette V.

    2017-01-01

    (IF) improves intestinal function, bacterial colonization and NEC resistance immediately after preterm birth, as tested in a preterm pig model. Mixtures of HMOs were investigated in intestinal epithelial cells and in preterm pigs (n=112) fed IF supplemented without (CON) or with a mixture of four HMOs...... (4-HMO) or >25 HMOs (25-HMO, 5-10 g/L given for 5 or 11 days). The 25-HMO blend decreased cell proliferation and both HMO blends decreased lipopolysaccharide-induced interleukin-8 secretion in IPEC-J2 cells, relative to control (P

  5. The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

    Science.gov (United States)

    Zaiss, Mario M.; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W.; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; McCoy, Kathleen D.; Macpherson, Andrew J.; Croese, John; Giacomin, Paul R.; Loukas, Alex; Junt, Tobias; Marsland, Benjamin J.; Harris, Nicola L.

    2015-01-01

    Summary Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions. PMID:26522986

  6. ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation.

    Science.gov (United States)

    Pearson, Claire; Thornton, Emily E; McKenzie, Brent; Schaupp, Anna-Lena; Huskens, Nicky; Griseri, Thibault; West, Nathaniel; Tung, Sim; Seddon, Benedict P; Uhlig, Holm H; Powrie, Fiona

    2016-01-18

    Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.

  7. The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease

    International Nuclear Information System (INIS)

    Teahon, K.; Smethurst, P.; Pearson, M.; Levi, A.J.; Bjarnason, I.

    1991-01-01

    This study examines whether treatment of acute Crohn's disease with an elemental diet improves intestinal integrity and inflammation as assessed by a 51Cr-labeled ethylenediaminetetraacetatic acid (EDTA) permeability test and the fecal excretion of 111In-labeled autologous leukocytes, respectively. Thirty-four patients with active Crohn's disease completed a 4-week treatment course with an elemental diet. Active disease was characterized by increased intestinal permeability [24-hour urine excretion of orally administered 51Cr-EDTA, 6.4% ± 0.6% (mean ± SE); normal, less than 3.0%] and by high fecal excretion of 111In-labeled leukocytes (14.2% ± 1.1%; normal, less than 1.0%). Twenty-seven (80%) went into clinical remission, usually within a week of starting treatment. After 4 weeks of treatment, there was a significant decrease in both the urine excretion of 51Cr-EDTA (to 3.4% ± 0.5%; P less than 0.01) and the fecal excretion of 111In (to 5.7% ± 1.0%; P less than 0.001), indicating that such treatment is not just symptomatic. A framework for the mechanism by which elemental diet works, centering around the importance of the integrity of the intestinal barrier function, is proposed, and also appears to provide a logical explanation for some relapses of the disease

  8. Does sucralfate prevent apoptosis occurring in the ischemia/reperfusion-induced intestinal injury?

    Science.gov (United States)

    Sencan, A; Yilmaz, O; Ozer, E; Günşar, C; Genç, K; Ulukuş, C; Taneli, C; Mir, E

    2003-08-01

    We have shown in a previous study that sucralfate is beneficial in the prophylaxis and treatment of hypoxia/reoxygenation-induced intestinal injury. The aim of this study is to investigate whether sucralfate has any effect on the prevention of apoptosis in the ischemia/reperfusion (I/R)-induced intestinal injury. Rats were randomized into three groups. Group 1 and 2 were subjected to I/R. Group 1 (treatment group) received sucralfate while group 2 (treatment control group) did not. Group 3 served as a normal control group (sham group). The terminal ileum was harvested for histopathologic investigation by light microscopy. The presence of apoptotic enterocytes (DNA fragmentation in cell nuclei) was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end-labeling (TUNEL) reaction. In treatment control group, 3 of 7 rats had severe inflammation. None of the sucralfate-treated rats showed severe inflammation, 6 of them only showed mild inflammatory changes (p < 0.05). The apoptotic percentage was found to be 37.1 +/- 9.4 in the sucralfate-treated group (group 1), whereas it was 45.4 +/- 3.9 in the untreated group (group 2) (p < 0.05). The sham group had a completely normal intestinal architecture. The present study shows that 1) the experimental model of I/R-induced intestinal injury induces enterocyte apoptosis; 2) sucralfate decreases enterocyte apoptosis in the experimental model of I/R-induced intestinal injury which may play a key role in the pathophysiological events leading to failure of the intrinsic gut barrier defense mechanisms.

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

    Directory of Open Access Journals (Sweden)

    Ashlee B. Carter

    2009-01-01

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

  10. Early administration of probiotic Lactobacillus acidophilus and/or prebiotic inulin attenuates pathogen-mediated intestinal inflammation and Smad 7 cell signaling

    Science.gov (United States)

    Foye, Ondulla T.; Huang, I-Fei; Chiou, Christine C.; Walker, W. Allan; Shi, Hai Ning

    2014-01-01

    Immaturity of gut-associated immunity may contribute to pediatric mortality associated with enteric infections. A murine model to parallel infantile enteric disease was used to determine the effects of probiotic, Lactobacillus acidophilus (La), prebiotic, inulin, or both (synbiotic, syn) on pathogen-induced inflammatory responses, NF-κB, and Smad 7 signaling. Newborn mice were inoculated bi-weekly for 4 weeks with La, inulin, or syn and challenged with Citrobacter rodentium (Cr) at 5 weeks. Mouse intestinal epithelial cells (CMT93) were exposed to Cr to determine temporal alterations in NF-Kappa B and Smad 7 levels. Mice with pretreatment of La, inulin, and syn show reduced intestinal inflammation following Cr infection compared with controls, which is associated with significantly reduced bacterial colonization in La, inulin, and syn animals. Our results further show that host defense against Cr infection correlated with enhanced colonic IL-10 and transforming growth factor-β expression and inhibition of NF-κB in syn-treated mice, whereas mice pretreated with syn, La, or inulin had attenuation of Cr-induced Smad 7 expression. There was a temporal Smad 7 and NF-κB intracellular accumulation post-Cr infection and post-tumor necrosis factor stimulation in CMT93 cells. These results, therefore, suggest that probiotic, La, prebiotic inulin, or synbiotic may promote host-protective immunity and attenuate Cr-induced intestinal inflammation through mechanisms affecting NF-κB and Smad 7 signaling. PMID:22524476

  11. Probiotics and Probiotic Metabolic Product Improved Intestinal Function and Ameliorated LPS-Induced Injury in Rats.

    Science.gov (United States)

    Deng, Bo; Wu, Jie; Li, Xiaohui; Men, Xiaoming; Xu, Ziwei

    2017-11-01

    In the present study, we sought to determine the effects of Bacillus subtilis (BAS) and Bacillus licheniformis (BAL) in rats after lipopolysaccharide (LPS)-induced acute intestinal inflammation. We also determined whether the B. subtilis metabolic product (BASM) is as effective as the live-cell probiotic. 60 male SD rats were randomly assigned to five groups and administered a diet containing 0.05% B. licheniformis (BAL group), 0.05% B. subtilis (BAS group), 0.5% B. subtilis metabolic product (BASM group), or a basic diet (PC group and NC group) for 40 days. On day 40, BAL, BAS, BASM, and NC groups were injected with 4 mg/kg body weight LPS. 4 h later, all rats were anesthetized and sacrificed. The results showed that the administration of B. licheniformis and B. subtilis improved intestinal function as evidenced by histology, increased enzyme activity, and mucosal thickness. They also increased the number of intraepithelial lymphocytes and decreased mucosal myeloperoxidase activity and plasma TNF-α. In addition, the cecal content of B. subtilis-treated rats had significantly increased microbial diversity, decreased numbers of Firmicutes, and increased numbers of Bacteroidetes as compared to rats fed basic diets. Similar to BAS group, the cecal content of B. licheniformis-treated rats decreased the number of Firmicutes. Administration of B. subtilis metabolic product had similar effects on intestinal function, inflammation response, and microbial diversity as B. subtilis but these effects were attenuated. In conclusion, administration of probiotic strains B. licheniformis or B. subtilis improved intestinal function, ameliorated the inflammation response, and modulated microflora after LPS-induced acute inflammation in rats. Non-living cells also exerted probiotic properties but live cells tended to function better.

  12. Staphylococcus aureus induces IL-8 expression through its lipoproteins in the human intestinal epithelial cell, Caco-2.

    Science.gov (United States)

    Kang, Seok-Seong; Noh, Su Young; Park, Ok-Jin; Yun, Cheol-Heui; Han, Seung Hyun

    2015-09-01

    Staphylococcus aureus can cause the intestinal inflammatory diseases. However, little is known about the molecular mechanism of S. aureus infection in the intestine. In the present study, we investigated whether S. aureus could stimulate human intestinal epithelial cells triggering inflammation. When the human intestinal epithelial cell-line, Caco-2, and the primary colon cells were stimulated with ethanol-inactivated S. aureus, IL-8 expression was induced in a dose-dependent manner. The inactivated S. aureus preferentially stimulated Toll-like receptor (TLR) 2 rather than TLR4. Lipoproteins, lipoteichoic acid (LTA), and peptidoglycan (PGN) are considered as potential TLR2 ligands of S. aureus. Interestingly, S aureus lipoproteins and Pam2CSK4 mimicking Gram-positive bacterial lipoproteins, but not LTA and PGN of S. aureus, significantly induced IL-8 expression in Caco-2 cells. Furthermore, lipoprotein-deficient S. aureus mutant strain failed to induce IL-8 production. Collectively, these results suggest that S. aureus stimulates the human intestinal epithelial cells to induce the chemokine IL-8 production through its lipoproteins, potentially contributing the development of intestinal inflammation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Plasma endocannabinoid levels in lean, overweight and obese humans: relationships with intestinal permeability markers, inflammation and incretin secretion.

    Science.gov (United States)

    Little, Tanya J; Cvijanovic, Nada; DiPatrizio, Nicholas V; Argueta, Donovan A; Rayner, Christopher K; Feinle-Bisset, Christine; Young, Richard L

    2018-02-13

    Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation, however little is known of these effects in humans. This study aimed to: (i) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl-sn-glycerol (2-AG) and OEA in humans, and (ii) examine relationships with intestinal permeability, inflammation markers and incretin hormone secretion. 20 lean, 18 overweight and 19 obese participants underwent intraduodenal Intralipid® infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumour necrosis factor-α (TNF-α), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and toll-like receptor-4 (TLR4) (RT-PCR), were assessed. Fasting plasma AEA was increased in obese, compared with lean and overweight (Plean (Plean and overweight. The relationships between plasma AEA with duodenal ZO-1 and IAP, and GIP, suggest that altered endocannabinoid signalling may contribute to changes in intestinal permeability, inflammation and incretin release in human obesity.

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

    NARCIS (Netherlands)

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

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

  15. E Durans Strain M4-5 Isolated From Human Colonic Flora Attenuates Intestinal Inflammation

    DEFF Research Database (Denmark)

    Avram-Hananel, L.; Stock, J.; Parlesak, Alexandr

    2010-01-01

    to examine in vivo effects of prevention and therapy with E durans on clinical, biochemical, and histologic parameters of inflammation. RESULTS: In the coculture model, treatment with E durans and with butyrate reduced basal as well as E coli stimulated secretion of IL-8, IL-6, and TNF-α and increased...... inflammation, and inhibited colonic transcription of proinflammatory immune factors. The effect of therapeutic treatment alone on these parameters was more moderate but still significant. CONCLUSIONS: We conclude that E durans strain M4 to 5 and its metabolic product butyrate induce significant anti...

  16. High level of fecal calprotectin at age 2 months as a marker of intestinal inflammation predicts atopic dermatitis and asthma by age 6

    NARCIS (Netherlands)

    Orivuori, L.; Mustonen, K.; de Goffau, M. C.; Hakala, S.; Paasela, M.; Roduit, C.; Dalphin, J. -C.; Genuneit, J.; Lauener, R.; Riedler, J.; Weber, J.; von Mutius, E.; Pekkanen, J.; Harmsen, H. J. M.; Vaarala, O.

    BackgroundGut microbiota and intestinal inflammation regulate the development of immune-mediated diseases, such as allergies. Fecal calprotectin is a biomarker of intestinal inflammation. ObjectiveWe evaluated the association of early-age fecal calprotectin levels to the later development of

  17. Intestinal upregulation of melanin-concentrating hormone in TNBS-induced enterocolitis in adult zebrafish.

    Directory of Open Access Journals (Sweden)

    Brenda M Geiger

    Full Text Available BACKGROUND: Melanin-concentrating hormone (MCH, an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD. Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzene-sulfonic acid (TNBS develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown. METHODS: In the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels. RESULTS: Treatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours post-challenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. CONCLUSIONS: Taken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species.

  18. Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms.

    Science.gov (United States)

    Lechuga, Susana; Ivanov, Andrei I

    2017-07-01

    The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Colonic insufflation with carbon monoxide gas inhibits the development of intestinal inflammation in rats

    Directory of Open Access Journals (Sweden)

    Takagi Tomohisa

    2012-09-01

    Full Text Available Abstract Background The pathogenesis of inflammatory bowel disease (IBD is complex, and an effective therapeutic strategy has yet to be established. Recently, carbon monoxide (CO has been reported to be capable of reducing inflammation by multiple mechanisms. In this study, we evaluated the role of colonic CO insufflation in acute colitis induced by trinitrobenzene sulfonic acid (TNBS in rats. Methods Acute colitis was induced with TNBS in male Wistar rats. Following TNBS administration, the animals were treated daily with 200 ppm of intrarectal CO gas. The distal colon was removed to evaluate various parameters of inflammation, including thiobarbituric acid (TBA-reactive substances, tissue-associated myeloperoxidase (MPO activity, and the expression of cytokine-induced neutrophil chemoattractant (CINC-1 in colonic mucosa 7 days after TNBS administration. Results The administration of TNBS induced ulceration with surrounding edematous swelling in the colon. In rats treated with CO gas, the colonic ulcer area was smaller than that of air-treated rats 7 days after TNBS administration. The wet colon weight was significantly increased in the TNBS-induced colitis group, which was markedly abrogated by colonic insufflation with CO gas. The increase of MPO activity, TBA-reactive substances, and CINC-1 expression in colonic mucosa were also significantly inhibited by colonic insufflation with CO gas. Conclusions Colonic insufflation with CO gas significantly ameliorated TNBS-induced colitis in rats. Clinical application of CO gas to improve colonic inflammatory conditions such as IBD might be useful.

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

    Directory of Open Access Journals (Sweden)

    Daniela Frasca

    2017-08-01

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

  1. Prophylactic Ozone Administration Reduces Intestinal Mucosa Injury Induced by Intestinal Ischemia-Reperfusion in the Rat

    Directory of Open Access Journals (Sweden)

    Ozkan Onal

    2015-01-01

    prevented intestine from ischemia reperfusion injury. It is thought that the therapeutic effect of ozone is associated with increase in antioxidant enzymes and protection of cells from oxidation and inflammation.

  2. The intestinal microbiota determines the colitis‐inducing potential of T‐bet‐deficient Th cells in mice

    Science.gov (United States)

    Zimmermann, Jakob; Durek, Pawel; Kühl, Anja A.; Schattenberg, Florian; Maschmeyer, Patrick; Siracusa, Francesco; Lehmann, Katrin; Westendorf, Kerstin; Weber, Melanie; Riedel, René; Müller, Susann; Radbruch, Andreas

    2017-01-01

    Abstract Conflicting evidence has been provided as to whether induction of intestinal inflammation by adoptive transfer of naïve T cells into Rag −/− mice requires expression of the transcription factor T‑bet by the T cells. Here, we formally show that the intestinal microbiota composition of the Rag −/− recipient determines whether or not T‐bet‐deficient Th cells can induce colitis and we have resolved the differences of the two microbiomes, permissive or non‐permissive to T‐bet‐independent colitis. Our data highlight the dominance of the microbiota over particular T cell differentiation programs in the pathogenesis of chronic intestinal inflammation. PMID:28875499

  3. Ferulic acid ameliorates radiation induced duodenal inflammation

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  4. Precision cut intestinal slices are an appropriate ex vivo model to study NSAID-induced intestinal toxicity in rats

    NARCIS (Netherlands)

    Niu, Xiaoyu; de Graaf, Inge A. M.; van der Bij, Hendrik A.; Groothuis, Geny M. M.

    2014-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used therapeutic agents, however, they are associated with a high prevalence of intestinal side effects. In this investigation, rat precision cut intestinal slices (PCIS) were evaluated as an ex vivo model to study NSAID-induced intestinal

  5. Eosinophils may play regionally disparate roles in influencing IgA(+) plasma cell numbers during large and small intestinal inflammation.

    Science.gov (United States)

    Forman, Ruth; Bramhall, Michael; Logunova, Larisa; Svensson-Frej, Marcus; Cruickshank, Sheena M; Else, Kathryn J

    2016-05-31

    Eosinophils are innate immune cells present in the intestine during steady state conditions. An intestinal eosinophilia is a hallmark of many infections and an accumulation of eosinophils is also observed in the intestine during inflammatory disorders. Classically the function of eosinophils has been associated with tissue destruction, due to the release of cytotoxic granule contents. However, recent evidence has demonstrated that the eosinophil plays a more diverse role in the immune system than previously acknowledged, including shaping adaptive immune responses and providing plasma cell survival factors during the steady state. Importantly, it is known that there are regional differences in the underlying immunology of the small and large intestine, but whether there are differences in context of the intestinal eosinophil in the steady state or inflammation is not known. Our data demonstrates that there are fewer IgA(+) plasma cells in the small intestine of eosinophil-deficient ΔdblGATA-1 mice compared to eosinophil-sufficient wild-type mice, with the difference becoming significant post-infection with Toxoplasma gondii. Remarkably, and in complete contrast, the absence of eosinophils in the inflamed large intestine does not impact on IgA(+) cell numbers during steady state, and is associated with a significant increase in IgA(+) cells post-infection with Trichuris muris compared to wild-type mice. Thus, the intestinal eosinophil appears to be less important in sustaining the IgA(+) cell pool in the large intestine compared to the small intestine, and in fact, our data suggests eosinophils play an inhibitory role. The dichotomy in the influence of the eosinophil over small and large intestinal IgA(+) cells did not depend on differences in plasma cell growth factors, recruitment potential or proliferation within the different regions of the gastrointestinal tract (GIT). We demonstrate for the first time that there are regional differences in the requirement of

  6. Effects of probiotic Lactobacillus rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS supplementation on intestinal and systemic markers of inflammation in ApoE*3Leiden mice consuming a high-fat diet.

    Science.gov (United States)

    Oksaharju, Anna; Kooistra, Teake; Kleemann, Robert; van Duyvenvoorde, Wim; Miettinen, Minja; Lappalainen, Jani; Lindstedt, Ken A; Kovanen, Petri T; Korpela, Riitta; Kekkonen, Riina A

    2013-07-14

    A high-fat diet disturbs the composition and function of the gut microbiota and generates local gut-associated and also systemic responses. Intestinal mast cells, for their part, secrete mediators which play a role in the orchestration of physiological and immunological functions of the intestine. Probiotic bacteria, again, help to maintain the homeostasis of the gut microbiota by protecting the gut epithelium and regulating the local immune system. In the present study, we explored the effects of two probiotic bacteria, Lactobacillus rhamnosus GG (GG) and Propionibacterium freudenreichii spp. shermanii JS (PJS), on high fat-fed ApoE*3Leiden mice by estimating the mast cell numbers and the immunoreactivity of TNF-α and IL-10 in the intestine, as well as plasma levels of several markers of inflammation and parameters of lipid metabolism. We found that mice that received GG and PJS exhibited significantly lower numbers of intestinal mast cells compared with control mice. PJS lowered intestinal immunoreactivity of TNF-α, while GG increased intestinal IL-10. PJS was also observed to lower the plasma levels of markers of inflammation including vascular cell adhesion molecule 1, and also the amount of gonadal adipose tissue. GG lowered alanine aminotransferase, a marker of hepatocellular activation. Collectively, these data demonstrate that probiotic GG and PJS tend to down-regulate both intestinal and systemic pro-inflammatory changes induced by a high-fat diet in this humanised mouse model.

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

    African Journals Online (AJOL)

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

  8. Radiation-induced recurrent intestinal pseudo-obstruction

    International Nuclear Information System (INIS)

    Conklin, J.L.; Anuras, S.

    1981-01-01

    The syndrome of intestinal pseudo-obstruction is a complex of signs and symptoms of intestinal obstruction without evidence of mechanical obstruction of the intestinal lumen. A patient with radiation-induced intestinal pseudoobstruction is described. The patient is a 74-year old woman with a history of chronic diarrhea, recurrent episodes of crampy abdominal pain, nausea and vomiting since receiving a 13,000 rad radiation dose to the pelvis in 1954. She has been hospitalized on many occasions for symptoms and signs of bowel obstruction. Upper gastrointestinal contrast roentgenograms with small bowel follow-through done during these episodes revealed multiple dilated loops of small bowel with no obstructing lesion. Barium enemas revealed no obstructing lesion. Each episode resolved with conservative therapy. Other secondary causes for intestinal pseudo-obstruction were ruled out in our patient. She gave no history of familial gastrointestinal disorders. Although postirradiation motility abnormalities have been demonstrated experimentally this is the first report of radiation induced intestinal pseudo-obstruction

  9. Saccharomyces cerevisiae Boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome

    Directory of Open Access Journals (Sweden)

    Imourana Alassane-Kpembi

    2018-05-01

    Full Text Available Type B trichothecene mycotoxin deoxynivalenol (DON is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae, have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE was observed after treatment by yeast only. By contrast, 3619 probes—corresponding to 2771 genes—were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes. Prototypical inflammation signaling pathways triggered by DON, including NF-κB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast.

  10. Saccharomyces cerevisiae Boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome.

    Science.gov (United States)

    Alassane-Kpembi, Imourana; Pinton, Philippe; Hupé, Jean-François; Neves, Manon; Lippi, Yannick; Combes, Sylvie; Castex, Mathieu; Oswald, Isabelle P

    2018-05-15

    Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro-inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae , have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probes-corresponding to 2771 genes-were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-κB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast.

  11. Intestinal CYP2E1: A mediator of alcohol-induced gut leakiness

    Directory of Open Access Journals (Sweden)

    Christopher B. Forsyth

    2014-01-01

    Full Text Available Chronic alcohol use can result in many pathological effects including alcoholic liver disease (ALD. While alcohol is necessary for the development of ALD, only 20–30% of alcoholics develop alcoholic steatohepatitis (ASH with progressive liver disease leading to cirrhosis and liver failure (ALD. This suggests that while chronic alcohol consumption is necessary it is not sufficient to induce clinically relevant liver damage in the absence of a secondary risk factor. Studies in rodent models and alcoholic patients show that increased intestinal permeability to microbial products like endotoxin play a critical role in promoting liver inflammation in ALD pathogenesis. Therefore identifying mechanisms of alcohol-induced intestinal permeability is important in identifying mechanisms of ALD and for designing new avenues for therapy. Cyp2e1 is a cytochrome P450 enzyme that metabolizes alcohol has been shown to be upregulated by chronic alcohol use and to be a major source of oxidative stress and liver injury in alcoholics and in animal and in vitro models of chronic alcohol use. Because Cyp2e1 is also expressed in the intestine and is upregulated by chronic alcohol use, we hypothesized it could play a role in alcohol-induced intestinal hyperpermeability. Our in vitro studies with intestinal Caco-2 cells and in mice fed alcohol showed that circadian clock proteins CLOCK and PER2 are required for alcohol-induced permeability. We also showed that alcohol increases Cyp2e1 protein and activity but not mRNA in Caco-2 cells and that an inhibitor of oxidative stress or siRNA knockdown of Cyp2e1 prevents the increase in CLOCK or PER2 proteins and prevents alcohol-induced hyperpermeability. With our collaborators we have also shown that Cyp2e1 knockout mice are resistant to alcohol-induced gut leakiness and liver inflammation. Taken together our data support a novel Cyp2e1-circadian clock protein mechanism for alcohol-induced gut leakiness that could provide new

  12. Curcumin Attenuates Gamma Radiation Induced Intestinal Damage in Rats

    International Nuclear Information System (INIS)

    EI-Tahawy, N.A.

    2009-01-01

    Small Intestine exhibits numerous morphological and functional alterations during radiation exposure. Oxidative stress, a factor implicated in the intestinal injury may contribute towards some of these alterations. The present work was designed to evaluate the efficacy of curcumin, a yellow pigment of turmeric on y-radiation-induced oxidative damage in the small intestine by measuring alterations in the level of thiobarbituric acid reactive substances (TSARS), serotonin metabolism, catecholamine levels, and monoamine oxidase (MAO) activity in parallel to changes in the architecture of intestinal tissues. In addition, monoamine level, MAO activity and TSARS level were determined in the serum. Curcumin was supplemented orally via gavages, to rats at a dose of (45 mg/ Kg body wt/ day) for 2 weeks pre-irradiation and the last supplementation was 30 min pre exposure to 6.5 Gy gamma radiations (applied as one shot dose). Animals were sacrificed on the 7th day after irradiation. The results demonstrated that, whole body exposure of rats to ionizing radiation has induced oxidative damage in small intestine obvious by significant increases of TSARS content, MAO activity and 5-hydroxy indole acetic acid (5-HIAA) and by significant decreases of serotonin (5-HT), dopamine (DA), norepinephrine (NE) and epinephrine (EPI) levels. In parallel histopathological studies of the small intestine of irradiated rats through light microscopic showed significant decrease in the number of villi, villus height, mixed sub mucosa layer with more fibres and fibroblasts. Intestinal damage was in parallel to significant alterations of serum MAO activity, TBARS, 5-HT, DA, NE and EPI levels. Administration of curcumin before irradiation has significantly improved the levels of monoamines in small intestine and serum of irradiated rats, which was associated with significant amelioration in MAO activity and TBARS contents

  13. Inhibition of Epithelial TNF-α Receptors by Purified Fruit Bromelain Ameliorates Intestinal Inflammation and Barrier Dysfunction in Colitis.

    Science.gov (United States)

    Zhou, Zijuan; Wang, Liang; Feng, Panpan; Yin, Lianhong; Wang, Chen; Zhi, Shengxu; Dong, Jianyi; Wang, Jingyu; Lin, Yuan; Chen, Dapeng; Xiong, Yongjian; Peng, Jinyong

    2017-01-01

    Activation of the TNF-α receptor (TNFR) leads to an inflammatory response, and anti-TNF therapy has been administered to reduce inflammation symptoms and heal mucosal ulcers in inflammatory bowel disease (IBD). Bromelain, a complex natural mixture of proteolytic enzymes, has been shown to exert anti-inflammatory effects. This study aimed to investigate the effect of purified fruit bromelain (PFB)-induced inhibition of epithelial TNFR in a rat colitis model. Colitis was established by intracolonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. Expression of TNFR1 and TNFR2 was measured by quantitative RT-PCR and western blotting. The effect of PFB on colitis was evaluated by examining the inflammatory response and intestinal epithelial barrier function. Our results showed that both TNFR1 and TNFR2 expression were significantly increased in a colitis model, and the increase was significantly reversed by PFB. Colitis symptoms, including infiltration of inflammatory cells, cytokine profiles, epithelial cell apoptosis, and epithelial tight junction barrier dysfunction were significantly ameliorated by PFB. Compared with fruit bromelain and stem bromelain complex, the inhibition of TNFR2 induced by PFB was stronger than that exhibited on TNFR1. These results indicate that PFB showed a stronger selective inhibitory effect on TNFR2 than TNFR1. In other words, purification of fruit bromelain increases its selectivity on TNFR2 inhibition. High expression of epithelial TNFRs in colitis was significantly counteracted by PFB, and PFB-induced TNFR inhibition ameliorated colitis symptoms. These results supply novel insights into potential IBD treatment by PFB.

  14. Evaluation value of intestinal flora detection for intestinal mucosal inflammation and immune response in patients with ulcerative colitis

    Directory of Open Access Journals (Sweden)

    Yan Zou

    2017-09-01

    Full Text Available Objective: To study the evaluation value of intestinal flora detection for intestinal mucosal inflammatory response and immune response in patients with ulcerative colitis. Methods: The patients who were diagnosed with ulcerative colitis in Zigong Fifth People’s Hospital between March 2015 and February 2017 were selected as the UC group, and those who were diagnosed with colonic polyps were selected as the control group. Fresh excreta were collected to detect the number of intestinal flora, and the diseased intestinal mucosa tissue was collected to detect the expression of inflammatory response molecules and immune cell transcription factors. Results: enterococcus contents in intestinal tract and TLR4, NF-kB, TNF-α, HMGB-1, T-bet and RORC mRNA expression levels in intestinal mucosa of UC group were significantly higher than those of control group while bifidobacteria contents in intestinal tract and SOCS2, SOCS3, Foxp3 and GATA-3 mRNA expression levels were significantly lower than those of control group; TLR4, NF-kB, TNF-α, HMGB-1, T-bet and RORC mRNA expression levels in intestinal mucosa of UC patients with grade II and grade III flora disturbance were significantly higher than those of UC patients with normal flora and grade I flora disturbance while SOCS2, SOCS3, Foxp3 and GATA-3 mRNA expression levels were significantly lower than those of UC patients with normal flora and grade I flora disturbance; TLR4, NF-kB, TNF-α, HMGB-1, T-bet and RORC mRNA expression levels in intestinal mucosa of UC patients with grade III flora disturbance were significantly higher than those of UC patients with grade II flora disturbance while SOCS2, SOCS3, Foxp3 and GATA-3 mRNA expression levels were significantly lower than those of UC patients with grade II flora disturbance. Conclusion: The intestinal flora disturbance in patients with ulcerative colitis can result in inflammatory response activation and immune response disorder.

  15. Melatonin prevents inflammation and oxidative stress caused by abdominopelvic and total body irradiation of rat small intestine.

    Science.gov (United States)

    Guney, Y; Hicsonmez, A; Uluoglu, C; Guney, H Z; Ozel Turkcu, U; Take, G; Yucel, B; Caglar, G; Bilgihan, A; Erdogan, D; Nalca Andrieu, M; Kurtman, C; Zengil, H

    2007-10-01

    We investigated the day-night differences in intestinal oxidative-injury and the inflammatory response following total body (TB) or abdominopelvic (AP) irradiation, and the influence of melatonin administration on tissue injury induced by radiation. Rats (male Wistar, weighing 220-280 g) in the irradiated groups were exposed to a dose of 8 Gy to the TB or AP region in the morning (resting period - 1 h after light onset) or evening (activity span - 13 h after light onset). Vehicle or melatonin was administered immediately before, immediately after and 24 h after irradiation (10, 2.0 and 10 mg/kg, ip, respectively) to the irradiated rats. AP (P < 0.05) and TB (P < 0.05) irradiation applied in the morning caused a significant increase in thiobarbituric acid reactive substance (TBARS) levels. Melatonin treatment in the morning (P < 0.05) or evening (P < 0.05) decreased TBARS levels after TB irradiation. After AP irradiation, melatonin treatment only in the morning caused a significant decrease in TBARS levels (P < 0.05). Although we have confirmed the development of inflammation after radiotherapy by histological findings, neither AP nor TB irradiation caused any marked changes in myeloperoxidase activity in the morning or evening. Our results indicate that oxidative damage is more prominent in rats receiving TB and AP irradiation in the morning and melatonin appears to have beneficial effects on oxidative damage irrespective of the time of administration. Increased neutrophil accumulation indicates that melatonin administration exerts a protective effect on AP irradiation-induced tissue oxidative injury, especially in the morning.

  16. Melatonin prevents inflammation and oxidative stress caused by abdominopelvic and total body irradiation of rat small intestine

    Directory of Open Access Journals (Sweden)

    Y. Guney

    2007-10-01

    Full Text Available We investigated the day-night differences in intestinal oxidative-injury and the inflammatory response following total body (TB or abdominopelvic (AP irradiation, and the influence of melatonin administration on tissue injury induced by radiation. Rats (male Wistar, weighing 220-280 g in the irradiated groups were exposed to a dose of 8 Gy to the TB or AP region in the morning (resting period - 1 h after light onset or evening (activity span - 13 h after light onset. Vehicle or melatonin was administered immediately before, immediately after and 24 h after irradiation (10, 2.0 and 10 mg/kg, ip, respectively to the irradiated rats. AP (P < 0.05 and TB (P < 0.05 irradiation applied in the morning caused a significant increase in thiobarbituric acid reactive substance (TBARS levels. Melatonin treatment in the morning (P < 0.05 or evening (P < 0.05 decreased TBARS levels after TB irradiation. After AP irradiation, melatonin treatment only in the morning caused a significant decrease in TBARS levels (P < 0.05. Although we have confirmed the development of inflammation after radiotherapy by histological findings, neither AP nor TB irradiation caused any marked changes in myeloperoxidase activity in the morning or evening. Our results indicate that oxidative damage is more prominent in rats receiving TB and AP irradiation in the morning and melatonin appears to have beneficial effects on oxidative damage irrespective of the time of administration. Increased neutrophil accumulation indicates that melatonin administration exerts a protective effect on AP irradiation-induced tissue oxidative injury, especially in the morning.

  17. Modulation of intestinal inflammation by minimal enteral nutrition with amniotic fluid in preterm pigs

    DEFF Research Database (Denmark)

    Østergaard, Mette Viberg; Bering, Stine Brandt; Jensen, Michael Ladegaard

    2014-01-01

    Background: Necrotizing enterocolitis (NEC) is a severe inflammatory disorder, associated with the difficult transition from parenteral to enteral feeding after preterm birth. We hypothesized that minimal enteral nutrition (MEN) with amniotic fluid (AF), prior to enteral formula feeding, would...... improve resistance to NEC in preterm pigs. Methods: Experiment 1: IEC-6 cells were incubated with porcine (pAF) and human AF (hAF) to test AF-stimulated enterocyte proliferation and migration in vitro. Experiment 2: Cesarean-delivered, preterm pigs were fed parenteral nutrition and MEN with pAF, h...... fed AF as MEN, but NEC incidences were similar (NEC-pAF) or increased (NEC-hAF) compared with controls. Conclusions: Intake of pAF or hAF improved body growth and modulated intestinal inflammatory cytokines during a period of parenteral nutrition, but did not protect against later formula-induced NEC...

  18. Endotoxin induced chorioamnionitis prevents intestinal development during gestation in fetal sheep.

    Directory of Open Access Journals (Sweden)

    Tim G A M Wolfs

    Full Text Available Chorioamnionitis is the most significant source of prenatal inflammation and preterm delivery. Prematurity and prenatal inflammation are associated with compromised postnatal developmental outcomes, of the intestinal immune defence, gut barrier function and the vascular system. We developed a sheep model to study how the antenatal development of the gut was affected by gestation and/or by endotoxin induced chorioamnionitis.Chorioamnionitis was induced at different gestational ages (GA. Animals were sacrificed at low GA after 2d or 14d exposure to chorioamnionitis. Long term effects of 30d exposure to chorioamnionitis were studied in near term animals after induction of chorioamnionitis. The cellular distribution of tight junction protein ZO-1 was shown to be underdeveloped at low GA whereas endotoxin induced chorioamnionitis prevented the maturation of tight junctions during later gestation. Endotoxin induced chorioamnionitis did not induce an early (2d inflammatory response in the gut in preterm animals. However, 14d after endotoxin administration preterm animals had increased numbers of T-lymphocytes, myeloperoxidase-positive cells and gammadelta T-cells which lasted till 30d after induction of chorioamnionitis in then near term animals. At early GA, low intestinal TLR-4 and MD-2 mRNA levels were detected which were further down regulated during endotoxin-induced chorioamnionitis. Predisposition to organ injury by ischemia was assessed by the vascular function of third-generation mesenteric arteries. Endotoxin-exposed animals of low GA had increased contractile response to the thromboxane A2 mimetic U46619 and reduced endothelium-dependent relaxation in responses to acetylcholine. The administration of a nitric oxide (NO donor completely restored endothelial dysfunction suggesting reduced NO bioavailability which was not due to low expression of endothelial nitric oxide synthase.Our results indicate that the distribution of the tight

  19. Mortality in children with complicated severe acute malnutrition is related to intestinal and systemic inflammation: an observational cohort study12

    Science.gov (United States)

    van Vliet, Sara J; Di Giovanni, Valeria; Zhang, Ling; Richardson, Susan; van Rheenen, Patrick F

    2016-01-01

    Background: Diarrhea affects a large proportion of children with severe acute malnutrition (SAM). However, its etiology and clinical consequences remain unclear. Objective: We investigated diarrhea, enteropathogens, and systemic and intestinal inflammation for their interrelation and their associations with mortality in children with SAM. Design: Intestinal pathogens (n = 15), cytokines (n = 29), fecal calprotectin, and the short-chain fatty acids (SCFAs) butyrate and propionate were determined in children aged 6–59 mo (n = 79) hospitalized in Malawi for complicated SAM. The relation between variables, diarrhea, and death was assessed with partial least squares (PLS) path modeling. Results: Fatal subjects (n = 14; 18%) were younger (mean ± SD age: 17 ± 11 compared with 25 ± 11 mo; P = 0.01) with higher prevalence of diarrhea (46% compared with 18%, P = 0.03). Intestinal pathogens Shigella (36%), Giardia (33%), and Campylobacter (30%) predominated, but their presence was not associated with death or diarrhea. Calprotectin was significantly higher in children who died [median (IQR): 1360 mg/kg feces (2443–535 mg/kg feces) compared with 698 mg/kg feces (1438–244 mg/kg feces), P = 0.03]. Butyrate [median (IQR): 31 ng/mL (112–22 ng/mL) compared with 2036 ng/mL (5800–149 ng/mL), P = 0.02] and propionate [median (IQR): 167 ng/mL (831–131 ng/mL) compared with 3174 ng/mL (5819–357 ng/mL), P = 0.04] were lower in those who died. Mortality was directly related to high systemic inflammation (path coefficient = 0.49), whereas diarrhea, high calprotectin, and low SCFA production related to death indirectly via their more direct association with systemic inflammation. Conclusions: Diarrhea, high intestinal inflammation, low concentrations of fecal SCFAs, and high systemic inflammation are significantly related to mortality in SAM. However, these relations were not mediated by the presence of intestinal pathogens. These findings offer an important understanding of

  20. Dietary intervention with green dwarf banana flour (Musa sp AAA) prevents intestinal inflammation in a trinitrobenzenesulfonic acid model of rat colitis

    OpenAIRE

    Scarminio, Viviane [UNESP; Fruet, Andrea C. [UNESP; Witaicenis, Aline [UNESP; Rall, Vera L. M. [UNESP; Di Stasi, Luiz C. [UNESP

    2012-01-01

    Dietary products are among the therapeutic approaches used to modify intestinal microflora and to promote protective effects during the intestinal inflammatory process. Because the banana plant is rich in resistant starch, which is used by colonic microbiota for the anaerobic production of the short-chain fatty acids that serve as a major fuel source for colonocytes: first, green dwarf banana flour produces protective effects on the intestinal inflammation acting as a prebiotic and, second, c...

  1. [Relationship between intestinal mucosal inflammation and mental disorders in patients with irritable bowel syndrome].

    Science.gov (United States)

    Hao, Jing-xin; Han, Mai; Duan, Li-ping; Han, Ya-jing; Ge, Ying; Huang, Yue-qin

    2012-08-28

    To examine the relationship between inflammation and the comorbidity of mental disorders with irritable bowel syndrome (IBS) by comparing intestinal mucosa inflammatory biomarkers in patients with and without mental disorders. A total of 43 consecutive IBS patients fulfilling the Rome III criteria and 15 volunteers serving as controls without digestive symptoms were recruited and interviewed with Composite International Diagnostic Interview (CIDI) by the well-trained staff and thus classified as with or without mental disorders. All subjects underwent colonoscopy and biopsies were acquired from the mucosa of distal ileum and colon. CD3(+) lymphocytes, mast cells, 5-HT positive cells and (indoleamine 2,3-dioxygenase) IDO positive cells were identified immunohistologically in mucosa biopsies in volunteers (n = 13), IBS patients without mental disorder (n = 24) and IBS patients with mental disorder (n = 19). The incidence of mental disorders in IBS patients was significantly higher than that in the volunteers (19/43 vs 2/15, P = 0.012), including 9 patients with anxiety disorders and 8 with mood disorders. (1) The number of mast cells in IBS patients with mental disorder and that in IBS patients without mental disorder has no statistical significance ((16.7 ± 3.6)/HP vs (15.4 ± 3.1)/HP in distal ileum, (12.8 ± 2.2)/HP vs (12.3 ± 2.5)/HP in sigmoid, both P > 0.05). Similar results were seen in 5-HT positive cells ((3.7 ± 0.9)/HP vs (3.4 ± 0.8)/HP in distal ileum, (6.1 ± 1.8)/HP vs (5.2 ± 1.8)/HP in sigmoid, both P > 0.05). In distal ileum, the number of CD3(+) cells in IBS patients with mental disorder has no statistical significance with that in the IBS patients without mental disorder ((62 ± 16)/HP vs (55 ± 22)/HP, P > 0.05). Similar results were seen in IDO positive cells (6(2, 8)/HP vs 2(1, 5)/HP, P > 0.05). (2) The number of IDO positive cells from distal ileum in IBS patients with anxiety disorder was significantly higher than that in the IBS patients

  2. An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation.

    Directory of Open Access Journals (Sweden)

    Jason E Shoemaker

    2015-06-01

    Full Text Available Influenza viruses present major challenges to public health, evident by the 2009 influenza pandemic. Highly pathogenic influenza virus infections generally coincide with early, high levels of inflammatory cytokines that some studies have suggested may be regulated in a strain-dependent manner. However, a comprehensive characterization of the complex dynamics of the inflammatory response induced by virulent influenza strains is lacking. Here, we applied gene co-expression and nonlinear regression analysis to time-course, microarray data developed from influenza-infected mouse lung to create mathematical models of the host inflammatory response. We found that the dynamics of inflammation-associated gene expression are regulated by an ultrasensitive-like mechanism in which low levels of virus induce minimal gene expression but expression is strongly induced once a threshold virus titer is exceeded. Cytokine assays confirmed that the production of several key inflammatory cytokines, such as interleukin 6 and monocyte chemotactic protein 1, exhibit ultrasensitive behavior. A systematic exploration of the pathways regulating the inflammatory-associated gene response suggests that the molecular origins of this ultrasensitive response mechanism lie within the branch of the Toll-like receptor pathway that regulates STAT1 phosphorylation. This study provides the first evidence of an ultrasensitive mechanism regulating influenza virus-induced inflammation in whole lungs and provides insight into how different virus strains can induce distinct temporal inflammation response profiles. The approach developed here should facilitate the construction of gene regulatory models of other infectious diseases.

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

    Science.gov (United States)

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

    2016-05-20

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

  4. Effects of zeolite supplementation on parameters of intestinal barrier integrity, inflammation, redoxbiology and performance in aerobically trained subjects.

    Science.gov (United States)

    Lamprecht, Manfred; Bogner, Simon; Steinbauer, Kurt; Schuetz, Burkhard; Greilberger, Joachim F; Leber, Bettina; Wagner, Bernhard; Zinser, Erwin; Petek, Thomas; Wallner-Liebmann, Sandra; Oberwinkler, Tanja; Bachl, Norbert; Schippinger, Gert

    2015-01-01

    Zeolites are crystalline compounds with microporous structures of Si-tetrahedrons. In the gut, these silicates could act as adsorbents, ion-exchangers, catalysts, detergents or anti-diarrheic agents. This study evaluated whether zeolite supplementation affects biomarkers of intestinal wall permeability and parameters of oxidation and inflammation in aerobically trained individuals, and whether it could improve their performance. In a randomized, double-blinded, placebo controlled trial, 52 endurance trained men and women, similar in body fat, non-smokers, 20-50 years, received 1.85 g of zeolite per day for 12 weeks. Stool samples for determination of intestinal wall integrity biomarkers were collected. From blood, markers of redox biology, inflammation, and DNA damage were determined at the beginning and the end of the study. In addition, VO2max and maximum performance were evaluated at baseline and after 12 weeks of treatment. For statistical analyses a 2-factor ANOVA was used. At baseline both groups showed slightly increased stool zonulin concentrations above normal. After 12 weeks with zeolite zonulin was significantly (p zeolite group. There were no significant changes observed in the other measured parameters. Twelve weeks of zeolite supplementation exerted beneficial effects on intestinal wall integrity as indicated via decreased concentrations of the tight junction modulator zonulin. This was accompanied by mild anti-inflammatory effects in this cohort of aerobically trained subjects. Further research is needed to explore mechanistic explanations for the observations in this study.

  5. Protective effects of seabuckthorn pulp and seed oils against radiation-induced acute intestinal injury

    International Nuclear Information System (INIS)

    Shi, Jing; Wang, Lan; Lu, Yan; Ji, Yue; Wang, Yaqing; Dong, Ke; Kong, Xiangqing; Sun, Wei

    2017-01-01

    Radiation-induced gastrointestinal syndrome, including nausea, diarrhea and dehydration, contributes to morbidity and mortality after medical or industrial radiation exposure. No safe and effective radiation countermeasure has been approved for clinical therapy. In this study, we aimed to investigate the potential protective effects of seabuckthorn pulp and seed oils against radiation-induced acute intestinal injury. C57/BL6 mice were orally administered seabuckthorn pulp oil, seed oil and control olive oil once per day for 7 days before exposure to total-body X-ray irradiation of 7.5 Gy. Terminal deoxynucleotidyl transferase dUTP nick end labeling, quantitative real-time polymerase chain reaction and western blotting were used for the measurement of apoptotic cells and proteins, inflammation factors and mitogen-activated protein (MAP) kinases. Seabuckthorn oil pretreatment increased the post-radiation survival rate and reduced the damage area of the small intestine villi. Both the pulp and seed oil treatment significantly decreased the apoptotic cell numbers and cleaved caspase 3 expression. Seabuckthorn oil downregulated the mRNA level of inflammatory factors, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and IL-8. Both the pulp and seed oils elevated the level of phosphorylated extracellular-signal-regulated kinase and reduced the levels of phosphorylated c-Jun N-terminal kinase and p38. Palmitoleic acid (PLA) and alpha linolenic acid (ALA) are the predominant components of pulp oil and seed oil, respectively. Pretreatment with PLA and ALA increased the post-radiation survival time. In conclusion, seabuckthorn pulp and seed oils protect against mouse intestinal injury from high-dose radiation by reducing cell apoptosis and inflammation. ALA and PLA are promising natural radiation countermeasure candidates.

  6. Creatine kinase activity in dogs with experimentally induced acute inflammation

    Directory of Open Access Journals (Sweden)

    Dimitrinka Zapryanova

    2013-01-01

    Full Text Available The main purpose of this study was to investigate the effect of acute inflammation on total creatine kinase (CK activity in dogs. In these animals, CK is an enzyme found predominantly in skeletal muscle and significantly elevated serum activity is largely associated with muscle damage. Plasma increases in dogs are associated with cell membrane leakage and will therefore be seen in any condition associated with muscular inflammation. The study was induced in 15 mongrel male dogs (n=9 in experimental group and n=6 in control group at the age of two years and body weight 12-15 kg. The inflammation was reproduced by inoculation of 2 ml turpentine oil subcutaneously in lumbar region. The plasma activity of creatine kinase was evaluated at 0, 6, 24, 48, 72 hours after inoculation and on days 7, 14 and 21 by a kit from Hospitex Diagnostics. In the experimental group, the plasma concentrations of the CK-activity were increased at the 48th hour (97.48±6.92 U/L and remained significantly higher (p<0.05 at the 72 hour (97.43±2.93 U/L compared to the control group (77.08±5.27 U/L. The results of this study suggest that the evaluation of creatine kinase in dogs with experimentally induced acute inflammation has a limited diagnostic value. It was observed that the creatine kinase activity is slightly affected by the experimentally induced acute inflammation in dogs.

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2017-11-01

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

  9. Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model.

    Science.gov (United States)

    Jung, Yong Gi; Lane, Andrew P

    2016-06-01

    To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (etanercept) on an inducible olfactory inflammation (IOI) mouse model. An in vivo study using a transgenic mouse model. Research laboratory. To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally controlled fashion within the olfactory epithelium. In one group of mice (n = 4), etanercept was injected intraperitoneally (100 μg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n = 2) underwent induction of TNF-α expression for 8 weeks, with etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with an equal-number control group. Compared with nontreated IOI mice, etanercept-treated IOI mice showed significantly improved EOG responses after 2 weeks (P loss of olfactory epithelium and no EOG response in nontreated IOI mice. However, in etanercept-treated mice, regeneration of olfactory epithelium was observed. Concomitant administration of etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

  10. Bile components and lecithin supplemented to plant based diets do not diminish diet related intestinal inflammation in Atlantic salmon.

    Science.gov (United States)

    Kortner, Trond M; Penn, Michael H; Bjӧrkhem, Ingemar; Måsøval, Kjell; Krogdahl, Åshild

    2016-09-07

    The present study was undertaken to gain knowledge on the role of bile components and lecithin on development of aberrations in digestive functions which seemingly have increased in Atlantic salmon in parallel with the increased use of plant ingredients in fish feed. Post smolt Atlantic salmon were fed for 77 days one of three basal diets: a high fish meal diet (HFM), a low fishmeal diet (LFM), or a diet with high protein soybean meal (HPS). Five additional diets were made from the LFM diet by supplementing with: purified taurocholate (1.8 %), bovine bile salt (1.8 %), taurine (0.4 %), lecithin (1.5 %), or a mix of supplements (suppl mix) containing taurocholate (1.8 %), cholesterol (1.5 %) and lecithin (0.4 %). Two additional diets were made from the HPS diet by supplementing with: bovine bile salt (1.8 %) or the suppl mix. Body and intestinal weights were recorded, and blood, bile, intestinal tissues and digesta were sampled for evaluation of growth, nutrient metabolism and intestinal structure and function. In comparison with fish fed the HFM diet fish fed the LFM and HPS diets grew less and showed reduced plasma bile salt and cholesterol levels. Histological examination of the distal intestine showed signs of enteritis in both LFM and HPS diet groups, though more pronounced in the HPS diet group. The HPS diet reduced digesta dry matter and capacity of leucine amino peptidase in the distal intestine. None of the dietary supplements improved endpoints regarding fish performance, gut function or inflammation in the distal intestine. Some endpoints rather indicated negative effects. Dietary supplementation with bile components or lecithin in general did not improve endpoints regarding performance or gut health in Atlantic salmon, in clear contrast to what has been previously reported for rainbow trout. Follow-up studies are needed to clarify if lower levels of bile salts and cholesterol may give different and beneficial effects, or if other supplements

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

    DEFF Research Database (Denmark)

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

    The number of obese women in the childbearing age is drastically increasing globally. As a consequence, more children are born by obese mothers. Unfortunately, maternal obesity and/ or high fat intake during pregnancy increase the risk of developing obesity, type-2 diabetes, cardiovascular disease...... and non-alcoholic fatty liver disease in the children, which passes obesity and metabolic dysfunction on from generation to generation. Several studies try to elucidate causative effects of maternal metabolic markers on the metabolic imprinting in the children; however diet induced obesity is also...... associated with chronic low grade inflammation. Nobody have yet investigated the role of this inflammatory phenotype, but here we demonst rate that obesity induced inflammation is reversed during pregnancy in mice, and is therefore less likely to affect the fetal programming of metabolic dysfunction. Instead...

  12. Milk diets influence doxorubicin-induced intestinal toxicity in piglets

    DEFF Research Database (Denmark)

    Shen, R. L.; Pontoppidan, P. E.; Rathe, M.

    2016-01-01

    IL-8 levels compared with DOX-Form (all P diet. Thus a single dose of DOX induces intestinal toxicity in preweaned pigs...... and may lead to a systemic inflammatory response. The toxicity is affected by type of enteral nutrition with more pronounced GI toxicity when formula is fed compared with bovine colostrum. The results indicate that bovine colostrum may be a beneficial supplementary diet for children subjected...

  13. Ageing sensitized by iPLA2β deficiency induces liver fibrosis and intestinal atrophy involving suppression of homeostatic genes and alteration of intestinal lipids and bile acids.

    Science.gov (United States)

    Jiao, Li; Gan-Schreier, Hongying; Zhu, Xingya; Wei, Wang; Tuma-Kellner, Sabine; Liebisch, Gerhard; Stremmel, Wolfgang; Chamulitrat, Walee

    2017-12-01

    Ageing is a major risk factor for various forms of liver and gastrointestinal (GI) disease and genetic background may contribute to the pathogenesis of these diseases. Group VIA phospholipase A2 or iPLA 2 β is a homeostatic PLA 2 by playing a role in phospholipid metabolism and remodeling. Global iPLA 2 β -/- mice exhibit aged-dependent phenotypes with body weight loss and abnormalities in the bone and brain. We have previously reported the abnormalities in these mutant mice showing susceptibility for chemical-induced liver injury and colitis. We hypothesize that iPLA 2 β deficiency may sensitize with ageing for an induction of GI injury. Male wild-type and iPLA 2 β -/- mice at 4 and 20-22months of age were studied. Aged, but not young, iPLA 2 β -/- mice showed increased hepatic fibrosis and biliary ductular expansion as well as severe intestinal atrophy associated with increased apoptosis, pro-inflammation, disrupted tight junction, and reduced number of mucin-containing globlet cells. This damage was associated with decreased expression of intestinal endoplasmic stress XBP1 and its regulator HNF1α, FATP4, ACSL5, bile-acid transport genes as well as nuclear receptors LXRα and FXR. By LC/MS-MS profiling, iPLA 2 β deficiency in aged mice caused an increase of intestinal arachidonate-containing phospholipids concomitant with a decrease in ceramides. By the suppression of intestinal FXR/FGF-15 signaling, hepatic bile-acid synthesis gene expression was increased leading to an elevation of secondary and hydrophobic bile acids in liver, bile, and intestine. In conclusions, ageing sensitized by iPLA 2 β deficiency caused a decline of key intestinal homeostatic genes resulting in the development of GI disease in a gut-to-liver manner. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation

    DEFF Research Database (Denmark)

    López-Posadas, Rocío; Becker, Christoph; Günther, Claudia

    2016-01-01

    Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing t...

  15. Radiation-induced intestinal lesions. Prognosis and surgical management

    International Nuclear Information System (INIS)

    Van Haecke, P.; Vitaux, J.; Michot, F.; Hay, J.-M.; Flamant, Y.; Maillard, J.-N.

    1981-01-01

    Thirteen patients with intestinal lesions consecutive to radiotherapy for carcinoma of the uterus were operated upon between 1973 and 1979. The small bowel was involved in 9 patients and the colon and rectum in 4 patients. Urinary tract lesions were associated in 3 patients of each group. Intestinal necrosis, progression of the lesions and extensive pelvic fibrosis were the only criteria of poor prognosis. Twenty-two operations were performed: 4 for urinary tract lesions and 18 for intestinal lesions. Five patients died during the immediate post-operative period and five died within 2 to 30 months after surgery, including 4 whose carcinoma recurred. The operative technique should be selected according to the extent and severity of radiation-induced damage, as determined by pre-operative examination and thorough exploration of the abdominal cavity once opened. Limited lesions of the small bowel can be treated by resection, but intestinal bypass with latero-lateral anastomosis seems to be preferable in cases with extensive lesions. Patients with colorectal lesions should have defunctioning colostomy prior to any other procedure dictated by the state of affairs. Multiple anastomosis, extensive resections and excessive dissections should be avoided [fr

  16. Mechanism for radiation-induced damage via TLR3 on the intestinal epithelium

    International Nuclear Information System (INIS)

    Takemura, Naoki; Uematsu, Satoshi

    2014-01-01

    When the small-intestinal epithelium is injured due to high-dose radiation exposure, radiation-induced gastrointestinal syndrome (GIS) such as absorption inhibition and intestinal bacterial infection occurs, and lead to subacute death. The authors immunologically analyzed the disease onset mechanism of GIS. In the small-intestinal mucosal epithelium, the intestinal epithelial stem cells of crypt structure and their daughter cells are renewed through proliferation and differentiation in the cycle of 3 or 4 days. When DNA is damaged by radiation, although p53 gene stops cell cycle and repairs DNA, cell death is induced if the repair is impossible. When stem cells perish, cell supply stops resulting in epithelial breakdown and fatal GIS. The authors analyzed the involvement in GIS of toll-like receptor (TLR) with the function of natural immunity, based on lethal γ-ray irradiation on KO mice and other methods. The authors found the mechanism, in which RNA that was leaked due to cell death caused by p53 gene elicits inflammation by activating TLR3, and leads to GIS through a wide range of cell death induction and stem cell extinction. The administration of a TLR3/RNA binding inhibitor before the irradiation of mice decreased crypt cell death and greatly improved survival rate. The administration one hour after the irradiation also showed improvement. The administration of the TLR3 specific inhibitor within a fixed time after the exposure is hopeful for the prevention of GIS, without affecting the DNA repair function of p53 gene. (A.O.)

  17. Noncanonical Effects of IRF9 in Intestinal Inflammation: More than Type I and Type III Interferons.

    Science.gov (United States)

    Rauch, Isabella; Rosebrock, Felix; Hainzl, Eva; Heider, Susanne; Majoros, Andrea; Wienerroither, Sebastian; Strobl, Birgit; Stockinger, Silvia; Kenner, Lukas; Müller, Mathias; Decker, Thomas

    2015-07-01

    The interferon (IFN)-stimulated gene factor 3 (ISGF3) transcription factor with its Stat1, Stat2, and interferon regulatory factor 9 (IRF9) subunits is employed for transcriptional responses downstream of receptors for type I interferons (IFN-I) that include IFN-α and IFN-β and type III interferons (IFN-III), also called IFN-λ. Here, we show in a murine model of dextran sodium sulfate (DSS)-induced colitis that IRF9 deficiency protects animals, whereas the combined loss of IFN-I and IFN-III receptors worsens their condition. We explain the different phenotypes by demonstrating a function of IRF9 in a noncanonical transcriptional complex with Stat1, apart from IFN-I and IFN-III signaling. Together, Stat1 and IRF9 produce a proinflammatory activity that overrides the benefits of the IFN-III response on intestinal epithelial cells. Our results further suggest that the CXCL10 chemokine gene is an important mediator of this proinflammatory activity. We thus establish IFN-λ as a potentially anticolitogenic cytokine and propose an important role for IRF9 as a component of noncanonical Stat complexes in the development of colitis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

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

    International Nuclear Information System (INIS)

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

    2006-01-01

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

  19. Platelet-activating factor induces TLR4 expression in intestinal epithelial cells: implication for the pathogenesis of necrotizing enterocolitis.

    Directory of Open Access Journals (Sweden)

    Antoine Soliman

    Full Text Available Necrotizing enterocolitis (NEC is a leading cause of morbidity and mortality in neonatal intensive care units, however its pathogenesis is not completely understood. We have previously shown that platelet activating factor (PAF, bacteria and TLR4 are all important factors in the development of NEC. Given that Toll-like receptors (TLRs are expressed at low levels in enterocytes of the mature gastrointestinal tract, but were shown to be aberrantly over-expressed in enterocytes in experimental NEC, we examined the regulation of TLR4 expression and signaling by PAF in intestinal epithelial cells using human and mouse in vitro cell lines, and the ex vivo rat intestinal loop model. In intestinal epithelial cell (IEC lines, PAF stimulation yielded upregulation of both TLR4 mRNA and protein expression and led to increased IL-8 secretion following stimulation with LPS (in an otherwise LPS minimally responsive cell line. PAF stimulation resulted in increased human TLR4 promoter activation in a dose dependent manner. Western blotting and immunohistochemical analysis showed PAF induced STAT3 phosphorylation and nuclear translocation in IEC, and PAF-induced TLR4 expression was inhibited by STAT3 and NFκB Inhibitors. Our findings provide evidence for a mechanism by which PAF augments inflammation in the intestinal epithelium through abnormal TLR4 upregulation, thereby contributing to the intestinal injury of NEC.

  20. Genome-Wide Immune Modulation of TLR3-Mediated Inflammation in Intestinal Epithelial Cells Differs between Single and Multi-Strain Probiotic Combination.

    Directory of Open Access Journals (Sweden)

    Chad W MacPherson

    Full Text Available Genome-wide transcriptional analysis in intestinal epithelial cells (IEC can aid in elucidating the impact of single versus multi-strain probiotic combinations on immunological and cellular mechanisms of action. In this study we used human expression microarray chips in an in vitro intestinal epithelial cell model to investigate the impact of three probiotic bacteria, Lactobacillus helveticus R0052 (Lh-R0052, Bifidobacterium longum subsp. infantis R0033 (Bl-R0033 and Bifidobacterium bifidum R0071 (Bb-R0071 individually and in combination, and of a surface-layer protein (SLP purified from Lh-R0052, on HT-29 cells' transcriptional profile to poly(I:C-induced inflammation. Hierarchical heat map clustering, Set Distiller and String analyses revealed that the effects of Lh-R0052 and Bb-R0071 diverged from those of Bl-R0033 and Lh-R0052-SLP. It was evident from the global analyses with respect to the immune, cellular and homeostasis related pathways that the co-challenge with probiotic combination (PC vastly differed in its effect from the single strains and Lh-R0052-SLP treatments. The multi-strain PC resulted in a greater reduction of modulated genes, found through functional connections between immune and cellular pathways. Cytokine and chemokine analyses based on specific outcomes from the TNF-α and NF-κB signaling pathways revealed single, multi-strain and Lh-R0052-SLP specific attenuation of the majority of proteins measured (TNF-α, IL-8, CXCL1, CXCL2 and CXCL10, indicating potentially different mechanisms. These findings indicate a synergistic effect of the bacterial combinations relative to the single strain and Lh-R0052-SLP treatments in resolving toll-like receptor 3 (TLR3-induced inflammation in IEC and maintaining cellular homeostasis, reinforcing the rationale for using multi-strain formulations as a probiotic.

  1. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    International Nuclear Information System (INIS)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G.; Castiglione, F.; Vanzi, E.; Bottoncetti, A.; Pupi, A.

    2011-01-01

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation-induced

  2. Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

    2011-10-15

    Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation-induced

  3. Mucus reduction promotes acetyl salicylic acid-induced small intestinal mucosal injury in rats.

    Science.gov (United States)

    Suyama, Yosuke; Handa, Osamu; Naito, Yuji; Takayama, Shun; Mukai, Rieko; Ushiroda, Chihiro; Majima, Atsushi; Yasuda-Onozawa, Yuriko; Higashimura, Yasuki; Fukui, Akifumi; Dohi, Osamu; Okayama, Tetsuya; Yoshida, Naohisa; Katada, Kazuhiro; Kamada, Kazuhiro; Uchiyama, Kazuhiko; Ishikawa, Takeshi; Takagi, Tomohisa; Konishi, Hideyuki; Itoh, Yoshito

    2018-03-25

    Acetyl salicylic acid (ASA) is a useful drug for the secondary prevention of cerebro-cardiovascular diseases, but it has adverse effects on the small intestinal mucosa. The pathogenesis and prophylaxis of ASA-induced small intestinal injury remain unclear. In this study, we focused on the intestinal mucus, as the gastrointestinal tract is covered by mucus, which exhibits protective effects against various gastrointestinal diseases. ASA was injected into the duodenum of rats, and small intestinal mucosal injury was evaluated using Evans blue dye. To investigate the importance of mucus, Polysorbate 80 (P80), an emulsifier, was used before ASA injection. In addition, rebamipide, a mucus secretion inducer in the small intestine, was used to suppress mucus reduction in the small intestine of P80-administered rats. The addition of P80 reduced the mucus and exacerbated the ASA-induced small intestinal mucosal injury. Rebamipide significantly suppressed P80-reduced small intestinal mucus and P80-increased intestinal mucosal lesions in ASA-injected rats, demonstrating that mucus is important for the protection against ASA-induced small intestinal mucosal injury. These results provide new insight into the mechanism of ASA-induced small intestinal mucosal injury. Mucus secretion-increasing therapy might be useful in preventing ASA-induced small intestinal mucosal injury. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-28

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-02-13

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

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

    International Nuclear Information System (INIS)

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani; Qiao, Juan; Lu, Yun

    2016-01-01

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

  7. Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis.

    Science.gov (United States)

    Choi, Sung Hee; Kim, Byung-Gyu; Robinson, Janet; Fink, Steve; Yan, Min; Sporn, Michael B; Markowitz, Sanford D; Letterio, John J

    2014-06-01

    Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-C28-methyl ester (CDDO-Me) suppresses CAC in mice. In a spontaneous, inflammation-driven intestinal neoplasia model, deletion of Smad4 specifically in T cells led to progressive production of inflammatory cytokines, including TNF-α, IFN-γ, iNOS, IL-6, IL-1β; as well as activation of STAT1 and STAT3; along with suppression of 15-PGDH expression. Oral administration of CDDO-Me to mice with SMAD4-deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of 15-PGDH. Induction of 15-PGDH by CDDO-Me was dose dependent in epithelial cells and was abrogated following treatment with TGF-β signaling inhibitors in vitro. Furthermore, CDDO-Me-dependent 15-PGDH induction was not observed in Smad3-/- mice. Similarly, CDDO-Me suppressed azoxymethane plus dextran sodium sulfate-induced carcinogenesis in wild-type animals, highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans.

  8. Radioprotective effects of sodium arginate on radiation induced intestinal damage

    Energy Technology Data Exchange (ETDEWEB)

    Nakatsugawa, Shigekazu; Yukawa, Yutaka; Abe, Mitsuyuki.

    1988-05-01

    Effects of sodium arginate were examined on radiation-induced intestinal death of mice and on the pathological changes of the ileum after whole or partial abdominal X-irradiation. BALB/c male mice (SPF, 7 approx. 8 week old, 21 approx. 28 g body weight) were irradiated with various doses of 10 MV of X-rays under general anesthesia (dose rate : 4 Gy/min). A radiation field covers either 2.5 or 5.0 cm width of abdomen from the anus. Sterilized water or 5 % sodium arginate solution (0.2 ml/body) was daily given per os through a stomach tube until the death of mice or 15 approx. 21 days after X-ray exposure. Intestinal death was examined daily. In another experiment, mice were daily sacrificed and pathological specimens were made. In order to study the effects of sodium arginate on peripheral blood circulation in the ileum after X-ray exposure, the microangiograms with Ba contrast media were also taken. Sodium arginate showed statistically significant radioprotective effects on intestinal death after 14.5 approx. 15.0 Gy of X-ray irradiation to the abdomen through a radiation field of 5.0 cm width or after 18.0 Gy of X-irradiation to the abdomen through a field of 2.5 cm width. The pathological studies suggest that the drug may protect the surface of the intestine against infection and potentiate the recovery processes of the mucosal membrane. This may elucidate the possible mechanisms of radioprotective effects of sodium arginate on esophagitis or on rectal ulcer induced by radiotherapy.

  9. Bifidobacterium breve alters immune function and ameliorates DSS-induced inflammation in weanling rats.

    Science.gov (United States)

    Izumi, Hirohisa; Minegishi, Mario; Sato, Yohei; Shimizu, Takashi; Sekine, Kazunori; Takase, Mitsunori

    2015-10-01

    Bifidobacterium breve M-16V (M16V) is a probiotic bacterial strain with a long tradition of use in neonatal intensive care units in some countries. Previous study showed that the effects of M16V administration on gene expression were greater during the weaning period than in the neonatal period and were greater in the colon than in the small intestine and spleen, suggesting that M16V has anti-inflammatory effects. In this study, we evaluated the effects of inflammation during the weaning period and the effects of M16V on normal and inflammatory conditions. From postnatal day (PD) 21 to 34, weanling rats were administered of 2.5 × 10(9) of M16V daily, and colitis was induced by administration of 2% dextran sulfate sodium from PD28 to 35. Colitis severity, immune function, and microbiota were investigated. Colitis caused a reduction in body weight gain, colon shortening, poor nutritional status, anemia, changes in blood and spleen lymphocyte populations, spleen T-cell malfunctions, and alterations in colon microbiota. M16V administration improved some but not all of the changes induced by colitis. M16V could suppress inflammation and, therefore, can be considered a safe strain to use not only during the neonatal period but also the weaning period.

  10. Lactobacillus acidophilus ameliorates H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways

    Directory of Open Access Journals (Sweden)

    Yang Yao-Jong

    2012-03-01

    Full Text Available Abstract Background H. pylori infection may trigger Smad7 and NFκB expression in the stomach, whereas probiotics promote gastrointestinal health and improve intestinal inflammation caused by pathogens. This study examines if probiotics can improve H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways. Results Challenge with H. pylori increased IL-8 and TNF-α expressions but not TGF-β1 in MKN45 cells. The RNA levels of Smad7 in AGS cells increased after H. pylori infection in a dose-dependent manner. A higher dose (MOI 100 of L. acidophilus pre-treatment attenuated the H. pylori-induced IL-8 expressions, but not TGF-β1. Such anti-inflammatory effect was mediated via increased cytoplasmic IκBα and depletion of nuclear NFκB. L. acidophilus also inhibited H. pylori-induced Smad7 transcription by inactivating the Jak1 and Stat1 pathways, which might activate the TGF-β1/Smad pathway. L. acidophilus pre-treatment ameliorated IFN-γ-induced Smad7 translation level and subsequently reduced nuclear NF-κB production, as detected by western blotting. Conclusions H. pylori infection induces Smad7, NFκB, IL-8, and TNF-α production in vitro. Higher doses of L. acidophilus pre-treatment reduce H. pylori-induced inflammation through the inactivation of the Smad7 and NFκB pathways.

  11. Saponin-containing subfractions of soybean molasses induce enteritis in the distal intestine of Atlantic salmon

    DEFF Research Database (Denmark)

    Knudsen, D.; Uran, P.; Arnous, Anis

    2007-01-01

    The current work aimed at tracing the causative components for soybean-induced enteritis in Atlantic salmon (Salmo salar L.). Soybean molasses was subjected to phase separation using n-butanol. Three subfractions were obtained as follows: butanol phase, precipitate, and water phase. The biochemical......-phase high-performance liquid chromatography. Finally, sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to evaluate the size distribution of the proteins present in each fraction. Molasses and the different subfractions were thereafter fed to Atlantic salmon in two successive fish trials....... The level of intestinal inflammation was evaluated by light microscopy using a semiquantitative scoring system. Histological assessments revealed that Atlantic salmon fed a combination of butanol phase and precipitate displayed significant enteritis. Atlantic salmon fed the water phase displayed normal...

  12. Disruptions of Host Immunity and Inflammation by Giardia Duodenalis: Potential Consequences for Co-Infections in the Gastro-Intestinal Tract

    Directory of Open Access Journals (Sweden)

    James A. Cotton

    2015-11-01

    Full Text Available Giardia duodenalis (syn. G. intestinalis, or G. lamblia is a leading cause of waterborne diarrheal disease that infects hundreds of millions of people annually. Research on Giardia has greatly expanded within the last few years, and our understanding of the pathophysiology and immunology on this parasite is ever increasing. At peak infection, Giardia trophozoites induce pathophysiological responses that culminate in the development of diarrheal disease. However, human data has suggested that the intestinal mucosa of Giardia-infected individuals is devoid of signs of overt intestinal inflammation, an observation that is reproduced in animal models. Thus, our understanding of host inflammatory responses to the parasite remain incompletely understood and human studies and experimental data have produced conflicting results. It is now also apparent that certain Giardia infections contain mechanisms capable of modulating their host’s immune responses. As the oral route of Giardia infection is shared with many other gastrointestinal (GI pathogens, co-infections may often occur, especially in places with poor sanitation and/or improper treatment of drinking water. Moreover, Giardia infections may modulate host immune responses and have been found to protect against the development of diarrheal disease in developing countries. The following review summarizes our current understanding of the immunomodulatory mechanisms of Giardia infections and their consequences for the host, and highlights areas for future research. Potential implications of these immunomodulatory effects during GI co-infection are also discussed.

  13. Bacterial Signaling at the Intestinal Epithelial Interface in Inflammation and Cancer

    Directory of Open Access Journals (Sweden)

    Olivia I. Coleman

    2018-01-01

    Full Text Available The gastrointestinal (GI tract provides a compartmentalized interface with an enormous repertoire of immune and metabolic activities, where the multicellular structure of the mucosa has acquired mechanisms to sense luminal factors, such as nutrients, microbes, and a variety of host-derived and microbial metabolites. The GI tract is colonized by a complex ecosystem of microorganisms, which have developed a highly coevolved relationship with the host’s cellular and immune system. Intestinal epithelial pattern recognition receptors (PRRs substantially contribute to tissue homeostasis and immune surveillance. The role of bacteria-derived signals in intestinal epithelial homeostasis and repair has been addressed in mouse models deficient in PRRs and signaling adaptors. While critical for host physiology and the fortification of barrier function, the intestinal microbiota poses a considerable health challenge. Accumulating evidence indicates that dysbiosis is associated with the pathogenesis of numerous GI tract diseases, including inflammatory bowel diseases (IBD and colorectal cancer (CRC. Aberrant signal integration at the epithelial cell level contributes to such diseases. An increased understanding of bacterial-specific structure recognition and signaling mechanisms at the intestinal epithelial interface is of great importance in the translation to future treatment strategies. In this review, we summarize the growing understanding of the regulation and function of the intestinal epithelial barrier, and discuss microbial signaling in the dynamic host–microbe mutualism in both health and disease.

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

    Science.gov (United States)

    Moss, Timothy J M; Westover, Alana J

    2017-06-01

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

  15. DNA damage-induced inflammation and nuclear architecture.

    Science.gov (United States)

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

    2017-07-01

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

  16. Bioactivities of Milk Polar Lipids in Influencing Intestinal Barrier Integrity, Systemic Inflammation, and Lipid Metabolism

    OpenAIRE

    Zhou, Albert Lihong

    2013-01-01

    The purpose of lactation is for nutrient provision and also importantly for protection from various environmental stressors. Milk polar lipids reduce cholesterol, protect against bacterial infection, reduce inflammation and help maintain gut integrity. Dynamic interactions within dietary fat, lipid metabolism, gut permeability and inflammatory cytokines remain unclear in the context of obesity and systemic inflammation. A rat model and three mouse models were developed to test the hypotheses ...

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

    Science.gov (United States)

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

    2014-05-01

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

  18. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.

    Science.gov (United States)

    Fasano, Alessio

    2011-01-01

    The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a "leaky gut" in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.

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

    Directory of Open Access Journals (Sweden)

    Yuichi Uchino

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

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

    Directory of Open Access Journals (Sweden)

    Runkuan Yang

    2017-01-01

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

  1. Fecal Markers of Intestinal Inflammation and Permeability Associated with the Subsequent Acquisition of Linear Growth Deficits in Infants

    Science.gov (United States)

    Kosek, Margaret; Haque, Rashidul; Lima, Aldo; Babji, Sudhir; Shrestha, Sanjaya; Qureshi, Shahida; Amidou, Samie; Mduma, Estomih; Lee, Gwenyth; Yori, Pablo Peñataro; Guerrant, Richard L.; Bhutta, Zulfiqar; Mason, Carl; Kang, Gagandeep; Kabir, Mamun; Amour, Caroline; Bessong, Pascal; Turab, Ali; Seidman, Jessica; Olortegui, Maribel Paredes; Quetz, Josiane; Lang, Dennis; Gratz, Jean; Miller, Mark; Gottlieb, Michael

    2013-01-01

    Enteric infections are associated with linear growth failure in children. To quantify the association between intestinal inflammation and linear growth failure three commercially available enzyme-linked immunosorbent assays (neopterin [NEO], alpha-anti-trypsin [AAT], and myeloperoxidase [MPO]) were performed in a structured sampling of asymptomatic stool from children under longitudinal surveillance for diarrheal illness in eight countries. Samples from 537 children contributed 1,169 AAT, 916 MPO, and 954 NEO test results that were significantly associated with linear growth. When combined to form a disease activity score, children with the highest score grew 1.08 cm less than children with the lowest score over the 6-month period following the tests after controlling for the incidence of diarrheal disease. This set of affordable non-invasive tests delineates those at risk of linear growth failure and may be used for the improved assessments of interventions to optimize growth during a critical period of early childhood. PMID:23185075

  2. Dietary l-threonine supplementation attenuates lipopolysaccharide-induced inflammatory responses and intestinal barrier damage of broiler chickens at an early age.

    Science.gov (United States)

    Chen, Yueping; Zhang, Hao; Cheng, Yefei; Li, Yue; Wen, Chao; Zhou, Yanmin

    2018-06-01

    This study was conducted to investigate the protective effects of l-threonine (l-Thr) supplementation on growth performance, inflammatory responses and intestinal barrier function of young broilers challenged with lipopolysaccharide (LPS). A total of 144 1-d-old male chicks were allocated to one of three treatments: non-challenged broilers fed a basal diet (control group), LPS-challenged broilers fed a basal diet without l-Thr supplementation and LPS-challenged broilers fed a basal diet supplemented with 3·0 g/kg l-Thr. LPS challenge was performed intraperitoneally at 17, 19 and 21 d of age, whereas the control group received physiological saline injection. Compared with the control group, LPS challenge impaired growth performance of broilers, and l-Thr administration reversed LPS-induced increase in feed/gain ratio. LPS challenge elevated blood cell counts related to inflammation, and pro-inflammatory cytokine concentrations in serum (IL-1β and TNF-α), spleen (IL-1β and TNF-α) and intestinal mucosa (jejunal interferon-γ (IFN-γ) and ileal IL-1β). The concentrations of intestinal cytokines in LPS-challenged broilers were reduced by l-Thr supplementation. LPS administration increased circulating d-lactic acid concentration, whereas it reduced villus height, the ratio between villus height and crypt depth and goblet density in both jejunum and ileum. LPS-induced decreases in jejunal villus height, intestinal villus height:crypt depth ratio and ileal goblet cell density were reversed with l-Thr supplementation. Similarly, LPS-induced alterations in the intestinal mRNA abundances of genes related to intestinal inflammation and barrier function (jejunal toll-like receptor 4, IFN- γ and claudin-3, and ileal IL-1 β and zonula occludens-1) were normalised with l-Thr administration. It can be concluded that l-Thr supplementation could attenuate LPS-induced inflammatory responses and intestinal barrier damage of young broilers.

  3. Vaccine-induced inflammation attenuates the vascular responses to mental stress

    NARCIS (Netherlands)

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

    2014-01-01

    Inflammation is associated with poorer vascular function, with evidence to suggest that inflammation can also impair the vascular responses to mental stress. This study examined the effects of vaccine-induced inflammation on vascular responses to mental stress in healthy participants. Eighteen male

  4. Infliximab's influence on anastomotic strength and degree of inflammation in intestinal surgery in a rabbit model

    DEFF Research Database (Denmark)

    Frostberg, Erik; Ström, Petter; Gerke, Oke

    2014-01-01

    and conclusions. The purpose of this study was to investigate whether a single dose infliximab has an adverse effect on the anastomotic healing process, observed as reduced anastomotic breaking strength and histopathologically verified lower grade of inflammatory response, in the small intestine of a rabbit......BACKGROUND: Infliximab, a TNF-alpha inhibitor, is a potent anti-inflammatory drug in the treatment of inflammatory bowel diseases. Recent studies have investigated the effect of infliximab treatment on postoperative complications such as anastomotic leakage, however, with conflicting results...... of infliximab, given one week prior to surgery, does not have an impact on the anastomotic breaking strength on the third postoperative day in the small intestine of rabbits....

  5. Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats.

    Directory of Open Access Journals (Sweden)

    Jana Cinova

    Full Text Available BACKGROUND AND AIMS: Celiac disease (CD is a chronic inflammatory disorder of the small intestine that is induced by dietary wheat gluten proteins (gliadins in genetically predisposed individuals. The overgrowth of potentially pathogenic bacteria and infections has been suggested to contribute to CD pathogenesis. We aimed to study the effects of gliadin and various intestinal bacterial strains on mucosal barrier integrity, gliadin translocation, and cytokine production. METHODOLOGY/PRINCIPAL FINDINGS: Changes in gut mucosa were assessed in the intestinal loops of inbred Wistar-AVN rats that were reared under germ-free conditions in the presence of various intestinal bacteria (enterobacteria and bifidobacteria isolated from CD patients and healthy children, respectively and CD-triggering agents (gliadin and IFN-γ by histology, scanning electron microscopy, immunofluorescence, and a rat cytokine antibody array. Adhesion of the bacterial strains to the IEC-6 rat cell line was evaluated in vitro. Gliadin fragments alone or together with the proinflammatory cytokine interferon (IFN-γ significantly decreased the number of goblet cells in the small intestine; this effect was more pronounced in the presence of Escherichia coli CBL2 and Shigella CBD8. Shigella CBD8 and IFN-γ induced the highest mucin secretion and greatest impairment in tight junctions and, consequently, translocation of gliadin fragments into the lamina propria. Shigella CBD8 and E. coli CBL2 strongly adhered to IEC-6 epithelial cells. The number of goblet cells in small intestine increased by the simultaneous incubation of Bifidobacterium bifidum IATA-ES2 with gliadin, IFN-γ and enterobacteria. B. bifidum IATA-ES2 also enhanced the production of chemotactic factors and inhibitors of metalloproteinases, which can contribute to gut mucosal protection. CONCLUSIONS: Our results suggest that the composition of the intestinal microbiota affects the permeability of the intestinal mucosa

  6. Intestinal congestion and right ventricular dysfunction: a link with appetite loss, inflammation, and cachexia in chronic heart failure.

    Science.gov (United States)

    Valentova, Miroslava; von Haehling, Stephan; Bauditz, Juergen; Doehner, Wolfram; Ebner, Nicole; Bekfani, Tarek; Elsner, Sebastian; Sliziuk, Veronika; Scherbakov, Nadja; Murín, Ján; Anker, Stefan D; Sandek, Anja

    2016-06-01

    Mechanisms leading to cachexia in heart failure (HF) are not fully understood. We evaluated signs of intestinal congestion in patients with chronic HF and their relationship with cachexia. Of the 165 prospectively enrolled outpatients with left ventricular ejection fraction ≤40%, 29 (18%) were cachectic. Among echocardiographic parameters, the combination of right ventricular dysfunction and elevated right atrial pressure (RAP) provided the best discrimination between cachectic and non-cachectic patients [area under the curve 0.892, 95% confidence interval (CI): 0.832-0.936]. Cachectic patients, compared with non-cachectic, had higher prevalence of postprandial fullness, appetite loss, and abdominal discomfort. Abdominal ultrasound showed a larger bowel wall thickness (BWT) in the entire colon and terminal ileum in cachectic than in non-cachectic patients. Bowel wall thickness correlated positively with gastrointestinal symptoms, high-sensitivity C-reactive protein, RAP, and truncal fat-free mass, the latter serving as a marker of the fluid content. Logistic regression analysis showed that BWT was associated with cachexia, even after adjusting for cardiac function, inflammation, and stages of HF (odds ratio 1.4, 95% CI: 1.0-1.8; P-value = 0.03). Among the cardiac parameters, only RAP remained significantly associated with cachexia after multivariable adjustment. Cardiac cachexia was associated with intestinal congestion irrespective of HF stage and cardiac function. Gastrointestinal discomfort, appetite loss, and pro-inflammatory activation provide probable mechanisms, by which intestinal congestion may trigger cardiac cachexia. However, our results are preliminary and larger studies are needed to clarify the intrinsic nature of this relationship. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  7. Lactoferrin in a Context of Inflammation-Induced Pathology

    Directory of Open Access Journals (Sweden)

    Marian L. Kruzel

    2017-11-01

    Full Text Available Much progress has been achieved to elucidate the function of lactoferrin (LTF, an iron-binding glycoprotein, in the milieu of immune functionality. This review represents a unique examination of LTF toward its importance in physiologic homeostasis as related to development of disease-associated pathology. The immunomodulatory nature of this protein derives from its unique ability to “sense” the immune activation status of an organism and act accordingly. Underlying mechanisms are proposed whereby LTF controls disease states, thereby pinpointing regions of entry for LTF in maintenance of various physiological pathways to limit the magnitude of tissue damage. LTF is examined as a first line mediator in immune defense and response to pathogenic and non-pathogenic injury, as well as a molecule critical for control of oxidative cell function. Mechanisms of interaction of LTF with its receptors are examined, with a focus on protective effects via regulation of enzyme activities and reactive oxygen species production, immune deviation, and prevention of cell apoptosis. Indeed, LTF serves as a critical control point in physiologic homeostasis, functioning as a sensor of immunological performance related to pathology. Specific mediation of tissue pathophysiology is described for maintenance of intestinal integrity during endotoxemia, elicited airway inflammation due to allergens, and pulmonary damage during tuberculosis. Finally, the role of LTF to alter differentiation of adaptive immune function is examined, with specific recognition of its utility as a vaccine adjuvant to control subsequent lymphocytic reactivity. Overall, it is clear that while the ability of LTF to both sequester iron and to direct reactive oxygen intermediates is a major factor in lessening damage due to excessive inflammatory responses, further effects are apparent through direct control over development of higher order immune functions that regulate pathology due to insult

  8. Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy.

    Science.gov (United States)

    Song, Jeong Ah; Park, Hyun-Ju; Yang, Mi-Jin; Jung, Kyung Jin; Yang, Hyo-Seon; Song, Chang-Woo; Lee, Kyuhong

    2014-07-01

    Polyhexamethyleneguanidine phosphate (PHMG-P) has been widely used as a disinfectant because of its strong bactericidal activity and low toxicity. However, in 2011, the Korea Centers for Disease Control and Prevention and the Ministry of Health and Welfare reported that a suspicious outbreak of pulmonary disease might have originated from humidifier disinfectants. The purpose of this study was to assess the toxicity of PHMG-P following direct exposure to the lung. PHMG-P (0.3, 0.9, or 1.5 mg/kg) was instilled into the lungs of mice. The levels of proinflammatory markers and fibrotic markers were quantified in lung tissues and flow cytometry was used to evaluate T cell distribution in the thymus. Administration of PHMG-P induced proinflammatory cytokines elevation and infiltration of immune cells into the lungs. Histopathological analysis revealed a dose-dependent exacerbation of both inflammation and pulmonary fibrosis on day 14. PHMG-P also decreased the total cell number and the CD4(+)/CD8(+) cell ratio in the thymus, with the histopathological examination indicating severe reduction of cortex and medulla. The mRNA levels of biomarkers associated with T cell development also decreased markedly. These findings suggest that exposure of lung tissue to PHMG-P leads to pulmonary inflammation and fibrosis as well as thymic atrophy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Inhibition of Epithelial TNF-α Receptors by Purified Fruit Bromelain Ameliorates Intestinal Inflammation and Barrier Dysfunction in Colitis

    OpenAIRE

    Zhou, Zijuan; Wang, Liang; Feng, Panpan; Yin, Lianhong; Wang, Chen; Zhi, Shengxu; Dong, Jianyi; Wang, Jingyu; Lin, Yuan; Chen, Dapeng; Xiong, Yongjian; Peng, Jinyong

    2017-01-01

    Activation of the TNF-α receptor (TNFR) leads to an inflammatory response, and anti-TNF therapy has been administered to reduce inflammation symptoms and heal mucosal ulcers in inflammatory bowel disease (IBD). Bromelain, a complex natural mixture of proteolytic enzymes, has been shown to exert anti-inflammatory effects. This study aimed to investigate the effect of purified fruit bromelain (PFB)-induced inhibition of epithelial TNFR in a rat colitis model. Colitis was established by intracol...

  10. Interferon-γ induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis.

    Directory of Open Access Journals (Sweden)

    Christoph Thelemann

    Full Text Available Immune responses against intestinal microbiota contribute to the pathogenesis of inflammatory bowel diseases (IBD and involve CD4(+ T cells, which are activated by major histocompatibility complex class II (MHCII molecules on antigen-presenting cells (APCs. However, it is largely unexplored how inflammation-induced MHCII expression by intestinal epithelial cells (IEC affects CD4(+ T cell-mediated immunity or tolerance induction in vivo. Here, we investigated how epithelial MHCII expression is induced and how a deficiency in inducible epithelial MHCII expression alters susceptibility to colitis and the outcome of colon-specific immune responses. Colitis was induced in mice that lacked inducible expression of MHCII molecules on all nonhematopoietic cells, or specifically on IECs, by continuous infection with Helicobacter hepaticus and administration of interleukin (IL-10 receptor-blocking antibodies (anti-IL10R mAb. To assess the role of interferon (IFN-γ in inducing epithelial MHCII expression, the T cell adoptive transfer model of colitis was used. Abrogation of MHCII expression by nonhematopoietic cells or IECs induces colitis associated with increased colonic frequencies of innate immune cells and expression of proinflammatory cytokines. CD4(+ T-helper type (Th1 cells - but not group 3 innate lymphoid cells (ILCs or Th17 cells - are elevated, resulting in an unfavourably altered ratio between CD4(+ T cells and forkhead box P3 (FoxP3(+ regulatory T (Treg cells. IFN-γ produced mainly by CD4(+ T cells is required to upregulate MHCII expression by IECs. These results suggest that, in addition to its proinflammatory roles, IFN-γ exerts a critical anti-inflammatory function in the intestine which protects against colitis by inducing MHCII expression on IECs. This may explain the failure of anti-IFN-γ treatment to induce remission in IBD patients, despite the association of elevated IFN-γ and IBD.

  11. Acrolein exposure suppresses antigen-induced pulmonary inflammation

    Science.gov (United States)

    2013-01-01

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

  12. Arginyl-glutamine dipeptide or docosahexaenoic acid attenuates hyperoxia-induced small intestinal injury in neonatal mice.

    Science.gov (United States)

    Li, Nan; Ma, Liya; Liu, Xueyan; Shaw, Lynn; Li Calzi, Sergio; Grant, Maria B; Neu, Josef

    2012-04-01

    Supplementation studies of glutamine, arginine, and docosahexaenoic acid (DHA) have established the safety of each of these nutrients in neonates; however, the potential for a more stable and soluble dipeptide, arginyl-glutamine (Arg-Gln) or DHA with anti-inflammatory properties, to exert benefits on hyperoxia-induced intestinal injury has not been investigated. Arg-Gln dipeptide has been shown to prevent retinal damage in a rodent model of oxygen-induced injury. The objective of the present study was to investigate whether Arg-Gln dipeptide or DHA could also attenuate markers of injury and inflammation to the small intestine in this same model. Seven-day-old mouse pups were placed with their dams in 75% oxygen for 5 days. After 5 days of hyperoxic exposure (P7-P12), pups were removed from hyperoxia and allowed to recover in atmospheric conditions for 5 days (P12-P17). Mouse pups received Arg-Gln (5g·kg·day) or DHA (5g·kg·day) or vehicle orally started on P12 through P17. Distal small intestine (DSI) histologic changes, myeloperoxidase (MPO), lactate dehydrogenase (LDH), inflammatory cytokines, and tissue apoptosis were evaluated. Hyperoxic mice showed a greater distortion of overall villus structure and with higher injury score (PDHA supplementation groups were more similar to the room air control group. Supplementation of Arg-Gln or DHA reduced hyperoxia-induced MPO activity (PDHA returned LDH activity to the levels of control. Hyperoxia induced apoptotic cell death in DSIs, and both Arg-Gln and DHA reversed this effect (PDHA may limit some inflammatory and apoptotic processes involved in hyperoxic-induced intestinal injury in neonatal mice.

  13. Marine hydroquinone zonarol prevents inflammation and apoptosis in dextran sulfate sodium-induced mice ulcerative colitis.

    Directory of Open Access Journals (Sweden)

    Sohsuke Yamada

    Full Text Available We previously identified an anti-inflammatory compound, zonarol, a hydroquinone isolated from the brown algae Dictyopteris undulata as a marine natural product. To ascertain the in vivo functions of zonarol, we examined the pharmacological effects of zonarol administration on dextran sulfate sodium (DSS-induced inflammation in a mouse model of ulcerative colitis (UC. Our goal is to establish a safe and effective cure for inflammatory bowel disease (IBD using zonarol.We subjected Slc:ICR mice to the administration of 2% DSS in drinking water for 14 days. At the same time, 5-aminosalicylic acid (5-ASA at a dose of 50 mg/kg (positive control and zonarol at doses of 10 and 20 mg/kg, were given orally once a day. DSS-treated animals developed symptoms similar to those of human UC, such as severe bloody diarrhea, which were evaluated by the disease activity index (DAI. Treatment with 20 mg/kg of zonarol, as well as 5-ASA, significantly suppressed the DAI score, and also led to a reduced colonic ulcer length and/or mucosal inflammatory infiltration by various immune cells, especially macrophages. Zonarol treatment significantly reduced the expression of pro-inflammatory signaling molecules, and prevented the apoptosis of intestinal epithelial cells. Finally, zonarol protected against in vitro lipopolysaccharide (LPS-induced activation in the RAW264.7 mouse macrophage cell line.This is the first report that a marine bioproduct protects against experimental UC via the inhibition of both inflammation and apoptosis, very similar to the standard-of-care sulfasalazine, a well-known prodrug that releases 5-ASA. We believe that the oral administration of zonarol might offer a better treatment for human IBDs than 5-ASA, or may be useful as an alternative/additive therapeutic strategy against UC, without any evidence of side effects.

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

    Directory of Open Access Journals (Sweden)

    Yoshihisa Hiraishi

    2016-10-01

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

  15. Protective effect of Bifidobacterium infantis CGMCC313-2 on ovalbumin-induced airway asthma and β-lactoglobulin-induced intestinal food allergy mouse models

    Science.gov (United States)

    Liu, Meng-Yun; Yang, Zhen-Yu; Dai, Wen-Kui; Huang, Jian-Qiong; Li, Yin-Hu; Zhang, Juan; Qiu, Chuang-Zhao; Wei, Chun; Zhou, Qian; Sun, Xin; Feng, Xin; Li, Dong-Fang; Wang, He-Ping; Zheng, Yue-Jie

    2017-01-01

    AIM To determine whether oral administration of Bifidobacterium infantis CGMCC313-2 (B. infantis CGMCC313-2) inhibits allergen-induced airway inflammation and food allergies in a mouse model. METHODS Ovalbumin (OVA)-induced allergic asthma and β-lactoglobulin-induced food allergy mouse models were used in this study. Following oral administration of B. infantis CGMCC313-2 during or after allergen sensitization, histopathologic changes in the lung and intestine were evaluated by hematoxylin and eosin (HE) staining. In the allergic asthma mouse model, we evaluated the proportion of lung-infiltrating inflammatory cells. OVA-specific IgE and IgG1 levels in serum and cytokine levels in bronchoalveolar lavage fluid (BALF) were also assessed. In the food allergy mouse model, the levels of total IgE and cytokines in serum were measured. RESULTS Oral administration of B. infantis CGMCC313-2 during or after allergen sensitization suppressed allergic inflammation in lung and intestinal tissues, while the proportion of infiltrating inflammatory cells was significantly decreased in the BALF of allergic asthma mice. Moreover, B. infantis CGMCC313-2 decreased the serum levels of total IgE in food allergy mice, and reductions in IgE and IgG1 were also observed in OVA-induced allergic asthma mice. The expression of interleukin-4 (IL-4) and IL-13 in both serum and BALF was suppressed following the administration of B. infantis CGMCC313-2, while an effect on serum IL-10 levels was not observed. CONCLUSION B. infantis CGMCC313-2 inhibits the secretion of allergen-induced IgE, IL-4 and IL-13, and attenuates allergic inflammation. PMID:28405142

  16. Intestinal Microbiota Contributes to Energy Balance, Metabolic Inflammation, and Insulin Resistance in Obesity

    Directory of Open Access Journals (Sweden)

    Joseph F. Cavallari

    2017-09-01

    Full Text Available Obesity is associated with increased risk of developing metabolic diseases such as type 2 diabetes. The origins of obesity are multi-factorial, but ultimately rooted in increased host energy accumulation or retention. The gut microbiota has been implicated in control of host energy balance and nutrient extraction from dietary sources. The microbiota also impacts host immune status and dysbiosis-related inflammation can augment insulin resistance, independently of obesity. Advances in microbial metagenomic analyses and directly manipulating bacterial-host models of obesity have contributed to our understanding of the relationship between gut bacteria and metabolic disease. Foodborne, or drug-mediated perturbations to the gut microbiota can increase metabolic inflammation, insulin resistance, and dysglycemia. There is now some evidence that specific bacterial species can influence obesity and related metabolic defects such as insulin sensitivity. Components of bacteria are sufficient to impact obesity-related changes in metabolism. In fact, different microbial components derived from the bacterial cell wall can increase or decrease insulin resistance. Improving our understanding of the how components of the microbiota alter host metabolism is positioned to aid in the development of dietary interventions, avoiding triggers of dysbiosis, and generating novel therapeutic strategies to combat increasing rates of obesity and diabetes.

  17. Infliximab's influence on anastomotic strength and degree of inflammation in intestinal surgery in a rabbit model

    DEFF Research Database (Denmark)

    Frostberg, Erik; Ström, Petter; Gerke, Oke

    2014-01-01

    and conclusions. The purpose of this study was to investigate whether a single dose infliximab has an adverse effect on the anastomotic healing process, observed as reduced anastomotic breaking strength and histopathologically verified lower grade of inflammatory response, in the small intestine of a rabbit....... METHODS: Thirty New Zealand rabbits (median weight 2.5 kg) were allocated to treatment with an intravenous bolus of either 10 mg/kg infliximab (n = 15) or placebo (n = 15). One week later all rabbits underwent two separate end-to-end anastomoses in the jejunum under general anesthesia. At postoperative...... day three, the anastomotic breaking strength was determined and histopathological changes were examined. RESULTS: The mean value of anastomotic breaking strength in the placebo group was 1.89 +/- 0.36 N and the corresponding value was 1.81 +/- 0.33 N in the infliximab treated rabbits...

  18. Investigation of Microbiota Alterations and Intestinal Inflammation Post-Spinal Cord Injury in Rat Model.

    Science.gov (United States)

    O'Connor, Gregory; Jeffrey, Elisabeth; Madorma, Derik; Marcillo, Alexander; Abreu, Maria T; Deo, Sapna K; Dietrich, W Dalton; Daunert, Sylvia

    2018-03-23

    Although there has been a significant amount of research focused on the pathophysiology of Spinal Cord Injury (SCI), there is limited information on the consequences of SCI on remote organs. SCI can produce significant effects on a variety of organ systems, including the gastrointestinal tract. Patients with SCI often suffer from severe, debilitating bowel dysfunction in addition to their physical disabilities, which is of major concern for these individuals due to the adverse impact on their quality of life. Herein, we report on our investigation into the effects of SCI and subsequent antibiotic treatment on the intestinal tissue and microbiota. For that, we employed a thoracic SCI rat model and investigated changes to the microbiota, pro-inflammatory cytokine levels, and bacterial communication molecule levels post injury and gentamicin treatment for seven days. We discovered significant changes, the most interesting being the differences in the gut microbiota beta diversity of 8-week SCI animals compared to control animals at the family, genus, and species level. Specifically, 35 Operational Taxonomic Units (OTUs) were enriched in the SCI animal group and 3 were identified at species level; Lactobacillus intestinalis, Clostridium disporicum, and Bifidobacterium choerinum. In contrast, Clostridium saccharogumia was identified as depleted in the SCI animal group. Pro-inflammatory cytokines IL-12, MIP-2, and TNF-α, were found to be significantly elevated in intestinal tissue homogenate 4-weeks post-SCI compared to 8-weeks post-injury. Further, levels of IL-1β, IL-12, and MIP-2 significantly correlated with changes in beta diversity 8-weeks post-SCI. Our data provide a greater understanding of the early effects of SCI on the microbiota and gastrointestinal tract, highlighting the need for further investigation to elucidate the mechanism underlying these effects.

  19. Deoxynivalenol induced mouse skin cell proliferation and inflammation via MAPK pathway

    International Nuclear Information System (INIS)

    Mishra, Sakshi; Tripathi, Anurag; Chaudhari, Bhushan P.; Dwivedi, Premendra D.; Pandey, Haushila P.; Das, Mukul

    2014-01-01

    Several toxicological manifestations of deoxynivalenol (DON), a mycotoxin, are well documented; however, dermal toxicity is not yet explored. The effect of topical application of DON to mice was studied using markers of skin proliferation, inflammation and tumor promotion. Single topical application of DON (84–672 nmol/mouse) significantly enhanced dermal hyperplasia and skin edema. DON (336 and 672 nmol) caused significant enhancement in [ 3 H]-thymidine uptake in DNA along with increased myeloperoxidase and ornithine decarboxylase activities, suggesting tissue inflammation and cell proliferation. Furthermore, DON (168 nmol) caused enhanced expression of RAS, and phosphorylation of PI3K/Akt, ERK, JNK and p38 MAPKs. DON exposure also showed activation of transcription factors, c-fos, c-jun and NF-κB along with phosphorylation of IkBα. Enhanced phosphorylation of NF-κB by DON caused over expression of target proteins, COX-2, cyclin D1 and iNOS in skin. Though a single topical application of DMBA followed by twice weekly application of DON (84 and 168 nmol) showed no tumorigenesis after 24 weeks, however, histopathological studies suggested hyperplasia of the epidermis and hypertrophy of hair follicles. Interestingly, intestine was also found to be affected as enlarged Peyer's patches were observed, suggesting inflammatory effects which were supported by elevation of inflammatory cytokines after 24 weeks of topical application of DON. These results suggest that DON induced cell proliferation in mouse skin is through the activation of MAPK signaling pathway involving transcription factors NFκB and AP-1, further leading to transcriptional activation of downstream target proteins c-fos, c-jun, cyclin D1, iNOS and COX-2 which might be responsible for its inflammatory potential. - Highlights: • Topical application of DON enhanced epidermal inflammation and cell proliferation. • DON follows PI3K/Akt/MAPK signaling cascade, with activation of AP-1 and NF

  20. Modulation of intestinal inflammation by yeasts and cell wall extracts: strain dependence and unexpected anti-inflammatory role of glucan fractions.

    Directory of Open Access Journals (Sweden)

    Samir Jawhara

    Full Text Available Yeasts and their glycan components can have a beneficial or adverse effect on intestinal inflammation. Previous research has shown that the presence of Saccharomyces cerevisiae var. boulardii (Sb reduces intestinal inflammation and colonization by Candida albicans. The aim of this study was to identify dietary yeasts, which have comparable effects to the anti-C. albicans and anti-inflammatory properties of Sb and to assess the capabilities of yeast cell wall components to modulate intestinal inflammation. Mice received a single oral challenge of C. albicans and were then given 1.5% dextran-sulphate-sodium (DSS for 2 weeks followed by a 3-day restitution period. S. cerevisiae strains (Sb, Sc1 to Sc4, as well as mannoprotein (MP and β-glucan crude fractions prepared from Sc2 and highly purified β-glucans prepared from C. albicans were used in this curative model, starting 3 days after C. albicans challenge. Mice were assessed for the clinical, histological and inflammatory responses related to DSS administration. Strain Sc1-1 gave the same level of protection against C. albicans as Sb when assessed by mortality, clinical scores, colonization levels, reduction of TNFα and increase in IL-10 transcription. When Sc1-1 was compared with the other S. cerevisiae strains, the preparation process had a strong influence on biological activity. Interestingly, some S. cerevisiae strains dramatically increased mortality and clinical scores. Strain Sc4 and MP fraction favoured C. albicans colonization and inflammation, whereas β-glucan fraction was protective against both. Surprisingly, purified β-glucans from C. albicans had the same protective effect. Thus, some yeasts appear to be strong modulators of intestinal inflammation. These effects are dependent on the strain, species, preparation process and cell wall fraction. It was striking that β-glucan fractions or pure β-glucans from C. albicans displayed the most potent anti-inflammatory effect in the

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

    International Nuclear Information System (INIS)

    Ding Tingting; Sun Jiao; Zhang Ping

    2009-01-01

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

  2. Protective effect of Korean Red Ginseng extract against Helicobacter pylori-induced gastric inflammation in Mongolian gerbils

    Directory of Open Access Journals (Sweden)

    Minkyung Bae

    2014-01-01

    Full Text Available Helicobacter pylori-induced gastric inflammation includes induction of inflammatory mediators interleukin (IL-8 and inducible nitric oxide synthase (iNOS, which are mediated by oxidant-sensitive transcription factor NF-κB. High levels of lipid peroxide (LPO and increased activity of myeloperoxidase (MPO, a biomarker of neutrophil infiltration, are observed in H. pylori-infected gastric mucosa. Panax ginseng Meyer, a Korean herb medicine, is widely used in Asian countries for its biological activities including anti-inflammatory efficacy. The present study aims to investigate whether Korean Red Ginseng extract (RGE inhibits H. pylori-induced gastric inflammation in Mongolian gerbils. One wk after intragastric inoculation with H. pylori, Mongolian gerbils were fed with either the control diet or the diet containing RGE (200 mg RGE/gerbil for 6 wk. The following were determined in gastric mucosa: the number of viable H. pylori in stomach; MPO activity; LPO level; mRNA and protein levels of keratinocyte chemoattractant factor (KC, a rodent IL-8 homolog, IL-1β, and iNOS; protein level of phospho-IκBα (which reflects the activation of NF-κB; and histology. As a result, RGE suppressed H. pylori-induced mRNA and protein levels of KC, IL-1β, and iNOS in gastric mucosa. RGE also inhibited H. pylori-induced phosphorylation of IκBα and increases in LPO level and MPO activity of gastric mucosa. RGE did not affect viable H. pylori colonization in the stomach, but improved the histological grade of infiltration of polymorphonuclear neutrophils, intestinal metaplasia, and hyperplasia. In conclusion, RGE inhibits H. pylori-induced gastric inflammation by suppressing induction of inflammatory mediators (KC, IL-1β, iNOS, MPO activity, and LPO level in H. pylori-infected gastric mucosa.

  3. The role of metabolism in diclofenac-induced intestinal toxicity in rat and human in vitro

    NARCIS (Netherlands)

    Niu, Xiaoyu; Makkinje, Miriam; de Graaf, Inge; Groothuis, Genoveva

    The use of Diclofenac (DCF), a non-steroidal anti-inflammatory drug is associated with severe gastro-intestinal side-effects. The mechanisms of drug-induced intestinal toxicity are largely unknown due to the lack of in vitro models. In vivo rat studies suggested that reactive metabolites of DCF

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

    Science.gov (United States)

    Zhang, Jinshan; Xue, Jinling; Xu, Bi; Xie, Jiani; Qiao, Juan; Lu, Yun

    2016-02-13

    Lipopolysaccharide (LPS, also called endotoxin) is a pro-inflammatory constituent of gram negative bacteria and cyanobacteria, which causes a potential health risk in the process of routine urban application of reclaimed water, such as car wash, irrigation, scenic water refilling, etc. Previous studies indicated that the common disinfection treatment, chlorination, has little effect on endotoxin activity removal measured by Limulus amebocyte lysate (LAL) assay. However, in this study, significant decrease of acute inflammatory effects was observed in mouse lung, while LAL assay still presented a moderate increase of endotoxin activity. To explore the possible mechanisms, the nuclear magnetic resonance (NMR) results showed the chlorination happened in alkyl chain of LPS molecules, which could affect the interaction between LPS and LPS-binding protein. Also the size of LPS aggregates was found to drop significantly after treatment, which could be another results of chlorination caused polarity change. In conclusion, our observation demonstrated that chlorination is effective to reduce the LPS induced inflammation in lung, and it is recommended to use health effect-based methods to assess risk removal of water treatment technologies. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Metagenomic analyses of alcohol induced pathogenic alterations in the intestinal microbiome and the effect of Lactobacillus rhamnosus GG treatment.

    Directory of Open Access Journals (Sweden)

    Lara Bull-Otterson

    Full Text Available Enteric dysbiosis plays an essential role in the pathogenesis of alcoholic liver disease (ALD. Detailed characterization of the alterations in the gut microbiome is needed for understanding their pathogenic role in ALD and developing effective therapeutic approaches using probiotic supplementation. Mice were fed liquid Lieber-DeCarli diet without or with alcohol (5% v/v for 6 weeks. A subset of mice were administered the probiotic Lactobacillus rhamnosus GG (LGG from 6 to 8 weeks. Indicators of intestinal permeability, hepatic steatosis, inflammation and injury were evaluated. Metagenomic analysis of the gut microbiome was performed by analyzing the fecal DNA by amplification of the V3-V5 regions of the 16S rRNA gene and large-scale parallel pyrosequencing on the 454 FLX Titanium platform. Chronic ethanol feeding caused a decline in the abundance of both Bacteriodetes and Firmicutes phyla, with a proportional increase in the gram negative Proteobacteria and gram positive Actinobacteria phyla; the bacterial genera that showed the biggest expansion were the gram negative alkaline tolerant Alcaligenes and gram positive Corynebacterium. Commensurate with the qualitative and quantitative alterations in the microbiome, ethanol caused an increase in plasma endotoxin, fecal pH, hepatic inflammation and injury. Notably, the ethanol-induced pathogenic changes in the microbiome and the liver were prevented by LGG supplementation. Overall, significant alterations in the gut microbiome over time occur in response to chronic alcohol exposure and correspond to increases in intestinal barrier dysfunction and development of ALD. Moreover, the altered bacterial communities of the gut may serve as significant therapeutic target for the prevention/treatment of chronic alcohol intake induced intestinal barrier dysfunction and liver disease.

  6. Effect of acute moderate exercise on induced inflammation and arterial function in older adults.

    Science.gov (United States)

    Ranadive, Sushant Mohan; Kappus, Rebecca Marie; Cook, Marc D; Yan, Huimin; Lane, Abbi Danielle; Woods, Jeffrey A; Wilund, Kenneth R; Iwamoto, Gary; Vanar, Vishwas; Tandon, Rudhir; Fernhall, Bo

    2014-04-01

    Acute inflammation reduces flow-mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate-intensity aerobic exercise can be anti-inflammatory. Taken together, we tested the hypothesis that acute moderate-intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty-nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow-mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow-mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and β-stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults.

  7. Teuvincenone F Suppresses LPS-Induced Inflammation and NLRP3 Inflammasome Activation by Attenuating NEMO Ubiquitination

    OpenAIRE

    Xibao Zhao; Xibao Zhao; Debing Pu; Debing Pu; Zizhao Zhao; Huihui Zhu; Hongrui Li; Hongrui Li; Yaping Shen; Xingjie Zhang; Ruihan Zhang; Jianzhong Shen; Weilie Xiao; Weilie Xiao; Weilin Chen

    2017-01-01

    Inflammation causes many diseases that are serious threats to human health. However, the molecular mechanisms underlying regulation of inflammation and inflammasome activation are not fully understood which has delayed the discovery of new anti-inflammatory drugs of urgent clinic need. Here, we found that the natural compound Teuvincenone F, which was isolated and purified from the stems and leaves of Premna szemaoensis, could significantly inhibit lipopolysaccharide (LPS)–induced pro-inflamm...

  8. Teuvincenone F Suppresses LPS-Induced Inflammation and NLRP3 Inflammasome Activation by Attenuating NEMO Ubiquitination

    OpenAIRE

    Zhao, Xibao; Pu, Debing; Zhao, Zizhao; Zhu, Huihui; Li, Hongrui; Shen, Yaping; Zhang, Xingjie; Zhang, Ruihan; Shen, Jianzhong; Xiao, Weilie; Chen, Weilin

    2017-01-01

    Inflammation causes many diseases that are serious threats to human health. However, the molecular mechanisms underlying regulation of inflammation and inflammasome activation are not fully understood which has delayed the discovery of new anti-inflammatory drugs of urgent clinic need. Here, we found that the natural compound Teuvincenone F, which was isolated and purified from the stems and leaves of Premna szemaoensis, could significantly inhibit lipopolysaccharide (LPS)?induced pro-inflamm...

  9. Dietary, nondigestible oligosaccharides and Bifidobacterium breve M-16V suppress allergic inflammation in intestine via targeting dendritic cell maturation.

    Science.gov (United States)

    de Kivit, Sander; Kostadinova, Atanaska I; Kerperien, JoAnn; Morgan, Mary E; Muruzabal, Veronica Ayechu; Hofman, Gerard A; Knippels, Leon M J; Kraneveld, Aletta D; Garssen, Johan; Willemsen, Linette E M

    2017-07-01

    Dietary intervention with short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and Bifidobacterium breve M-16V ( Bb ) (GF/ Bb ) suppresses food allergic symptoms in mice, potentially via intestinal epithelial cell (IEC)-derived galectin-9. Furthermore, in vitro studies showed galacto- and fructo-oligosaccharides (GF) to enhance the immunomodulatory capacity of a TLR9 ligand representing bacterial CpG DNA when exposed to IEC. In this study, we investigated whether GF/ Bb modulates dendritic cells (DCs) and subsequent Th2 and regulatory T cell (T reg ) frequency in the small intestinal lamina propria (SI-LP). BALB/c mice were fed GF/ Bb during oral OVA sensitization. DC and T cell phenotype were determined in SI-LP mononuclear cells using flow cytometry. Murine bone marrow-derived DCs (BMDCs) were exposed to recombinant galectin-9 or human monocyte-derived DCs (moDCs) and were cultured in IEC-conditioned medium from GF and TLR9 ligand-exposed HT-29 cells. GF/ Bb reduced allergic symptoms and enhanced serum galectin-9 levels, while suppressing activation, restoring phagocytic capacity, and normalizing CD103 expression of SI-LP DCs of OVA-allergic mice. In vitro, galectin-9 suppressed LPS-induced activation markers and cytokine secretion by BMDCs, and IEC-conditioned medium suppressed moDC activation in a galectin-9-dependent manner. Besides suppression of SI-LP DC activation, dietary GF/ Bb also lowered the frequency of activated Th2 cells, while enhancing T reg in the SI-LP of OVA-allergic mice compared to the control diet. Dietary intervention with GF/ Bb enhances galectin-9 and suppresses allergic symptoms of OVA-allergic mice in association with reduced intestinal DC and Th2 activation and increased T reg frequency in these mice. © Society for Leukocyte Biology.

  10. Intestinal metaplasia induced by x-irradiation in rat

    International Nuclear Information System (INIS)

    Watanabe, Hiromitsu; Terada, Yoritaka; Fujii, Isao; Yamamoto, Yukiko; Takizawa, Shoichi

    1978-01-01

    Total 400 rad of x-ray was given in 100 or 150 rad doses to the whole body of rats at intervals of one week, and one year and a half later, rats were killed. Disaccharidase was formed in most of animals, intestinal metaplasia only with goblet cells occurred in 65% of animals, and that with intestinal type of lacuna occurred in 36% of them. When 500 rad of x-ray was irradiated to each part of stomach day after day up to the total dose of 3,000 rad, biochemical intestinal metaplasia already occurred one week after the irradiation, and intestinal type lacuna occurred 2 months after the irradiation. Intestinal type lacuna was recognized in all animals killed 499 days after the irradiation, and intestinal metaplasia with Paneth's cells occurred in 6 out of 11 cases (56%). When a dose of 1,000 rad was irradiated to stomach three times at intervals of 2 days up to the total of 3,000 rad, much intestinal type lacuna was recognized 2 months after the irradiation, gastric adenoid cancerous changes appeared 4 months after, and gastric adenoid cancer occurred 6 months after. The above-mentioned results clarified that even if x-ray of a small dose was irradiated, intestinal metaplasia occurred, and that the period from the irradiation to occurrence of intestinal metaplasia was shortened by increasing a dose of x-ray. It was also clarified that not only intestinal metaplasia but also gastric adenoic cancer occurred due to a great amount of x-ray irradiation. (Ueda, J.)

  11. Intestinal metaplasia induced by x-irradiation in rat

    Energy Technology Data Exchange (ETDEWEB)

    Watanabe, H; Terada, Y; Fujii, I; Yamamoto, Y; Takizawa, S [Hiroshima Univ. (Japan). Research Inst. for Nuclear Medicine and Biology

    1978-04-01

    Total 400 rad of x-ray was given in 100 or 150 rad doses to the whole body of rats at intervals of one week, and one year and a half later, rats were killed. Disaccharidase was formed in most of animals, intestinal metaplasia only with goblet cells occurred in 65% of animals, and that with intestinal type of lacuna occurred in 36% of them. When 500 rad of x-ray was irradiated to each part of stomach day after day up to the total dose of 3,000 rad, biochemical intestinal metaplasia already occurred one week after the irradiation, and intestinal type lacuna occurred 2 months after the irradiation. Intestinal type lacuna was recognized in all animals killed 499 days after the irradiation, and intestinal metaplasia with Paneth's cells occurred in 6 out of 11 cases (56%). When a dose of 1,000 rad was irradiated to stomach three times at intervals of 2 days up to the total of 3,000 rad, much intestinal type lacuna was recognized 2 months after the irradiation, gastric adenoid cancerous changes appeared 4 months after, and gastric adenoid cancer occurred 6 months after. The above-mentioned results clarified that even if x-ray of a small dose was irradiated, intestinal metaplasia occurred, and that the period from the irradiation to occurrence of intestinal metaplasia was shortened by increasing a dose of x-ray. It was also clarified that not only intestinal metaplasia but also gastric adenoic cancer occurred due to a great amount of x-ray irradiation.

  12. Adaptive immunity alters distinct host feeding pathways during nematode induced inflammation, a novel mechanism in parasite expulsion.

    Directory of Open Access Journals (Sweden)

    John J Worthington

    2013-01-01

    Full Text Available Gastrointestinal infection is often associated with hypophagia and weight loss; however, the precise mechanisms governing these responses remain poorly defined. Furthermore, the possibility that alterations in feeding during infection may be beneficial to the host requires further study. We used the nematode Trichinella spiralis, which transiently inhabits the small intestine before migrating to skeletal muscle, as a biphasic model of infection to determine the cellular and molecular pathways controlling feeding during enteric and peripheral inflammation. Through the infection of genetically modified mice lacking cholecystokinin, Tumor necrosis factor α receptors and T and B-cells, we observed a biphasic hypophagic response to infection resulting from two separate immune-driven mechanisms. The enteroendocrine I-cell derived hormone cholecystokinin is an essential mediator of initial hypophagia and is induced by CD4+ T-cells during enteritis. In contrast, the second hypophagic response is extra-intestinal and due to the anorectic effects of TNFα during peripheral infection of the muscle. Moreover, via maintaining naive levels of the adipose secreted hormone leptin throughout infection we demonstrate a novel feedback loop in the immunoendocrine axis. Immune driven I-cell hyperplasia and resultant weight loss leads to a reduction in the inflammatory adipokine leptin, which in turn heightens protective immunity during infection. These results characterize specific immune mediated mechanisms which reduce feeding during intestinal or peripheral inflammation. Importantly, the molecular mediators of each phase are entirely separate. The data also introduce the first evidence that I-cell hyperplasia is an adaptively driven immune response that directly impinges on the outcome to infection.

  13. The common parasite Toxoplasma gondii induces prostatic inflammation and microglandular hyperplasia in a mouse model.

    Science.gov (United States)

    Colinot, Darrelle L; Garbuz, Tamila; Bosland, Maarten C; Wang, Liang; Rice, Susan E; Sullivan, William J; Arrizabalaga, Gustavo; Jerde, Travis J

    2017-07-01

    Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia and prostate cancer. Several factors have been hypothesized to cause inflammation, yet the role each may play in the etiology of prostatic inflammation remains unclear. This study examined the possibility that the common protozoan parasite Toxoplasma gondii induces prostatic inflammation and reactive hyperplasia in a mouse model. Male mice were infected systemically with T. gondii parasites and prostatic inflammation was scored based on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation. We found that T. gondii infects the mouse prostate within the first 14 days of infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of proliferative inflammatory microglandular hyperplasia in inflamed mouse prostates. This study identifies the common parasite T. gondii as a new trigger of prostatic inflammation, which we used to develop a novel mouse model of prostatic inflammation. This is the first report that T. gondii chronically encysts and induces chronic inflammation within the prostate of any species. Furthermore, T. gondii-induced prostatic inflammation persists and progresses without genetic manipulation in mice, offering a powerful new mouse model for the study of chronic prostatic inflammation and microglandular hyperplasia. © 2017 Wiley Periodicals, Inc.

  14. Surgical treatment of radiation induced injuries of the intestine

    Energy Technology Data Exchange (ETDEWEB)

    Schmitt, E.H.; Symmonds, R.E.

    1981-12-01

    In the patient who has received high dose irradiation of the pelvis and abdomen, all abdominopelvic operations should be avoided, unless it is absolutely essential. Persisting obstruction, hemorrhage, intestinal perforation with peritonitis and with abscess and fistula formation are valid indications for surgical intervention. Ninety-three patients have been operated upon for these complications after irradiation. Some anastomotic dehiscence occurred in ten patients. Six operative deaths occurred. Of the 93 patients, 65 were managed by means of complete resection of the involved segment of intestine, followed by restoration of intestinal continuity by means of an end-to-end anastomosis. This is the treatment of choice when the involved area can be safely resected. In the absence of actual intestinal necrosis and when segments of strictured small intestine are adherent deep in the pelvis, and intestinal bypass procedure may represent the treatment of choice. This was accomplished in 20 patients, two of whom eventually required a second operation for resection of the bypassed segment of intestine.

  15. Surgical treatment of radiation induced injuries of the intestine

    International Nuclear Information System (INIS)

    Schmitt, E.H.; Symmonds, R.E.

    1981-01-01

    In the patient who has received high dose irradiation of the pelvis and abdomen, all abdominopelvic operations should be avoided, unless it is absolutely essential. Persisting obstruction, hemorrhage, intestinal perforation with peritonitis and with abscess and fistula formation are valid indications for surgical intervention. Ninety-three patients have been operated upon for these complications after irradiation. Some anastomotic dehiscence occurred in ten patients. Six operative deaths occurred. Of the 93 patients, 65 were managed by means of complete resection of the involved segment of intestine, followed by restoration of intestinal continuity by means of an end-to-end anastomosis. This is the treatment of choice when the involved area can be safely resected. In the absence of actual intestinal necrosis and when segments of strictured small intestine are adherent deep in the pelvis, and intestinal bypass procedure may represent the treatment of choice. This was accomplished in 20 patients, two of whom eventually required a second operation for resection of the bypassed segment of intestine

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

    NARCIS (Netherlands)

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

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Nemmar A

    2014-06-01

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

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

    Science.gov (United States)

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

    2014-10-28

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

  19. Symbiotic formulation in experimentally induced liver fibrosis in rats: intestinal microbiota as a key point to treat liver damage?

    Science.gov (United States)

    D'Argenio, Giuseppe; Cariello, Rita; Tuccillo, Concetta; Mazzone, Giovanna; Federico, Alessandro; Funaro, Annalisa; De Magistris, Laura; Grossi, Enzo; Callegari, Maria L; Chirico, Marilena; Caporaso, Nicola; Romano, Marco; Morelli, Lorenzo; Loguercio, Carmela

    2013-05-01

    Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis. CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-β, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls. Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis. © 2013 John Wiley & Sons A/S.

  20. Precision-cut intestinal slices as an in vitro model to predict NSAID induced intestinal toxicity

    NARCIS (Netherlands)

    Niu, Xiaoyu; van der Bijl, Henk; Groothuis, Geny; de Graaf, Inge

    2013-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with high prevalence of gastro-intestinal side-effects. In vivo studies suggest that uncoupling of oxidative phosphorylation is an important cause of the toxicity and that the toxicity is aggravated by enterohepatic circulation.

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

    Science.gov (United States)

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

  2. Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats

    Directory of Open Access Journals (Sweden)

    Pedro M. G. Soares

    2011-03-01

    Full Text Available CONTEXT: Methotrexate and other anticancer agents can induce intestinal mucositis, which is one of the most common limiting factor that prevent further dose escalation of the methotrexate. OBJECTIVES: To evaluate the gastric emptying and gastrointestinal transit of liquids in methotrexate-induced intestinal mucositis. METHODS: Wistar rats received methotrexate (2.5 mg/kg/day for 3 days, subcutaneously or saline. After 1, 3 and 7 days, sections of duodenum, jejunum and ileum were removed for assessment of epithelial damage and myeloperoxidase activity (biochemical marker of granulocyte infiltration. Others rats were pre-treated with methotrexate or saline, gavage-fed after 3 or 7 days with a standard test liquid meal, and sacrificed 10, 20 or 30-min later. Gastric and small intestine dye recoveries were measured by spectrophotometry. RESULTS: After 3 days of methotrexate, there was an epithelial intestinal damage in all segments, with myeloperoxidase activity increase in both in duodenum and ileum. Seven days after methotrexate, we observed a complete reversion of this intestinal damage. There was an increase in gastric dye recoveries after 10, 20, and 30-min post-prandial intervals after 3 days, but not after 7 days, of methotrexate. Intestine dye recoveries were decreased in the first and second segments at 10 min, in the third at 20 min, and in the second and third at 30 min, only after 3 days of methotrexate treatment. CONCLUSION: Methotrexate-induced intestinal mucositis delays gastric emptying and gastrointestinal transit of liquids in awake rats.

  3. Tanshinone IIA Sodium Sulfonate Attenuates LPS-Induced Intestinal Injury in Mice

    Directory of Open Access Journals (Sweden)

    Xin-Jing Yang

    2018-01-01

    Full Text Available Background. Tanshinone IIA sodium sulfonate (TSS is known to possess anti-inflammatory effects and has exhibited protective effects in various inflammatory conditions; however, its role in lipopolysaccharide- (LPS- induced intestinal injury is still unknown. Objective. The present study is designed to explore the role and possible mechanism of TSS in LPS-induced intestinal injury. Methods. Male C57BL/6J mice, challenged with intraperitoneal LPS injection, were treated with or without TSS 0.5 h prior to LPS exposure. At 1, 6, and 12 h after LPS injection, mice were sacrificed, and the small intestine was excised. The intestinal tissue injury was analyzed by HE staining. Inflammatory factors (TNF-α, IL-1β, and IL-6 in the intestinal tissue were examined by ELISA and RT-PCR. In addition, expressions of autophagy markers (microtubule-associated light chain 3 (LC3 and Beclin-1 were detected by western blot and RT-PCR. A number of autophagosomes were also observed under electron microscopy. Results. TSS treatment significantly attenuated small intestinal epithelium injury induced by LPS. LPS-induced release of inflammatory mediators, including TNF-α, IL-1β, and IL-6, were markedly inhibited by TSS. Furthermore, TSS treatment could effectively upregulate LPS-induced decrease of autophagy levels, as evidenced by the increased expression of LC3 and Beclin-1, and more autophagosomes. Conclusion. The protective effect of TSS on LPS-induced small intestinal injury may be attributed to the inhibition of inflammatory factors and promotion of autophagy levels. The present study may provide novel insight into the molecular mechanisms of TSS on the treatment of intestinal injury.

  4. HTLV-1 bZIP factor induces inflammation through labile Foxp3 expression.

    Directory of Open Access Journals (Sweden)

    Nanae Yamamoto-Taguchi

    2013-09-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. The HTLV-1 basic leucine zipper factor (HBZ gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4⁺Foxp3⁺ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-γ (IFN-γ. In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4⁺ T cells were enhanced in these mice. Foxp3⁻CD4⁺ T cells produced higher amounts of IFN-γ compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-γ, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3⁻T cells producing IFN-γ. The HBZ-mediated proinflammatory phenotype of CD4⁺ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation.

  5. RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-04-29

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

  6. RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis

    International Nuclear Information System (INIS)

    Meng, Lingjun; Jin, Wei; Wang, Yuhui; Huang, Huanwei; Li, Jia; Zhang, Cai

    2016-01-01

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

  7. Carrageenan-Induced Colonic Inflammation Is Reduced in Bcl10 Null Mice and Increased in IL-10-Deficient Mice

    Directory of Open Access Journals (Sweden)

    Sumit Bhattacharyya

    2013-01-01

    Full Text Available The common food additive carrageenan is a known activator of inflammation in mammalian tissues and stimulates both the canonical and noncanonical pathways of NF-κB activation. Exposure to low concentrations of carrageenan (10 μg/mL in the water supply has produced glucose intolerance, insulin resistance, and impaired insulin signaling in C57BL/6 mice. B-cell leukemia/lymphoma 10 (Bcl10 is a mediator of inflammatory signals from Toll-like receptor (TLR 4 in myeloid and epithelial cells. Since the TLR4 signaling pathway is activated in diabetes and by carrageenan, we addressed systemic and intestinal inflammatory responses following carrageenan exposure in Bcl10 wild type, heterozygous, and null mice. Fecal calprotectin and circulating keratinocyte chemokine (KC, nuclear RelA and RelB, phospho(Thr559-NF-κB-inducing kinase (NIK, and phospho(Ser36-IκBα in the colonic epithelial cells were significantly less (P<0.001 in the carrageenan-treated Bcl10 null mice than in controls. IL-10-deficient mice exposed to carrageenan in a germ-free environment showed an increase in activation of the canonical pathway of NF-κB (RelA activation, but without increase in RelB or phospho-Bcl10, and exogenous IL-10 inhibited only the canonical pathway of NF-κB activation in cultured colonic cells. These findings demonstrate a Bcl10 requirement for maximum development of carrageenan-induced inflammation and lack of complete suppression by IL-10 of carrageenan-induced inflammation.

  8. Circulating and Tissue-Resident CD4+ T Cells With Reactivity to Intestinal Microbiota Are Abundant in Healthy Individuals and Function Is Altered During Inflammation.

    Science.gov (United States)

    Hegazy, Ahmed N; West, Nathaniel R; Stubbington, Michael J T; Wendt, Emily; Suijker, Kim I M; Datsi, Angeliki; This, Sebastien; Danne, Camille; Campion, Suzanne; Duncan, Sylvia H; Owens, Benjamin M J; Uhlig, Holm H; McMichael, Andrew; Bergthaler, Andreas; Teichmann, Sarah A; Keshav, Satish; Powrie, Fiona

    2017-11-01

    Interactions between commensal microbes and the immune system are tightly regulated and maintain intestinal homeostasis, but little is known about these interactions in humans. We investigated responses of human CD4 + T cells to the intestinal microbiota. We measured the abundance of T cells in circulation and intestinal tissues that respond to intestinal microbes and determined their clonal diversity. We also assessed their functional phenotypes and effects on intestinal resident cell populations, and studied alterations in microbe-reactive T cells in patients with chronic intestinal inflammation. We collected samples of peripheral blood mononuclear cells and intestinal tissues from healthy individuals (controls, n = 13-30) and patients with inflammatory bowel diseases (n = 119; 59 with ulcerative colitis and 60 with Crohn's disease). We used 2 independent assays (CD154 detection and carboxy-fluorescein succinimidyl ester dilution assays) and 9 intestinal bacterial species (Escherichia coli, Lactobacillus acidophilus, Bifidobacterium animalis subsp lactis, Faecalibacterium prausnitzii, Bacteroides vulgatus, Roseburia intestinalis, Ruminococcus obeum, Salmonella typhimurium, and Clostridium difficile) to quantify, expand, and characterize microbe-reactive CD4 + T cells. We sequenced T-cell receptor Vβ genes in expanded microbe-reactive T-cell lines to determine their clonal diversity. We examined the effects of microbe-reactive CD4 + T cells on intestinal stromal and epithelial cell lines. Cytokines, chemokines, and gene expression patterns were measured by flow cytometry and quantitative polymerase chain reaction. Circulating and gut-resident CD4 + T cells from controls responded to bacteria at frequencies of 40-4000 per million for each bacterial species tested. Microbiota-reactive CD4 + T cells were mainly of a memory phenotype, present in peripheral blood mononuclear cells and intestinal tissue, and had a diverse T-cell receptor Vβ repertoire. These

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

    International Nuclear Information System (INIS)

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

    2009-01-01

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

  10. Histologic features of mesotherapy-induced orbital fat inflammation.

    Science.gov (United States)

    Nabavi, Cameron B; Minckler, Donald S; Tao, Jeremiah P

    2009-01-01

    A 67-year-old man developed acute orbital inflammation after receiving cosmetic mesotherapy (Lipo-Dissolve) to the inferior orbital fat compartments. The injection was intended to cause lipolysis and shrinkage of fat lobules with subsequent cosmetic improvement. Injections of a mixture of bile salts, phospholipid, and alcohol preservative bilaterally in inferior orbital fat lobules led to an acute inflammatory reaction characterized histologically 12 days later by mild lymphocytic infiltration, fat necrosis, and fibrosis in the target areas. Benign proliferation of peripheral nerve trunks consistent with a traumatic neuroma was also noted histologically on one side. Inflammation including fat necrosis and traumatic neuroma are all possible consequences of mesotherapy.

  11. Saccharomyces boulardii ameliorates clarithromycin- and methotrexate-induced intestinal and hepatic injury in rats.

    Science.gov (United States)

    Duman, Deniz Güney; Kumral, Zarife Nigâr Özdemir; Ercan, Feriha; Deniz, Mustafa; Can, Güray; Cağlayan Yeğen, Berrak

    2013-08-28

    Saccharomyces boulardii is a probiotic used for the prevention of antibiotic-associated diarrhoea. We aimed to investigate whether S. boulardii could alter the effects of clarithromycin (CLA) and methotrexate (MTX) on oro-caecal intestinal transit and oxidative damage in rats. Rats were divided into two groups receiving a single dose of MTX (20 mg/kg) or CLA (20 mg/kg per d) for 1 week. Groups were treated with either saline or S. boulardii (500 mg/kg) twice per d throughout the experiment. The control group was administered only saline. Following decapitation, intestinal transit and inflammation markers of glutathione (GSH), malondialdehyde and myeloperoxidase were measured in intestinal and hepatic tissues. CLA and MTX increased intestinal transit, while S. boulardii treatment slowed down CLA-facilitated transit back to control level. Both MTX and CLA increased lipid peroxidation while depleting the antioxidant GSH content in the hepatic and ileal tissues. Conversely, lipid peroxidation was depressed and GSH levels were increased in the ileal and hepatic tissues of S. boulardii-treated rats. Increased ileal neutrophil infiltration due to MTX and CLA treatments was also reduced by S. boulardii treatment. Histological analysis supported that S. boulardii protected intestinal tissues against the inflammatory effects of both agents. These findings suggest that S. boulardii ameliorates intestinal injury and the accompanying hepatic inflammation by supporting the antioxidant state of the tissues and by inhibiting the recruitment of neutrophils. Moreover, a preventive effect on MTXinduced toxicity is a novel finding of S. boulardii, proposing it as an adjunct to chemotherapy regimens.

  12. Crotoxin from Crotalus durissus terrificus is able to down-modulate the acute intestinal inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Caroline de Souza Almeida

    Full Text Available Inflammatory bowel diseases (IBD is the result of dysregulation of mucosal innate and adaptive immune responses. Factors such as genetic, microbial and environmental are involved in the development of these disorders. Accordingly, animal models that mimic human diseases are tools for the understanding the immunological processes of the IBD as well as to evaluate new therapeutic strategies. Crotoxin (CTX is the main component of Crotalus durissus terrificus snake venom and has an immunomodulatory effect. Thus, we aimed to evaluate the modulatory effect of CTX in a murine model of colitis induced by 2,4,6- trinitrobenzene sulfonic acid (TNBS. The CTX was administered intraperitoneally 18 hours after the TNBS intrarectal instillation in BALB/c mice. The CTX administration resulted in decreased weight loss, disease activity index (DAI, macroscopic tissue damage, histopathological score and myeloperoxidase (MPO activity analyzed after 4 days of acute TNBS colitis. Furthermore, the levels of TNF-α, IL-1β and IL-6 were lower in colon tissue homogenates of TNBS-mice that received the CTX when compared with untreated TNBS mice. The analysis of distinct cell populations obtained from the intestinal lamina propria showed that CTX reduced the number of group 3 innate lymphoid cells (ILC3 and Th17 population; CTX decreased IL-17 secretion but did not alter the frequency of CD4+Tbet+ T cells induced by TNBS instillation in mice. In contrast, increased CD4+FoxP3+ cell population as well as secretion of TGF-β, prostaglandin E2 (PGE2 and lipoxin A4 (LXA4 was observed in TNBS-colitis mice treated with CTX compared with untreated TNBS-colitis mice. In conclusion, the CTX is able to modulate the intestinal acute inflammatory response induced by TNBS, resulting in the improvement of clinical status of the mice. This effect of CTX is complex and involves the suppression of the pro-inflammatory environment elicited by intrarectal instillation of TNBS due to the

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

    Science.gov (United States)

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

    2015-01-01

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

  14. Mechanisms of methicillin-resistant Staphylococcus aureus pneumonia-induced intestinal epithelial apoptosis.

    Science.gov (United States)

    Perrone, Erin E; Jung, Enjae; Breed, Elise; Dominguez, Jessica A; Liang, Zhe; Clark, Andrew T; Dunne, W Michael; Burd, Eileen M; Coopersmith, Craig M

    2012-07-01

    Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia-induced sepsis is a common cause of morbidity in the intensive care unit. Although pneumonia is initiated in the lungs, extrapulmonary manifestations occur commonly. In light of the key role the intestine plays in the pathophysiology of sepsis, we sought to determine whether MRSA pneumonia induces intestinal injury. FVB/N mice were subjected to MRSA or sham pneumonia and killed 24 h later. Septic animals had a marked increase in intestinal epithelial apoptosis by both hematoxylin-eosin and active caspase 3 staining. Methicillin-resistant S. aureus-induced intestinal apoptosis was associated with an increase in the expression of the proapoptotic proteins Bid and Bax and the antiapoptotic protein Bcl-xL in the mitochondrial pathway. In the receptor-mediated pathway, MRSA pneumonia induced an increase in Fas ligand but decreased protein levels of Fas, FADD, pFADD, TNF-R1, and TRADD. To assess the functional significance of these changes, MRSA pneumonia was induced in mice with genetic manipulations in proteins in either the mitochondrial or receptor-mediated pathways. Both Bid-/- mice and animals with intestine-specific overexpression of Bcl-2 had decreased intestinal apoptosis compared with wild-type animals. In contrast, Fas ligand-/- mice had no alterations in apoptosis. To determine if these findings were organism-specific, similar experiments were performed in mice subjected to Pseudomonas aeruginosa pneumonia. Pseudomonas aeruginosa induced gut apoptosis, but unlike MRSA, this was associated with increased Bcl-2 and TNF-R1 and decreased Fas. Methicillin-resistant S. aureus pneumonia thus induces organism-specific changes in intestinal apoptosis via changes in both the mitochondrial and receptor-mediated pathways, although the former may be more functionally significant.

  15. Rifaximin-extended intestinal release induces remission in patients with moderately active Crohn's disease.

    Science.gov (United States)

    Prantera, Cosimo; Lochs, Herbert; Grimaldi, Maria; Danese, Silvio; Scribano, Maria Lia; Gionchetti, Paolo

    2012-03-01

    Bacteria might be involved in the development and persistence of inflammation in patients with Crohn's disease (CD), and antibiotics could be used in therapy. We performed a clinical phase 2 trial to determine whether a gastroresistant formulation of rifaximin (extended intestinal release [EIR]) induced remission in patients with moderately active CD. We performed a multicenter, randomized, double-blind trial of the efficacy and safety of 400, 800, and 1200 mg rifaximin-EIR, given twice daily to 402 patients with moderately active CD for 12 weeks. Data from patients given rifaximin-EIR were compared with those from individuals given placebo, and collected during a 12-week follow-up period. The primary end point was remission (Crohn's Disease Activity Index <150) at the end of the treatment period. At the end of the 12-week treatment period, 62% of patients who received the 800-mg dosage of rifaximin-EIR (61 of 98) were in remission, compared with 43% of patients who received placebo (43 of 101) (P = .005). A difference was maintained throughout the 12-week follow-up period (45% [40 of 89] vs 29% [28 of 98]; P = .02). Remission was achieved by 54% (56 of 104) and 47% (47 of 99) of the patients given the 400-mg and 1200-mg dosages of rifaximin-EIR, respectively; these rates did not differ from those of placebo. Patients given the 400-mg and 800-mg dosages of rifaximin-EIR had low rates of withdrawal from the study because of adverse events; rates were significantly higher among patients given the 1200-mg dosage (16% [16 of 99]). Administration of 800 mg rifaximin-EIR twice daily for 12 weeks induced remission with few adverse events in patients with moderately active CD. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Increased hypothalamic serotonin turnover in inflammation-induced anorexia

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  18. Rebamipide suppresses diclofenac-induced intestinal permeability via mitochondrial protection in mice.

    Science.gov (United States)

    Diao, Lei; Mei, Qiao; Xu, Jian-Ming; Liu, Xiao-Chang; Hu, Jing; Jin, Juan; Yao, Qiang; Chen, Mo-Li

    2012-03-14

    To investigate the protective effect and mechanism of rebamipide on small intestinal permeability induced by diclofenac in mice. Diclofenac (2.5 mg/kg) was administered once daily for 3 d orally. A control group received the vehicle by gavage. Rebamipide (100 mg/kg, 200 mg/kg, 400 mg/kg) was administered intragastrically once a day for 3 d 4 h after diclofenac administration. Intestinal permeability was evaluated by Evans blue and the FITC-dextran method. The ultrastructure of the mucosal barrier was evaluated by transmission electron microscopy (TEM). Mitochondrial function including mitochondrial swelling, mitochondrial membrane potential, mitochondrial nicotinamide adenine dinucleotide-reduced (NADH) levels, succinate dehydrogenase (SDH) and ATPase activities were measured. Small intestinal mucosa was collected for assessment of malondialdehyde (MDA) content and myeloperoxidase (MPO) activity. Compared with the control group, intestinal permeability was significantly increased in the diclofenac group, which was accompanied by broken tight junctions, and significant increases in MDA content and MPO activity. Rebamipide significantly reduced intestinal permeability, improved inter-cellular tight junctions, and was associated with decreases in intestinal MDA content and MPO activity. At the mitochondrial level, rebamipide increased SDH and ATPase activities, NADH level and decreased mitochondrial swelling. Increased intestinal permeability induced by diclofenac can be attenuated by rebamipide, which partially contributed to the protection of mitochondrial function.

  19. Diacylglycerol kinase regulation of protein kinase D during oxidative stress-induced intestinal cell injury

    International Nuclear Information System (INIS)

    Song Jun; Li Jing; Mourot, Joshua M.; Mark Evers, B.; Chung, Dai H.

    2008-01-01

    We recently demonstrated that protein kinase D (PKD) exerts a protective function during oxidative stress-induced intestinal epithelial cell injury; however, the exact role of DAG kinase (DGK)ζ, an isoform expressed in intestine, during this process is unknown. We sought to determine the role of DGK during oxidative stress-induced intestinal cell injury and whether DGK acts as an upstream regulator of PKD. Inhibition of DGK with R59022 compound or DGKζ siRNA transfection decreased H 2 O 2 -induced RIE-1 cell apoptosis as measured by DNA fragmentation and increased PKD phosphorylation. Overexpression of kinase-dead DGKζ also significantly increased PKD phosphorylation. Additionally, endogenous nuclear DGKζ rapidly translocated to the cytoplasm following H 2 O 2 treatment. Our findings demonstrate that DGK is involved in the regulation of oxidative stress-induced intestinal cell injury. PKD activation is induced by DGKζ, suggesting DGK is an upstream regulator of oxidative stress-induced activation of the PKD signaling pathway in intestinal epithelial cells

  20. Resolution of PMA-Induced Skin Inflammation Involves Interaction of IFN-γ and ALOX15

    Directory of Open Access Journals (Sweden)

    Guojun Zhang

    2013-01-01

    Full Text Available Background. Acute inflammation and its timely resolution play important roles in the body’s responses to the environmental stimulation. Although IFN-γ is well known for the induction of inflammation, its role in the inflammation resolution is still poorly understood. Methodology and Principal Findings. In this study, we investigated the function of interferon gamma (IFN-γ during the resolution of PMA-induced skin inflammation in vivo. The results revealed that the expression levels of IL-6, TNF-α, and monocyte chemoattractant protein 1 (MCP-1 in skin decreased during the resolution stage of PMA-induced inflammation, while IFN-γ is still maintained at a relatively high level. Neutralization of endogenous IFN-γ led to accelerated reduction of epidermal thickness and decreased epithelial cell proliferation. Similarly, decreased infiltration of inflammatory cells (Gr1+ or CD11b+ cells and a significant reduction of proinflammatory cytokines were also observed upon the blockade of IFN-γ. Furthermore, neutralization of IFN-γ boosted ALOX15 expression of the skin during inflammation resolution. In accordance, application of lipoxin A4 (LXA4, a product of ALOX15 obtained a proresolution effect similar to neutralization of IFN-γ. These results demonstrated that through upregulating ALOX15-LXA4 pathway, blockage of IFN-γ can promote the resolution of PMA-induced skin inflammation.

  1. Effects of growth hormone plus a hyperproteic diet on methotrexate-induced injury in rat intestines.

    Science.gov (United States)

    Ortega, M; Gomez-de-Segura, I A; Vázquez, I; López, J M; de Guevara, C L; De-Miguel, E

    2001-01-01

    The aim of this study was to determine whether growth hormone treatment reduces injury to the intestinal mucosa induced by methotrexate (MTX). Wistar rats with intestinal injury induced by methotrexate were treated with daily growth hormone, beginning 3 days before MTX treatment until 3 or 4 days after MTX administration. The rats were killed at 3 or 7 days post-MTX administration. The rats were fed with either a normoproteic diet or a hyperproteic diet. Body weight, mortality, bacterial translocation, intestinal morphometry, proliferation and apoptosis and blood somatostatin and IGF-1 were determined. Combined administration of growth hormone and a hyperproteic diet reduces MTX-induced mortality. This effect was accompanied by increased cell proliferation and decreased apoptosis within the crypt. Morphometric data showed complete recovery of the mucosa by day 7 post-MTX administration. These results indicate a synergistic protective action of growth hormone combined with a hyperproteic diet to MTX-induced injury.

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

    International Nuclear Information System (INIS)

    Takeda-Watanabe, Ai; Kitada, Munehiro; Kanasaki, Keizo; Koya, Daisuke

    2012-01-01

    Highlights: ► SIRT1 inactivation decreases autophagy in THP-1 cell. ► Inhibition of autophagy induces inflammation. ► SIRT1 inactivation induces inflammation through NF-κB activation. ► The p62/Sqstm1 accumulation by impairment of autophagy is related to NF-κB activation. ► SIRT1 inactivation is involved in the activation of mTOR and decreased AMPK activation. -- Abstract: Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are some of the cells involved in the inflammatory process in atherogenesis. Autophagy exerts a protective effect against cellular stresses like inflammation, and it is regulated by nutrient-sensing pathways. The nutrient-sensing pathway includes SIRT1, a NAD + -dependent histone deacetylase, which is implicated in the regulation of a variety of cellular processes including inflammation and autophagy. The mechanism through which the dysfunction of SIRT1 contributes to the regulation of inflammation in relation to autophagy in monocytes/macrophages is unclear. In the present study, we demonstrate that treatment with 2-[(2-Hydroxynaphthalen-1-ylmethylene)amino]-N-(1-phenethyl)benzamide (Sirtinol), a chemical inhibitor of SIRT1, induces the overexpression of inflammation-related genes such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 through nuclear factor (NF)-κB signaling activation, which is associated with autophagy dysfunction, as shown through p62/Sqstm1 accumulation and decreased expression of light chain (LC) 3 II in THP-1 cells. The autophagy inhibitor, 3-methyladenine, also induces inflammation-related NF-κB activation. In p62/Sqstm1 knockdown cells, Sirtinol-induced inflammation through NF-κB activation is blocked. In addition, inhibition of SIRT1 is involved in the activation of the mammalian target of rapamycin (mTOR) pathway and is implicated in decreased 5′-AMP activated kinase (AMPK) activation, leading to the impairment of autophagy. The mTOR inhibitor, rapamycin, abolishes

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-10-12

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

  4. Is a high-fiber diet able to influence ovalbumin-induced allergic airway inflammation in a mouse model?

    Science.gov (United States)

    Zhang, Zhiyu; Shi, Lei; Pang, Wenhui; Wang, Xiaoting; Li, Jianfeng; Wang, Haibo; Shi, Guanggang

    2016-01-01

    More recently, a large amount of experimental and clinical discovered that dietary- fiber intake would decrease the susceptibility to allergic airway disease (AAD) and respiratory inflammation. To investigate whether a fiber-intake supplement is able to influence the induction of AAD and to elucidate the interactive relationship. AAD model mice and control mice were raised on a fundamental diet with standard 4% fiber content, whereas other mice were fed a 10% fiber-content diet in the high fiber-content group, along with a 25% fiber-content diet instead in very-high fiber-content group. All experimental mice were sensitized and challenged with ovalbumin to induce allergic inflammation in both the upper and lower airways. Hallmarks of AAD were examined in terms of eosinophil infiltration and goblet cell metaplasia in subepithelial mucosa, T-helper type 1 (Th1) to Th2 skewing of the immune response. Furthermore, to elucidate the interrelations, we generated 16S ribosomal DNA from fecal samples and further validated the variation of colony composition in each group. The excessive high-fiber supplement induced a promoting effect rather than a suppressive effect, including a rise in nasal rubbing and sneezing, an increase in eosinophil inflammation and goblet cell metaplasia in subepithelial mucosa, and promoted Th2 skewing of the immune response as well as the production of serum levels of ovalbumin-specific immunoglobulin E. Moreover, overconsumption of dietary fiber greatly altered the construction of bacterial flora in the intestinal tract, including an increased proportion of Firmicutes, Actinobacteria, and Proteobacteria, and a decreased proportion of Bacteroidetes. Our work indicated that, instead of a protecting impact, excessive fiber intake preformed a negative influence on the induction of AAD. Therefore, we suspected that an excessive supplement of dietary fiber might not be an advisable method for the prevention and treatment of AADs.

  5. Frondanol, a Nutraceutical Extract from Cucumaria frondosa, Attenuates Colonic Inflammation in a DSS-Induced Colitis Model in Mice

    Directory of Open Access Journals (Sweden)

    Sandeep B. Subramanya

    2018-04-01

    Full Text Available Frondanol is a nutraceutical lipid extract of the intestine of the edible Atlantic sea cucumber, Cucumaria frondosa, with potent anti-inflammatory effects. In the current study, we investigated Frondanol as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J were given 3% dextran sodium sulfate (DSS in drinking water for 7 days to induce colitis. The colitis group received oral Frondanol (100 mg/kg body weight/per day by gavage and were compared with a control group and the DSS group. Disease activity index (DAI and colon histology were scored for macroscopic and microscopic changes. Colonic tissue length, myeloperoxidase (MPO concentration, neutrophil and macrophage marker mRNA, pro-inflammatory cytokine proteins, and their respective mRNAs were measured using ELISA and real-time RT-PCR. The tissue content of leukotriene B4 (LTB4 was also measured using ELISA. Frondanol significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue MPO concentrations, neutrophil and macrophage mRNA expression (F4/80 and MIP-2, and pro-inflammatory cytokine content (IL-1β, IL-6 and TNF-α both at the protein and mRNA level were significantly reduced by Frondanol. The increase in content of the pro-inflammatory mediator leukotriene B4 (LTB4 induced by DSS was also significantly inhibited by Frondanol. It was thus found that Frondanol supplementation attenuates colon inflammation through its potent anti-inflammatory activity.

  6. Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue.

    Directory of Open Access Journals (Sweden)

    Audrey M Neyrinck

    Full Text Available Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®, at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity.Mice were fed either a control diet (CT, a high fat (HF diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet associated with white pepper (0.01 % for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation.These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.

  7. Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue.

    Science.gov (United States)

    Neyrinck, Audrey M; Alligier, Maud; Memvanga, Patrick B; Névraumont, Elodie; Larondelle, Yvan; Préat, Véronique; Cani, Patrice D; Delzenne, Nathalie M

    2013-01-01

    Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity. Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation. These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition.

  8. Dietary intervention with green dwarf banana flour (Musa sp AAA) prevents intestinal inflammation in a trinitrobenzenesulfonic acid model of rat colitis.

    Science.gov (United States)

    Scarminio, Viviane; Fruet, Andrea C; Witaicenis, Aline; Rall, Vera L M; Di Stasi, Luiz C

    2012-03-01

    Dietary products are among the therapeutic approaches used to modify intestinal microflora and to promote protective effects during the intestinal inflammatory process. Because the banana plant is rich in resistant starch, which is used by colonic microbiota for the anaerobic production of the short-chain fatty acids that serve as a major fuel source for colonocytes: first, green dwarf banana flour produces protective effects on the intestinal inflammation acting as a prebiotic and, second, combination of this dietary supplementation with prednisolone presents synergistic effects. For this, we used the trinitrobenzenesulphonic acid (TNBS) model of rat colitis. Our results revealed that the protective effect produced by a combination of 10% green dwarf banana flour with prednisolone was more pronounced than those promoted by a single administration of prednisolone or a diet containing 10% or 20% banana flour. This beneficial effect was associated with an improvement in the colonic oxidative status because the banana flour diet prevented the glutathione depletion and inhibited myeloperoxidase activity and lipid peroxidation. In addition, the intestinal anti-inflammatory activity was associated with an inhibition of alkaline phosphatase activity, a reduction in macroscopic and microscopic scores, and an extension of the lesions. In conclusion, the dietary use of the green dwarf banana flour constitutes an important dietary supplement and complementary medicine product to prevention and treatment of human inflammatory bowel disease. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Olive oil bioactives protect pigs against experimentally-induced chronic inflammation independently of alterations in gut microbiota.

    Directory of Open Access Journals (Sweden)

    Martin Liehr

    Full Text Available Subclinical chronic inflammation (SCI is associated with impaired animal growth. Previous work has demonstrated that olive-derived plant bioactives exhibit anti-inflammatory properties that could possibly counteract the growth-depressing effects of SCI. To test this hypothesis and define the underlying mechanism, we conducted a 30-day study in which piglets fed an olive-oil bioactive extract (OBE and their control counterparts (C+ were injected repeatedly during the last 10 days of the study with increasing doses of Escherichia coli lipopolysaccharides (LPS to induce SCI. A third group of piglets remained untreated throughout the study and served as a negative control (C-. In C+ pigs, SCI increased the circulating concentration of interleukin 1 beta (p < 0.001 and decreased feed ingestion (p < 0.05 and weight gain (p < 0.05. These responses were not observed in OBE animals. Although intestinal inflammation and colonic microbial ecology was not altered by treatments, OBE enhanced ileal mRNA abundance of tight and adherens junctional proteins (p < 0.05 and plasma recovery of mannitol (p < 0.05 compared with C+ and C-. In line with these findings, OBE improved transepithelial electrical resistance (p < 0.01 in TNF-α-challenged Caco-2/TC-7 cells, and repressed the production of inflammatory cytokines (p < 0.05 in LPS-stimulated macrophages. In summary, this work demonstrates that OBE attenuates the suppressing effect of SCI on animal growth through a mechanism that appears to involve improvements in intestinal integrity unrelated to alterations in gut microbial ecology and function.

  10. Airborne Particulate Matter Induces Nonallergic Eosinophilic Sinonasal Inflammation in Mice.

    Science.gov (United States)

    Ramanathan, Murugappan; London, Nyall R; Tharakan, Anuj; Surya, Nitya; Sussan, Thomas E; Rao, Xiaoquan; Lin, Sandra Y; Toskala, Elina; Rajagopalan, Sanjay; Biswal, Shyam

    2017-07-01

    Exposure to airborne particulate matter (PM) has been linked to aggravation of respiratory symptoms, increased risk of cardiovascular disease, and all-cause mortality. Although the health effects of PM on the lower pulmonary airway have been extensively studied, little is known regarding the impact of chronic PM exposure on the upper sinonasal airway. We sought to test the impact of chronic airborne PM exposure on the upper respiratory system in vivo. Mice were subjected, by inhalation, to concentrated fine (2.5 μm) PM 6 h/d, 5 d/wk, for 16 weeks. Mean airborne fine PM concentration was 60.92 μm/m 3 , a concentration of fine PM lower than that reported in some major global cities. Mice were then killed and analyzed for evidence of inflammation and barrier breakdown compared with control mice. Evidence of the destructive effects of chronic airborne PM on sinonasal health in vivo, including proinflammatory cytokine release, and macrophage and neutrophil inflammatory cell accumulation was observed. A significant increase in epithelial barrier dysfunction was observed, as assessed by serum albumin accumulation in nasal airway lavage fluid, as well as decreased expression of adhesion molecules, including claudin-1 and epithelial cadherin. A significant increase in eosinophilic inflammation, including increased IL-13, eotaxin-1, and eosinophil accumulation, was also observed. Collectively, although largely observational, these studies demonstrate the destructive effects of chronic airborne PM exposure on the sinonasal airway barrier disruption and nonallergic eosinophilic inflammation in mice.

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

    International Nuclear Information System (INIS)

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

    2017-01-01

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

  12. The effect of Saccharomyces boulardii on human colon cells and inflammation in rats with trinitrobenzene sulfonic acid-induced colitis.

    Science.gov (United States)

    Lee, Sang Kil; Kim, Youn Wha; Chi, Sung-Gil; Joo, Yeong-Shil; Kim, Hyo Jong

    2009-02-01

    Saccharomyces boulardii (S. boulardii) has beneficial effects in the treatment of intestinal inflammation; however, little is known about the mechanisms by which these effects occur. We investigated the effects of S. boulardii on the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and interleukin-8 (IL-8), using human HT-29 colonocytes and a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. The effect of S. boulardii on gene expression was assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Northern blot and Western blot assays. Pharmacological inhibitors for various signaling pathways were used to determine the signaling pathways implicated in the S. boulardii regulation of PPAR-gamma and IL-8. We found that S. boulardii up-regulated and down-regulated PPAR-gamma and IL-8 expression at the transcription level, both in vitro and in vivo (P Saccharomyces boulardii blocked tumor necrosis factor-alpha (TNF-alpha) regulation of PPAR-gamma and IL-8 through disruption of TNF-alpha-mediated nuclear factor kappa B (NF-kappaB) activation. Furthermore, S. boulardii suppressed colitis and expression of pro-inflammatory cytokine genes in vivo (P boulardii reduces colonic inflammation and regulates inflammatory gene expression.

  13. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes.

    NARCIS (Netherlands)

    Diepen, van Janna A.; Hooiveld, Guido; Stienstra, Rinke; Deen, Peter M.

    2017-01-01

    Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by

  14. Glufosinate aerogenic exposure induces glutamate and IL-1 receptor dependent lung inflammation.

    Science.gov (United States)

    Maillet, Isabelle; Perche, Olivier; Pâris, Arnaud; Richard, Olivier; Gombault, Aurélie; Herzine, Ameziane; Pichon, Jacques; Huaux, Francois; Mortaud, Stéphane; Ryffel, Bernhard; Quesniaux, Valérie F J; Montécot-Dubourg, Céline

    2016-11-01

    Glufosinate-ammonium (GLA), the active component of an herbicide, is known to cause neurotoxicity. GLA shares structural analogy with glutamate. It is a powerful inhibitor of glutamine synthetase (GS) and may bind to glutamate receptors. Since these potentials targets of GLA are present in lung and immune cells, we asked whether airway exposure to GLA may cause lung inflammation in mice. A single GLA exposure (1 mg/kg) induced seizures and inflammatory cell recruitment in the broncho-alveolar space, and increased myeloperoxidase (MPO), inducible NO synthase (iNOS), interstitial inflammation and disruption of alveolar septae within 6-24 h. Interleukin 1β (IL-1β) was increased and lung inflammation depended on IL-1 receptor 1 (IL-1R1). We demonstrate that glutamate receptor pathway is central, since the N-methyl-D-aspartate (NMDA) receptor inhibitor MK-801 prevented GLA-induced lung inflammation. Chronic exposure (0.2 mg/kg 3× per week for 4 weeks) caused moderate lung inflammation and enhanced airway hyperreactivity with significant increased airway resistance. In conclusion, GLA aerosol exposure causes glutamate signalling and IL-1R-dependent pulmonary inflammation with airway hyperreactivity in mice. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  15. Dunnione ameliorates cisplatin-induced small intestinal damage by modulating NAD{sup +} metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Pandit, Arpana; Kim, Hyung-Jin; Oh, Gi-Su; Shen, AiHua; Lee, Su-Bin; Khadka, Dipendra; Lee, SeungHoon [Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Shim, Hyeok; Yang, Sei-Hoon; Cho, Eun-Young [Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Kwon, Kang-Beom [Department of Oriental Medical Physiology, School of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Kwak, Tae Hwan [PAEAN Biotechnology, 160 Techno-2 Street, Yuseong-gu, Daejeon 305-500 (Korea, Republic of); Choe, Seong-Kyu; Park, Raekil [Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); So, Hong-Seob, E-mail: jeanso@wku.ac.kr [Center for Metabolic Function Regulation & Department of Microbiology, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of)

    2015-11-27

    Although cisplatin is a widely used anticancer drug for the treatment of a variety of tumors, its use is critically limited because of adverse effects such as ototoxicity, nephrotoxicity, neuropathy, and gastrointestinal damage. Cisplatin treatment increases oxidative stress biomarkers in the small intestine, which may induce apoptosis of epithelial cells and thereby elicit damage to the small intestine. Nicotinamide adenine dinucleotide (NAD{sup +}) is a cofactor for various enzymes associated with cellular homeostasis. In the present study, we demonstrated that the hyper-activation of poly(ADP-ribose) polymerase-1 (PARP-1) is closely associated with the depletion of NAD{sup +} in the small intestine after cisplatin treatment, which results in downregulation of sirtuin1 (SIRT1) activity. Furthermore, a decrease in SIRT1 activity was found to play an important role in cisplatin-mediated small intestinal damage through nuclear factor (NF)-κB p65 activation, facilitated by its acetylation increase. However, use of dunnione as a strong substrate for the NADH:quinone oxidoreductase 1 (NQO1) enzyme led to an increase in intracellular NAD{sup +} levels and prevented the cisplatin-induced small intestinal damage correlating with the modulation of PARP-1, SIRT1, and NF-κB. These results suggest that direct modulation of cellular NAD{sup +} levels by pharmacological NQO1 substrates could be a promising therapeutic approach for protecting against cisplatin-induced small intestinal damage. - Highlights: • NAD{sup +} acts as a cofactor for numerous enzymes including Sirtuins and PARP. • Up-regulation of SIRT1 could attenuate the cisplatin-induced intestinal damage. • Modulation of the cellular NAD{sup +} could be a promising therapeutic approach.

  16. Lactobacillus salivarius reverse diabetes-induced intestinal defense impairment in mice through non-defensin protein.

    Science.gov (United States)

    Chung, Pei-Hsuan; Wu, Ying-Ying; Chen, Pei-Hsuan; Fung, Chang-Phone; Hsu, Ching-Mei; Chen, Lee-Wei

    2016-09-01

    Altered intestinal microbiota and subsequent endotoxemia play pathogenic roles in diabetes. We aimed to study the mechanisms of intestinal defense impairment in type 1 diabetes and the effects of Lactobacillus salivarius as well as fructooligosaccharides (FOS) supplementation on diabetes-induced bacterial translocation. Alterations in the enteric microbiome, expression of mucosal antibacterial proteins and bacteria-killing activity of the intestinal mucosa in streptozotocin (STZ)-induced diabetic mice and Ins2(Akita) mice were investigated. The effects of dead L. salivarius (2×10(8)CFU/ml) and FOS (250 mg per day) supplementation for 1 week on endotoxin levels and Klebsiella pneumoniae translocation were also examined. Finally, germ-free mice were cohoused with wild-type or Ins2(Akita) mice for 2 weeks to examine the contribution of microbiota on the antibacterial protein expression. STZ-induced diabetic mice developed intestinal defense impairment as demonstrated by decreased mucosal bacteria-killing activity; reduction of non-defensin family proteins, such as Reg3β, Reg3γ, CRP-ductin and RELMβ, but not the defensin family proteins; and increased bacterial translocation. Intestinal bacteria overgrowth, enteric dysbiosis and increased intestinal bacterial translocation, particularly pathogenic K. pneumoniae in STZ-induced diabetic mice and Ins2(Akita) mice, were noted. Treating diabetic mice with dead L. salivarius or FOS reversed enteric dysbiosis, restored mucosal antibacterial protein and lessened endotoxin levels as well as K. pneumoniae translocation. Moreover, germ-free mice cohoused with wild-type mice demonstrated more intestinal Reg3β and RELMβ expression than those cohoused with Ins2(Akita) mice. These results indicate that hyperglycemia induces enteric dysbiosis, reduction of non-defensin proteins as well as bacteria-killing activity of the intestinal mucosa and intestinal defense impairment. Reversal of enteric dysbiosis with dead L. salivarius or

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

    Science.gov (United States)

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

    2016-01-01

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

  18. Spontaneous and x-irradiation induced carcinomas of small intestine in Wistar-Furth rats

    Energy Technology Data Exchange (ETDEWEB)

    Maeura, Y; Kosaki, G; Kitamura, H [Osaka Univ. (Japan). Faculty of Medicine; Nagatomo, T

    1980-04-01

    Spontaneous carcinoma of the small intestine in Wistar-Furth (WF) rats and carcinoma of the small intestine induced by local x-ray irradiation to the abdomen of WF rats without carcinoma were observed, and x-ray sensitivity of the small intestine mucosa was reported. Out of 19 rats with spontaneous carcinoma of the small intestine, 18 also had carcinoma of the colon, and 4 also had gastric cancer. They already had spontaneous carcinoma of the small intestine within 2 weeks after their birth, and the ratio of female and male was 13 : 6. Histological type of this carcinoma in all 19 rats was highly differentiated adenocarcinoma, and small intestine epithelium around carcinoma presented atypical epithelium. As to mice without carcinoma, x-ray, 1,000 R, 1,500 R, and 2,000 R, was irradiated to the abdomen of Sprague-Dawley (SD) and WF rats. In the irradiation with 1,000 R, carcinogenesis was not found in rats of both strains. In the irradiation with 1,500 R, carcinogenesis was hardly found, but in the irradiation with 2,000 R, carcinoma of small intestine occurred in 5 of 17 rats 15 weeks after the irradiation, 9 of 19 rats 25 weeks after the irradiation, and 9 of 14 rats 35 weeks after the irradiation. Histological type of carcinoma in irradiated rats was highly differentiated adenocarcinoma. The incidence of carcinoma in irradiated rats was higher in WF rats than SD rats through the course after the irradiation, which suggested that x-ray sensitivity of WF rats was higher than that of SD rats. Therefore, carcinoma of the small intestine in irradiated mice seemed to be induced by x-ray.

  19. PAI-1-dependent endothelial cell death determines severity of radiation-induced intestinal injury.

    Directory of Open Access Journals (Sweden)

    Rym Abderrahmani

    Full Text Available Normal tissue toxicity still remains a dose-limiting factor in clinical radiation therapy. Recently, plasminogen activator inhibitor type 1 (SERPINE1/PAI-1 was reported as an essential mediator of late radiation-induced intestinal injury. However, it is not clear whether PAI-1 plays a role in acute radiation-induced intestinal damage and we hypothesized that PAI-1 may play a role in the endothelium radiosensitivity. In vivo, in a model of radiation enteropathy in PAI-1 -/- mice, apoptosis of radiosensitive compartments, epithelial and microvascular endothelium was quantified. In vitro, the role of PAI-1 in the radiation-induced endothelial cells (ECs death was investigated. The level of apoptotic ECs is lower in PAI-1 -/- compared with Wt mice after irradiation. This is associated with a conserved microvascular density and consequently with a better mucosal integrity in PAI-1 -/- mice. In vitro, irradiation rapidly stimulates PAI-1 expression in ECs and radiation sensitivity is increased in ECs that stably overexpress PAI-1, whereas PAI-1 knockdown increases EC survival after irradiation. Moreover, ECs prepared from PAI-1 -/- mice are more resistant to radiation-induced cell death than Wt ECs and this is associated with activation of the Akt pathway. This study demonstrates that PAI-1 plays a key role in radiation-induced EC death in the intestine and suggests that this contributes strongly to the progression of radiation-induced intestinal injury.

  20. Association of enteric parasitic infections with intestinal inflammation and permeability in asymptomatic infants of São Tomé Island.

    Science.gov (United States)

    Garzón, Marisol; Pereira-da-Silva, Luis; Seixas, Jorge; Papoila, Ana Luísa; Alves, Marta; Ferreira, Filipa; Reis, Ana

    2017-05-01

    The cumulative effect of repeated asymptomatic enteric infections on intestinal barrier is not fully understood in infants. We aimed to evaluate the association between previous enteric parasitic infections and intestinal inflammation and permeability at 24-months of age, in asymptomatic infants of São Tomé Island. A subset of infants from a birth cohort, with intestinal parasite evaluations in at least four points of assessment, was eligible. Intestinal inflammatory response and permeability were assessed using fecal S100A12 and alpha-1-antitrypsin (A1AT), respectively. The cutoff parasitic infections explained variability of fecal biomarkers, after adjusting for potential confounders. Eighty infants were included. Giardia duodenalis and soil-transmitted helminths (STH) were the most frequent parasites. The median (interquartile range) levels were 2.87 μg/g (2.41-3.92) for S100A12 and 165.1 μg/g (66.0-275.6) for A1AT. Weak evidence of association was found between S100A12 levels and G. duodenalis (p = 0.080) and STH infections (p = 0.089), and between A1AT levels and parasitic infection of any etiology (p = 0.089), at 24-months of age. Significant associations between A1AT levels and wasting (p = 0.006) and stunting (p = 0.044) were found. Previous parasitic infections were not associated with fecal biomarkers at 24 months of age. To summarize, previous asymptomatic parasitic infections showed no association with intestinal barrier dysfunction. Notwithstanding, a tendency toward increased levels of the inflammatory biomarker was observed for current G. duodenalis and STH infections, and increased levels of the permeability biomarker were significantly associated with stunting and wasting.

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

    Directory of Open Access Journals (Sweden)

    Caiqi Zhao

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

  2. Allergic Conjunctivitis-induced Retinal Inflammation Promotes Myopia Progression

    Directory of Open Access Journals (Sweden)

    Chang-Ching Wei

    2018-02-01

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

  3. Long chain poly-unsaturated fatty acids attenuate the IL-1?-induced pro-inflammatory response in human fetal intestinal epithelial cells

    OpenAIRE

    Wijendran, Vasuki; Brenna, JT; Wang, Dong Hao; Zhu, Weishu; Meng, Di; Ganguli, Kriston; Kothapalli, Kumar SD; Requena, Pilar; Innis, Sheila; Walker, WA

    2015-01-01

    Background Evidence suggests that excessive inflammation of the immature intestine may predispose premature infants to necrotizing enterocolitis (NEC). We investigated the anti-inflammatory effects of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (ARA) in human fetal and adult intestinal epithelial cells (IEC) in primary culture. Methods Human fetal IEC in culture were derived from a healthy fetal small intestine (H4) or resected small intestine of a neonate wit...

  4. A mixture of Lactobacillus species isolated from traditional fermented foods promote recovery from antibiotic-induced intestinal disruption in mice.

    Science.gov (United States)

    Shi, Y; Zhao, X; Zhao, J; Zhang, H; Zhai, Q; Narbad, A; Chen, W

    2018-03-01

    This study evaluated the antibiotic-induced changes in microbial ecology, intestinal dysbiosis and low-grade inflammation; and the combined effect of four different Lactobacillus species on recovery of microbiota composition and improvement of gut barrier function in mice. Administration of the antibiotic ampicillin for 2 weeks decreased microbial community diversity, induced caecum tumefaction and increased gut permeability in mice. Application of a probiotic cocktail of four Lactobacillus species (JUP-Y4) modulated the microbiota community structure and promoted the abundance of potentially beneficial bacteria such as Akkermansia. Ampicillin administration led to a decline in Bacteroidetes from 46·6 ± 3·91% to 0·264 ± 0·0362%; the addition of JUP-Y4 restored this to 41·4 ± 2·87%. This probiotic supplementation was more effective than natural restoration, where the levels of Bacteroidetes were only restored to 29·3 ± 2·07%. Interestingly, JUP-Y4 treatment was more effective in the restoration of microbiota in faecal samples than in caecal samples. JUP-Y4 also significantly reduced the levels of d-lactate and endotoxin (lipopolysaccharide, LPS) in the serum of mice, and increased the expression of tight-junction proteins while reducing the production of inflammatory cytokines (TNF-α, IL-6, MCP-1, IFN-γ and IL-1β) in the ileum and the colon of antibiotic-treated mice. JUP-Y4 not only promoted recovery from antibiotic-induced gut dysbiosis, but also enhanced the function of the gut barrier, reduced inflammation and lowered levels of circulating endotoxin in mice. Consumption of a mixture of Lactobacillus species may encourage faster recovery from antibiotic-induced gut dysbiosis and gut microbiota-related immune disturbance. © 2018 The Society for Applied Microbiology.

  5. Effects of experimentally induced intestinal obstruction on the electrolyte profile in dogs

    International Nuclear Information System (INIS)

    Dar, E.M.; Khan, M.A.; Mehmood, A.K.

    2004-01-01

    This study was conducted to quantitatively asses the changes in serum electrolyte profile after experimentally induced upper and lower intestinal obstruction in dogs. Ten dogs of either sex ranging in weight from 20-25 Kg were selected. After thorough physical examination, de-worming and vaccination they were randomly divided into 3 groups. Groups A and B comprised of four animals each while group C had two animals. After preparing the operation site, upper intestinal obstruction was induced in animals of group A and lower intestinal obstruction was induced in all animals of group B through mid line laparotomy under general anesthesia. Animals of group C were kept as control without induction of any obstruction. Proper post-operative care was given to the operated animals. Blood samples were collected from all animals at an interval of 24 hours and evaluated to observe changes in serum sodium, potassium and chloride levels. The results of this study showed marked decline in electrolyte levels in animals of both groups A and B, however this decline was more severe and rapid in group A than group B, while group c acted normally. It can be concluded that upper intestinal obstruction is more fatal in its consequences than lower intestinal obstruction, which is relatively less dangerous in producing its ill effects. (author)

  6. Effects of Berberine Against Radiation-Induced Intestinal Injury in Mice

    International Nuclear Information System (INIS)

    Li Guanghui; Zhang Yaping; Tang Jinliang; Chen Zhengtang; Hu Yide; Wei Hong; Li Dezhi; Hao Ping; Wang Donglin

    2010-01-01

    Purpose: Radiation-induced intestinal injury is a significant clinical problem in patients undergoing abdominal radiotherapy (RT). Berberine has been used as an antimicrobial, anti-inflammatory, and antimotility agent. The present study investigated the protective effect of berberine against radiation-induced intestinal injury. Methods and Materials: The mice were administrated berberine or distilled water. A total of 144 mice underwent 0, 3, 6, 12, or 16 Gy single session whole-abdominal RT and 16 mice underwent 3 Gy/fraction/d for four fractions of fractionated abdominal RT. Tumor necrosis factor-α, interleukin-10, diamine oxidase, intestinal fatty acid-binding protein, malonaldehyde, and apoptosis were assayed in the mice after RT. The body weight and food intake of the mice receiving fractionated RT were recorded. Another 72 mice who had undergone 12, 16, or 20 Gy abdominal RT were monitored for mortality every 12 h. Results: The body weight and food intake of the mice administered with distilled water decreased significantly compared with before RT. After the same dose of abdominal RT, tumor necrosis factor-α, diamine oxidase, intestinal fatty acid-binding protein in plasma and malonalhehyde and apoptosis of the intestine were significantly greater in the control group than in the mice administered berberine (p < .05-.01). In contrast, interleukin-10 in the mice with berberine treatment was significantly greater than in the control group (p < .01). A similar result was found in the fractionated RT experiment and at different points after 16 Gy abdominal RT (p < .05-.01). Berberine treatment significantly delayed the point of death after 20 Gy, but not 16 Gy, abdominal RT (p < .01). Conclusion: Treatment with berberine can delay mortality and attenuated intestinal injury in mice undergoing whole abdominal RT. These findings could provide a useful therapeutic strategy for radiation-induced intestinal injury.

  7. Low grade inflammation inhibits VEGF induced HUVECs migration in p53 dependent manner

    International Nuclear Information System (INIS)

    Panta, Sushil; Yamakuchi, Munekazu; Shimizu, Toshiaki; Takenouchi, Kazunori; Oyama, Yoko; Koriyama, Toyoyasu; Kojo, Tsuyoshi; Hashiguchi, Teruto

    2017-01-01

    In the course of studying crosstalk between inflammation and angiogenesis, high doses of pro-inflammatory factors have been reported to induce apoptosis in cells. Under normal circumstances also the pro-inflammatory cytokines are being released in low doses and are actively involved in cell signaling pathways. We studied the effects of low grade inflammation in growth factor induced angiogenesis using tumor necrosis factor alfa (TNFα) and vascular endothelial growth factor A (VEGF) respectively. We found that low dose of TNFα can inhibit VEGF induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Low dose of TNFα induces mild upregulation and moreover nuclear localization of tumor suppressor protein 53 (P53) which causes decrease in inhibitor of DNA binding-1 (Id1) expression and shuttling to the cytoplasm. In absence of Id1, HUVECs fail to upregulate β 3 -integrin and cell migration is decreased. Connecting low dose of TNFα induced p53 to β 3 -integrin through Id1, we present additional link in cross talk between inflammation and angiogenesis. - Highlights: • Low grade inflammation (low dose of TNF alfa) inhibits VEGF induced endothelial cells migration. • The low grade inflammation with VEGF treatment upregulates P53 to a nonlethal level. • P53 activation inhibits Id1 shuttling to the cytoplasm in endothelial cells. • Inhibition of Id1 resulted in downregulation of β 3 -integrin which cause decrease in cell migration. • Inflammation and angiogenesis might cross-talk by P53 – Id1 – β 3 -integrin pathway in endothelial cells.

  8. Shikonin ameliorates isoproterenol (ISO)-induced myocardial damage through suppressing fibrosis, inflammation, apoptosis and ER stress.

    Science.gov (United States)

    Yang, Jun; Wang, Zhao; Chen, Dong-Lin

    2017-09-01

    Shikonin, isolated from the roots of herbal plant Lithospermum erythrorhizon, is a naphthoquinone. It has been reported to exert beneficial anti-inflammatory effects and anti-oxidant properties in various diseases. Isoproterenol (ISO) has been widely used to establish cardiac injury in vivo and in vitro. However, shikonin function in ISO-induced cardiac injury remains uncertain. In our study, we attempted to investigate the efficiency and possible molecular mechanism of shikonin in cardiac injury treatment induced by ISO. In vivo, C57BL6 mice were subcutaneously injected with 5mg/kg ISO to induce heart failure. And mice were given a gavage of shikonin (2 or 4mg/kg/d, for four weeks). Cardiac function, fibrosis indices, inflammation response, apoptosis and endoplasmic reticulum (ER) stress were calculated. Pathological alterations, fibrosis-, inflammation-, apoptosis- and ER stress-related molecules were examined. In ISO-induced cardiac injury, shikonin significantly ameliorated heart function, decreased myocardial fibrosis, suppressed inflammation, attenuated apoptosis and ER stress through impeding collagen accumulation, Toll like receptor 4/nuclear transcription factor κB (TLR4/NF-κB), Caspase-3 and glucose-regulated protein 78 (GRP78) signaling pathways activity, relieving heart failure in vivo. Also, in vitro, shikonin attenuated ISO-induced cardiac muscle cells by reducing fibrosis, inflammation, apoptosis and ER stress. Our findings indicated that shikonin treatment attenuated ISO-induced heart injury, providing an effective therapeutic strategy for heart failure treatment for future. Copyright © 2017. Published by Elsevier Masson SAS.

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

    Science.gov (United States)

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

    2016-05-15

    The rapidly expanding manufacturing, production and use of nanomaterials have raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Currently, efforts are made to increase the knowledge on the characteristics of nanomaterials that can be used to categorise them into hazard groups according to these characteristics. Grouping helps to gather information on nanomaterials in an efficient way with the aim to aid risk assessment. Here, we discuss different ways of grouping nanomaterials for their risk assessment after inhalation. Since the relation between single intrinsic particle characteristics and the severity of pulmonary inflammation is unknown, grouping of nanomaterials by their intrinsic characteristics alone is not sufficient to predict their risk after inhalation. The biokinetics of nanomaterials should be taken into account as that affects the dose present at a target site over time. The parameters determining the kinetic behaviour are not the same as the hazard-determining parameters. Furthermore, characteristics of nanomaterials change in the life-cycle, resulting in human exposure to different forms and doses of these nanomaterials. As information on the biokinetics and in situ characteristics of nanomaterials is essential but often lacking, efforts should be made to include these in testing strategies. Grouping nanomaterials will probably be of the most value to risk assessors when information on intrinsic characteristics, life-cycle, biokinetics and effects are all combined. Copyright © 2015 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Connie Slocum

    2014-07-01

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

  11. The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Bromhaar Mechteld

    2008-05-01

    Full Text Available Abstract Background Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. The development of these metabolic disorders is frequently studied, but mainly in liver, skeletal muscle, and adipose tissue. To gain more insight in the role of the small intestine in development of obesity and insulin resistance, dietary fat-induced differential gene expression was determined along the longitudinal axis of small intestines of C57BL/6J mice. Methods Male C57BL/6J mice were fed a low-fat or a high-fat diet that mimicked the fatty acid composition of a Western-style human diet. After 2, 4 and 8 weeks of diet intervention small intestines were isolated and divided in three equal parts. Differential gene expression was determined in mucosal scrapings using Mouse genome 430 2.0 arrays. Results The high-fat diet significantly increased body weight and decreased oral glucose tolerance, indicating insulin resistance. Microarray analysis showed that dietary fat had the most pronounced effect on differential gene expression in the middle part of the small intestine. By overrepresentation analysis we found that the most modulated biological processes on a high-fat diet were related to lipid metabolism, cell cycle and inflammation. Our results further indicated that the nuclear receptors Ppars, Lxrs and Fxr play an important regulatory role in the response of the small intestine to the high-fat diet. Next to these more local dietary fat effects, a secretome analysis revealed differential gene expression of secreted proteins, such as Il18, Fgf15, Mif, Igfbp3 and Angptl4. Finally, we linked the fat-induced molecular changes in the small intestine to development of obesity and insulin resistance. Conclusion During dietary fat-induced development of obesity and insulin resistance, we found substantial changes in gene expression in the small intestine, indicating modulations of biological processes, especially related to lipid

  12. St. John's wort attenuates irinotecan-induced diarrhea via down-regulation of intestinal pro-inflammatory cytokines and inhibition of intestinal epithelial apoptosis

    International Nuclear Information System (INIS)

    Hu Zeping; Yang Xiaoxia; Chan Suiyung; Xu Anlong; Duan Wei; Zhu Yizhun; Sheu, F.-S.; Boelsterli, Urs Alex; Chan, Eli; Zhang Qiang; Wang, J.-C.; Ee, Pui Lai Rachel; Koh, H.L.; Huang Min; Zhou Shufeng

    2006-01-01

    Diarrhea is a common dose-limiting toxicity associated with cancer chemotherapy, in particular for drugs such as irinotecan (CPT-11), 5-fluouracil, oxaliplatin, capecitabine and raltitrexed. St. John's wort (Hypericum perforatum, SJW) has anti-inflammatory activity, and our preliminary study in the rat and a pilot study in cancer patients found that treatment of SJW alleviated irinotecan-induced diarrhea. In the present study, we investigated whether SJW modulated various pro-inflammatory cytokines including interleukins (IL-1β, IL-2, IL-6), interferon (IFN-γ) and tumor necrosis factor-α (TNF-α) and intestinal epithelium apoptosis in rats. The rats were treated with irinotecan at 60 mg/kg for 4 days in combination with oral SJW or SJW-free control vehicle at 400 mg/kg for 8 days. Diarrhea, tissue damage, body weight loss, various cytokines including IL-1β, IL-2, IL-6, IFN-γ and TNF-α and intestinal epithelial apoptosis were monitored over 11 days. Our studies demonstrated that combined SJW markedly reduced CPT-11-induced diarrhea and intestinal lesions. The production of pro-inflammatory cytokines such as IL-1β, IFN-γ and TNF-α was significantly up-regulated in intestine. In the mean time, combined SJW significantly suppressed the intestinal epithelial apoptosis induced by CPT-11 over days 5-11. In particular, combination of SJW significantly inhibited the expression of TNF-α mRNA in the intestine over days 5-11. In conclusion, inhibition of pro-inflammatory cytokines and intestinal epithelium apoptosis partly explained the protective effect of SJW against the intestinal toxicities induced by irinotecan. Further studies are warranted to explore the potential for STW as an agent in combination with chemotherapeutic drugs to lower their dose-limiting toxicities

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

    Directory of Open Access Journals (Sweden)

    Wei-Chi Chou

    2015-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-03-01

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

  15. A Refined Culture System for Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids

    Directory of Open Access Journals (Sweden)

    Yu Takahashi

    2018-01-01

    Full Text Available Gut epithelial organoids are routinely used to investigate intestinal biology; however, current culture methods are not amenable to genetic manipulation, and it is difficult to generate sufficient numbers for high-throughput studies. Here, we present an improved culture system of human induced pluripotent stem cell (iPSC-derived intestinal organoids involving four methodological advances. (1 We adopted a lentiviral vector to readily establish and optimize conditioned medium for human intestinal organoid culture. (2 We obtained intestinal organoids from human iPSCs more efficiently by supplementing WNT3A and fibroblast growth factor 2 to induce differentiation into definitive endoderm. (3 Using 2D culture, followed by re-establishment of organoids, we achieved an efficient transduction of exogenous genes in organoids. (4 We investigated suspension organoid culture without scaffolds for easier harvesting and assays. These techniques enable us to develop, maintain, and expand intestinal organoids readily and quickly at low cost, facilitating high-throughput screening of pathogenic factors and candidate treatments for gastrointestinal diseases.

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

    Energy Technology Data Exchange (ETDEWEB)

    Braakhuis, Hedwig M., E-mail: hedwig.braakhuis@rivm.nl [National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); Department of Toxicogenomics, Maastricht University, PO Box 616, 6200 MD Maastricht (Netherlands); Oomen, Agnes G. [National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); Cassee, Flemming R. [National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven (Netherlands); Institute of Risk Assessment Sciences, Utrecht University, PO Box 80.163, 3508 TD Utrecht (Netherlands)

    2016-05-15

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

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

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  18. Probiotic supplementation affects markers of intestinal barrier, oxidation, and inflammation in trained men; a randomized, double-blinded, placebo-controlled trial

    Directory of Open Access Journals (Sweden)

    Lamprecht Manfred

    2012-09-01

    Full Text Available Abstract Background Probiotics are an upcoming group of nutraceuticals claiming positive effects on athlete’s gut health, redox biology and immunity but there is lack of evidence to support these statements. Methods We conducted a randomized, double-blinded, placebo controlled trial to observe effects of probiotic supplementation on markers of intestinal barrier, oxidation and inflammation, at rest and after intense exercise. 23 trained men received multi-species probiotics (1010 CFU/day, Ecologic®Performance or OMNi-BiOTiC®POWER, n = 11 or placebo (n = 12 for 14 weeks and performed an intense cycle ergometry over 90 minutes at baseline and after 14 weeks. Zonulin and α1-antitrypsin were measured from feces to estimate gut leakage at baseline and at the end of treatment. Venous blood was collected at baseline and after 14 weeks, before and immediately post exercise, to determine carbonyl proteins (CP, malondialdehyde (MDA, total oxidation status of lipids (TOS, tumor necrosis factor-alpha (TNF-α, and interleukin-6 (IL-6. Statistical analysis used multifactorial analysis of variance (ANOVA. Level of significance was set at p  Results Zonulin decreased with supplementation from values slightly above normal into normal ranges ( 0.1. CP increased significantly from pre to post exercise in both groups at baseline and in the placebo group after 14 weeks of treatment (p = 0.006. After 14 weeks, CP concentrations were tendentially lower with probiotics (p = 0.061. TOS was slightly increased above normal in both groups, at baseline and after 14 weeks of treatment. There was no effect of supplementation or exercise on TOS. At baseline, both groups showed considerably higher TNF-α concentrations than normal. After 14 weeks TNF-α was tendentially lower in the supplemented group (p = 0.054. IL-6 increased significantly from pre to post exercise in both groups (p = 0.001, but supplementation had no effect. MDA

  19. Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.

    Directory of Open Access Journals (Sweden)

    Elias Gounaris

    Full Text Available Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO, the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice.In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation.Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4, product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice.This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.

  20. The effect of bovine colostrum products on intestinal dysfunction and inflammation in a preterm pig model of necrotizing enterocolitis

    DEFF Research Database (Denmark)

    Støy, Ann Cathrine Findal

    Necrotizing enterocolitis (NEC), primarily seen in preterm infants, is associated with high morbidity and mortality. The pathogenesis is not fully understood but risk factors include prematurity, enteral feeding (especially with milk formula), and the intestinal microbiota. Mother’s milk, rich...... in bioactive factors, has a protective effect against NEC, but not all preterm infants are able to receive mother’s milk. The overall aim of this thesis was to investigate if bovine colostrum (BC), also rich in bioactive factors, could serve as an alternative to mother’s milk. A preterm pig model of NEC...... formula. All three BC products maintained trophic and anti-inflammatory effects on the immature pig intestine. A simple and standardized system was required to investigate the effects of milk formula versus BC on intestinal epithelial cells. In Study III, the IPEC-J2 cell line was evaluated as an in vitro...

  1. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    International Nuclear Information System (INIS)

    Lee, Ae Sin; Jung, Yu Jin; Kim, Dal; Nguyen-Thanh, Tung; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Kim, Won

    2014-01-01

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

  2. SIRT2 ameliorates lipopolysaccharide-induced inflammation in macrophages

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-08-08

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

  3. Oxysterol Sensing through the Receptor GPR183 Promotes the Lymphoid-Tissue-Inducing Function of Innate Lymphoid Cells and Colonic Inflammation.

    Science.gov (United States)

    Emgård, Johanna; Kammoun, Hana; García-Cassani, Bethania; Chesné, Julie; Parigi, Sara M; Jacob, Jean-Marie; Cheng, Hung-Wei; Evren, Elza; Das, Srustidhar; Czarnewski, Paulo; Sleiers, Natalie; Melo-Gonzalez, Felipe; Kvedaraite, Egle; Svensson, Mattias; Scandella, Elke; Hepworth, Matthew R; Huber, Samuel; Ludewig, Burkhard; Peduto, Lucie; Villablanca, Eduardo J; Veiga-Fernandes, Henrique; Pereira, João P; Flavell, Richard A; Willinger, Tim

    2018-01-16

    Group 3 innate lymphoid cells (ILC3s) sense environmental signals and are critical for tissue integrity in the intestine. Yet, which signals are sensed and what receptors control ILC3 function remain poorly understood. Here, we show that ILC3s with a lymphoid-tissue-inducer (LTi) phenotype expressed G-protein-coupled receptor 183 (GPR183) and migrated to its oxysterol ligand 7α,25-hydroxycholesterol (7α,25-OHC). In mice lacking Gpr183 or 7α,25-OHC, ILC3s failed to localize to cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Gpr183 deficiency in ILC3s caused a defect in CP and ILF formation in the colon, but not in the small intestine. Localized oxysterol production by fibroblastic stromal cells provided an essential signal for colonic lymphoid tissue development, and inflammation-induced increased oxysterol production caused colitis through GPR183-mediated cell recruitment. Our findings show that GPR183 promotes lymphoid organ development and indicate that oxysterol-GPR183-dependent positioning within tissues controls ILC3 activity and intestinal homeostasis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Treatment and prophylaxis with sucralfate ameliorates hypoxia/reoxygenation-induced intestinal injury in pup rats.

    Science.gov (United States)

    Sencan, Arzu Bostanci; Sencan, Aydin; Aktas, Safiye; Habif, Sara; Kabaroglu, Ceyda; Parildar, Zuhal; Karaca, Irfan

    2005-04-01

    Sucralfate is widely used as a cytoprotective agent in patients with peptic ulcer and other intestinal mucosal injury. The aim of this study is to investigate whether sucralfate has any effect on the prevention and treatment of hypoxia/reoxygenation-induced intestinal injury. Four groups of 10 1-day-old rat pups were studied. Hypoxia/reoxygenation (H/O)-induced intestinal injury was created. Group 1 was subjected to H/O just after birth and sacrificed at the end of the third day (Treatment Control). Group 2 was subjected to H/O just after birth and treated with sucralfate for 3 days. They were sacrificed at the end of the third day (Treatment). Group 3 was subjected to H/O on the third day after birth and then sacrificed (Prophylaxis Control). Group 4 was treated with sucralfate for the first 3 days, then H/O was created. Just after H/O, the pups were sacrificed (Prophylaxis). The intestinal tissues were harvested for histopathological investigation. Malondialdehyde (MDA) levels in the intestinal tissues were determined. The mucosal injury grades of the treatment and prophylaxis groups were significantly lower than those of control groups (p<0.05). The mean MDA level in the treatment and prophylaxis groups were 0.42+/-0.17 and 0.21+/-0.23 nmol/mg respectively. The MDA levels of both groups were significantly lower than in the control groups (p<0.05). The present study shows that sucralfate has beneficial effects in an experimental model of hypoxia/reoxygenation-induced intestinal injury.

  5. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Halliday, Gary M. [Dermatology Research Laboratories, Division of Medicine, Melanoma and Skin Cancer Research Institute, Royal Prince Alfred Hospital at the University of Sydney, Sydney, NSW (Australia)]. E-mail: garyh@med.usyd.edu.au

    2005-04-01

    Ultraviolet (UV) radiation causes inflammation, gene mutation and immunosuppression in the skin. These biological changes are responsible for photocarcinogenesis. UV radiation in sunlight is divided into two wavebands, UVB and UVA, both of which contribute to these biological changes, and therefore probably to skin cancer in humans and animal models. Oxidative damage caused by UV contributes to inflammation, gene mutation and immunosuppression. This article reviews evidence for the hypothesis that UV oxidative damage to these processes contributes to photocarcinogenesis. UVA makes a larger impact on oxidative stress in the skin than UVB by inducing reactive oxygen and nitrogen species which damage DNA, protein and lipids and which also lead to NAD+ depletion, and therefore energy loss from the cell. Lipid peroxidation induces prostaglandin production that in association with UV-induced nitric oxide production causes inflammation. Inflammation drives benign human solar keratosis (SK) to undergo malignant conversion into squamous cell carcinoma (SCC) probably because the inflammatory cells produce reactive oxygen species, thus increasing oxidative damage to DNA and the immune system. Reactive oxygen or nitrogen appears to cause the increase in mutational burden as SK progress into SCC in humans. UVA is particularly important in causing immunosuppression in both humans and mice, and UV lipid peroxidation induced prostaglandin production and UV activation of nitric oxide synthase is important mediators of this event. Other immunosuppressive events are likely to be initiated by UV oxidative stress. Antioxidants have also been shown to reduce photocarcinogenesis. While most of this evidence comes from studies in mice, there is supporting evidence in humans that UV-induced oxidative damage contributes to inflammation, gene mutation and immunosuppression. Available evidence implicates oxidative damage as an important contributor to sunlight-induced carcinogenesis in humans.

  6. Inflammation, gene mutation and photoimmunosuppression in response to UVR-induced oxidative damage contributes to photocarcinogenesis

    International Nuclear Information System (INIS)

    Halliday, Gary M.

    2005-01-01

    Ultraviolet (UV) radiation causes inflammation, gene mutation and immunosuppression in the skin. These biological changes are responsible for photocarcinogenesis. UV radiation in sunlight is divided into two wavebands, UVB and UVA, both of which contribute to these biological changes, and therefore probably to skin cancer in humans and animal models. Oxidative damage caused by UV contributes to inflammation, gene mutation and immunosuppression. This article reviews evidence for the hypothesis that UV oxidative damage to these processes contributes to photocarcinogenesis. UVA makes a larger impact on oxidative stress in the skin than UVB by inducing reactive oxygen and nitrogen species which damage DNA, protein and lipids and which also lead to NAD+ depletion, and therefore energy loss from the cell. Lipid peroxidation induces prostaglandin production that in association with UV-induced nitric oxide production causes inflammation. Inflammation drives benign human solar keratosis (SK) to undergo malignant conversion into squamous cell carcinoma (SCC) probably because the inflammatory cells produce reactive oxygen species, thus increasing oxidative damage to DNA and the immune system. Reactive oxygen or nitrogen appears to cause the increase in mutational burden as SK progress into SCC in humans. UVA is particularly important in causing immunosuppression in both humans and mice, and UV lipid peroxidation induced prostaglandin production and UV activation of nitric oxide synthase is important mediators of this event. Other immunosuppressive events are likely to be initiated by UV oxidative stress. Antioxidants have also been shown to reduce photocarcinogenesis. While most of this evidence comes from studies in mice, there is supporting evidence in humans that UV-induced oxidative damage contributes to inflammation, gene mutation and immunosuppression. Available evidence implicates oxidative damage as an important contributor to sunlight-induced carcinogenesis in humans

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

    Science.gov (United States)

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

    2007-03-01

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

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

    Science.gov (United States)

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

  9. Gastrointestinal microbiota and local inflammation during oxazolone-induced dermatitis in BALB/cA Mice

    DEFF Research Database (Denmark)

    Lundberg, Randi; Knoth Clausen, Susanne; Pang, Wanyong

    2012-01-01

    -induced skin inflammation model of atopic dermatitis. BALB/cA mice were sensitized with oxazolone over a 28-d period and variation in gastrointestinal microbiota in fecal and cecal samples was assessed by PCR-denaturing gradient gel electrophoresis. Clinical parameters included transepidermal water loss, ear...

  10. Exercise protects against high-fat diet-induced hypothalamic inflammation

    NARCIS (Netherlands)

    Yi, Chun-Xia; Al-Massadi, Omar; Donelan, Elizabeth; Lehti, Maarit; Weber, Jon; Ress, Chandler; Trivedi, Chitrang; Müller, Timo D.; Woods, Stephen C.; Hofmann, Susanna M.

    2012-01-01

    Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing

  11. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes

    NARCIS (Netherlands)

    Diepen, van Janna A.; Robben, Joris H.; Hooiveld, Guido J.; Carmone, Claudia; Alsady, Mohammad; Boutens, Lily; Bekkenkamp-Grovenstein, Melissa; Hijmans, Anneke; Engelke, Udo F.H.; Wevers, Ron A.; Netea, Mihai G.; Tack, Cees J.; Stienstra, Rinke; Deen, Peter M.T.

    2017-01-01

    Aims/hypothesis: Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal

  12. Enhanced SCAP glycosylation by inflammation induces macrophage foam cell formation.

    Directory of Open Access Journals (Sweden)

    Chao Zhou

    Full Text Available Inflammatory stress promotes foam cell formation by disrupting LDL receptor feedback regulation in macrophages. Sterol Regulatory Element Binding Proteins (SREBPs Cleavage-Activating Protein (SCAP glycosylation plays crucial roles in regulating LDL receptor and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCoAR feedback regulation. The present study was to investigate if inflammatory stress disrupts LDL receptor and HMGCoAR feedback regulation by affecting SCAP glycosylation in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assay. The expression of molecules controlling cholesterol homeostasis was examined using real-time quantitative RT-PCR and Western blotting. The translocation of SCAP from the endoplasmic reticulum (ER to the Golgi was detected by confocal microscopy. We demonstrated that exposure to inflammatory cytokines increased lipid accumulation in THP-1 macrophages, accompanying with an increased SCAP expression even in the presence of a high concentration of LDL. These inflammatory cytokines also prolonged the half-life of SCAP by enhancing glycosylation of SCAP due to the elevated expression of the Golgi mannosidase II. This may enhance translocation and recycling of SCAP between the ER and the Golgi, escorting more SREBP2 from the ER to the Golgi for activation by proteolytic cleavages as evidenced by an increased N-terminal of SREBP2 (active form. As a consequence, the LDL receptor and HMGCoAR expression were up-regulated. Interestingly, these effects could be blocked by inhibitors of Golgi mannosidases. Our results indicated that inflammation increased native LDL uptake and endogenous cholesterol de novo synthesis, thereby causing foam cell formation via increasing transcription and protein glycosylation of SCAP in macrophages. These data imply that inhibitors of Golgi processing enzymes might have a potential vascular-protective role in prevention of atherosclerotic foam

  13. Flaxseed Oil Attenuates Intestinal Damage and Inflammation by Regulating Necroptosis and TLR4/NOD Signaling Pathways Following Lipopolysaccharide Challenge in a Piglet Model.

    Science.gov (United States)

    Zhu, Huiling; Wang, Haibo; Wang, Shuhui; Tu, Zhixiao; Zhang, Lin; Wang, Xiuying; Hou, Yongqing; Wang, Chunwei; Chen, Jie; Liu, Yulan

    2018-05-01

    Flaxseed oil is a rich source of α-linolenic acid (ALA), which is the precursor of the long-chain n-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This study investigates the protective effect of flaxseed oil against intestinal injury induced by lipopolysaccharide (LPS). Twenty-four weaned pigs were used in a 2 × 2 factorial experiment with dietary treatment (5% corn oil vs 5% flaxseed oil) and LPS challenge (saline vs LPS). On day 21 of the experiment, pigs were administrated with LPS or saline. At 2 h and 4 h post-administration, blood samples were collected. After the blood harvest at 4 h, all piglets were slaughtered and intestinal samples were collected. Flaxseed oil supplementation led to the enrichment of ALA, EPA, and total n-3 PUFAs in intestine. Flaxseed oil improved intestinal morphology, jejunal lactase activity, and claudin-1 protein expression. Flaxseed oil downregulated the mRNA expression of intestinal necroptotic signals. Flaxseed oil also downregulated the mRNA expression of intestinal toll-like receptors 4 (TLR4) and its downstream signals myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF-κB), and nucleotide-binding oligomerization domain proteins 1, 2 (NOD1, NOD2) and its adapter molecule, receptor-interacting protein kinase 2 (RIPK2). These results suggest that dietary addition of flaxseed oil enhances intestinal integrity and barrier function, which is involved in modulating necroptosis and TLR4/NOD signaling pathways. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    African Journals Online (AJOL)

    Results: Compared with control group, cell viability was notably elevated after treatment with 50-100. μM EE for 48 ... DOX induced higher rates of cell apoptosis in H9c2 cells (29.5 ± 3.56 %) ..... No conflict of interest associated with this work.

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

    Directory of Open Access Journals (Sweden)

    Eunsun Jung

    2013-12-01

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

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

    International Nuclear Information System (INIS)

    Takai, Atsushi; Marusawa, Hiroyuki; Chiba, Tsutomu

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Javier Freire

    2013-08-01

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

  18. Neurotensin Is a Lipid-Induced Gastrointestinal Peptide Associated with Visceral Adipose Tissue Inflammation in Obesity.

    Science.gov (United States)

    Barchetta, Ilaria; Cimini, Flavia Agata; Capoccia, Danila; Bertoccini, Laura; Ceccarelli, Valentina; Chiappetta, Caterina; Leonetti, Frida; Di Cristofano, Claudio; Silecchia, Gianfranco; Orho-Melander, Marju; Melander, Olle; Cavallo, Maria Gisella

    2018-04-23

    Neurotensin (NT) is a 13-amino acid peptide localized in the neuroendocrine cells of the small intestine, which promotes fat absorption and fatty acids translocation in response to lipid ingestion. NT-knock-out mice fed with a high-fat diet are protected from obesity, fatty liver, and the development of insulin-resistance. In humans, higher plasma levels of pro-NT, which is the stable circulating precursor of NT, predict obesity, type 2 diabetes (T2D), and cardiovascular disease. In obesity, the presence of visceral adipose tissue (VAT) inflammation leads to unfavorable metabolic outcomes and is associated with the development of T2D and non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between plasma pro-NT levels and the presence of VAT inflammation in biopsies from 40 morbidly obese subjects undergoing bariatric surgery. We demonstrated that higher proNT levels are significantly associated with greater macrophages infiltration, HIF-1α, WISP-1, and UNC5B expression in VAT (all p < 0.01) due to the diagnosis of T2D and NAFLD. The overall results show that, in obesity, pro-NT is a biomarker of VAT inflammation and insulin-resistance. Additionally, NT may be involved in the development of dysmetabolic conditions likely mediated by increased gut fat absorption and the presence of a proinflammatory milieu in the adipose tissue.

  19. Spred-2 deficiency exacerbates lipopolysaccharide-induced acute lung inflammation in mice.

    Directory of Open Access Journals (Sweden)

    Yang Xu

    Full Text Available BACKGROUND: Acute respiratory distress syndrome (ARDS is a severe and life-threatening acute lung injury (ALI that is caused by noxious stimuli and pathogens. ALI is characterized by marked acute inflammation with elevated alveolar cytokine levels. Mitogen-activated protein kinase (MAPK pathways are involved in cytokine production, but the mechanisms that regulate these pathways remain poorly characterized. Here, we focused on the role of Sprouty-related EVH1-domain-containing protein (Spred-2, a negative regulator of the Ras-Raf-extracellular signal-regulated kinase (ERK-MAPK pathway, in lipopolysaccharide (LPS-induced acute lung inflammation. METHODS: Wild-type (WT mice and Spred-2(-/- mice were exposed to intratracheal LPS (50 µg in 50 µL PBS to induce pulmonary inflammation. After LPS-injection, the lungs were harvested to assess leukocyte infiltration, cytokine and chemokine production, ERK-MAPK activation and immunopathology. For ex vivo experiments, alveolar macrophages were harvested from untreated WT and Spred-2(-/- mice and stimulated with LPS. In in vitro experiments, specific knock down of Spred-2 by siRNA or overexpression of Spred-2 by transfection with a plasmid encoding the Spred-2 sense sequence was introduced into murine RAW264.7 macrophage cells or MLE-12 lung epithelial cells. RESULTS: LPS-induced acute lung inflammation was significantly exacerbated in Spred-2(-/- mice compared with WT mice, as indicated by the numbers of infiltrating leukocytes, levels of alveolar TNF-α, CXCL2 and CCL2 in a later phase, and lung pathology. U0126, a selective MEK/ERK inhibitor, reduced the augmented LPS-induced inflammation in Spred-2(-/- mice. Specific knock down of Spred-2 augmented LPS-induced cytokine and chemokine responses in RAW264.7 cells and MLE-12 cells, whereas Spred-2 overexpression decreased this response in RAW264.7 cells. CONCLUSIONS: The ERK-MAPK pathway is involved in LPS-induced acute lung inflammation. Spred-2 controls

  20. Alpha-Melanocyte Stimulating Hormone Protects against Cytokine-Induced Barrier Damage in Caco-2 Intestinal Epithelial Monolayers.

    Directory of Open Access Journals (Sweden)

    Judit Váradi

    Full Text Available Alpha-melanocyte-stimulating hormone (α-MSH is a potent anti-inflammatory peptide with cytoprotective effect in various tissues. The present investigation demonstrates the ability of α-MSH to interact with intestinal epithelial cell monolayers and mitigate inflammatory processes of the epithelial barrier. The protective effect of α-MSH was studied on Caco-2 human intestinal epithelial monolayers, which were disrupted by exposure to tumor necrosis factor-α and interleukin-1β. The barrier integrity was assessed by measuring transepithelial electric resistance (TEER and permeability for marker molecules. Caco-2 monolayers were evaluated by immunohistochemistry for expression of melanocortin-1 receptor and tight junction proteins ZO-1 and claudin-4. The activation of nuclear factor kappa beta (NF-κB was detected by fluorescence microscopy and inflammatory cytokine expression was assessed by flow cytometric bead array cytokine assay. Exposure of Caco-2 monolayers to proinflammatory cytokines lowered TEER and increased permeability for fluorescein and albumin, which was accompanied by changes in ZO-1 and claudin-4 immunostaining. α-MSH was able to prevent inflammation-associated decrease of TEER in a dose-dependent manner and reduce the increased permeability for paracellular marker fluorescein. Further immunohistochemistry analysis revealed proinflammatory cytokine induced translocation of the NF-κB p65 subunit into Caco-2 cell nuclei, which was inhibited by α-MSH. As a result the IL-6 and IL-8 production of Caco-2 monolayers were also decreased with different patterns by the addition of α-MSH to the culture medium. In conclusion, Caco-2 cells showed a positive immunostaining for melanocortin-1 receptor and α-MSH protected Caco-2 cells against inflammatory barrier dysfunction and inflammatory activation induced by tumor necrosis factor-α and interleukin-1β cytokines.

  1. Farnesoid X Receptor as a homeostat for hepatic nutrient metabolism, proliferation and intestinal inflammation : Novel insights into mechanisms of regulation

    NARCIS (Netherlands)

    Massafra, V

    2017-01-01

    Our body hosts several molecules that function as hormones to regulate metabolism in the liver. Bile acids (BAs) are molecules produced by the liver and stored in the gall bladder. After eating a meal, BAs are secreted in the intestine, where they help the digestion of fats and vitamins.

  2. Lactobacillus GG and tributyrin supplementation reduce antibiotic-induced intestinal injury.

    Science.gov (United States)

    Cresci, Gail; Nagy, Laura E; Ganapathy, Vadivel

    2013-11-01

    Antibiotic therapy negatively alters the gut microbiota. Lactobacillus GG (LGG) decreases antibiotic-associated diarrhea (AAD) symptoms, but the mechanisms are unknown. Butyrate has beneficial effects on gut health. Altered intestinal gene expression occurs in the absence of gut microbiota. We hypothesized that antibiotic-induced changes in gut microbiota reduce butyrate production, varying genes involved with gut barrier integrity and water and electrolyte absorption, lending to AAD, and that simultaneous supplementation with LGG and/or tributyrin would prevent these changes. C57BL/6 mice aged 6-8 weeks received a chow diet while divided into 8 treatment groups (± saline, ± LGG, ± tributyrin, or both). Mice received treatments orally for 7 days with ± broad-spectrum antibiotics. Water intake was recorded daily and body weight was measured. Intestine tissue samples were obtained and analyzed for expression of genes and proteins involved with water and electrolyte absorption, butyrate transport, and gut integrity via polymerase chain reaction and immunohistochemistry. Antibiotics decreased messenger RNA (mRNA) expression (butyrate transporter and receptor, Na(+)/H(+) exchanger, Cl(-)/HCO3 (-), and a water channel) and protein expression (butyrate transporter, Na(+)/H(+) exchanger, and tight junction proteins) in the intestinal tract. LGG and/or tributyrin supplementation maintained intestinal mRNA expression to that of the control animals, and tributyrin maintained intestinal protein intensity expression to that of control animals. Broad-spectrum antibiotics decrease expression of anion exchangers, butyrate transporter and receptor, and tight junction proteins in mouse intestine. Simultaneous oral supplementation with LGG and/or tributyrin minimizes these losses. Optimizing intestinal health with LGG and/or tributyrin may offer a preventative therapy for AAD.

  3. Changes in the composition of intestinal fungi and their role in mice with dextran sulfate sodium-induced colitis.

    Science.gov (United States)

    Qiu, Xinyun; Zhang, Feng; Yang, Xi; Wu, Na; Jiang, Weiwei; Li, Xia; Li, Xiaoxue; Liu, Yulan

    2015-05-27

    Intestinal fungi are increasingly believed to greatly influence gut health. However, the effects of fungi on intestinal inflammation and on gut bacterial constitution are not clear. Here, based on pyrosequencing method, we reveal that fungal compositions vary in different intestinal segments (ileum, cecum, and colon), prefer different colonization locations (mucosa and feces), and are remarkably changed during intestinal inflammation in dextran sulfate sodium (DSS)-colitis mouse models compare to normal controls: Penicillium, Wickerhamomyces, Alternaria, and Candida are increased while Cryptococcus, Phialemonium, Wallemia and an unidentified Saccharomycetales genus are decreased in the guts of DSS-colitis mice. Fungi-depleted mice exhibited aggravated acute DSS-colitis associated with gain of Hallella, Barnesiella, Bacteroides, Alistipes, and Lactobacillus and loss of butyrate-producing Clostridium XIVa, and Anaerostipes compare with normal control. In contrast, bacteria-depleted mice show attenuated acute DSS-colitis. Mice with severely chronic recurrent DSS-colitis show increased plasma (1,3)-β-D-glucan level and fungal translocation into the colonic mucosa, mesenteric lymph nodes and spleen. This work demonstrate the different roles of fungi in acute and chronic recurrent colitis: They are important counterbalance to bacteria in maintaining intestinal micro-ecological homeostasis and health in acutely inflamed intestines, but can harmfully translocate into abnormal sites and could aggravate disease severity in chronic recurrent colitis.

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

    Directory of Open Access Journals (Sweden)

    Cristiane Miranda da Silva

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

  5. Beneficial effect of an omega-6 PUFA-rich diet in non-steroidal anti-inflammatory drug-induced mucosal damage in the murine small intestine.

    Science.gov (United States)

    Ueda, Toshihide; Hokari, Ryota; Higashiyama, Masaaki; Yasutake, Yuichi; Maruta, Koji; Kurihara, Chie; Tomita, Kengo; Komoto, Shunsuke; Okada, Yoshikiyo; Watanabe, Chikako; Usui, Shingo; Nagao, Shigeaki; Miura, Soichiro

    2015-01-07

    To investigate the effect of a fat rich diet on non-steroidal anti-inflammatory drug (NSAID)-induced mucosal damage in the murine small intestine. C57BL6 mice were fed 4 types of diets with or without indomethacin. One group was fed standard laboratory chow. The other groups were fed a fat diet consisting of 8% w/w fat, beef tallow (rich in SFA), fish oil, (rich in omega-3 PUFA), or safflower oil (rich in omega-6 PUFA). Indomethacin (3 mg/kg) was injected intraperitoneally from day 8 to day 10. On day 11, intestines and adhesions to submucosal microvessels were examined. In the indomethacin-treated groups, mucosal damage was exacerbated by diets containing beef tallow and fish oil, and was accompanied by leukocyte infiltration (P safflower oil diet than in mice fed the beef tallow or fish oil diet (P safflower oil significantly decreased monocyte and platelet recruitment (P < 0.05). A diet rich in SFA and omega-3 PUFA exacerbated NSAID-induced small intestinal damage via increased leukocyte infiltration. Importantly, a diet rich in omega-6-PUFA did not aggravate inflammation as monocyte migration was blocked.

  6. Intestinal helminths induce haematological changes in dogs from Jabalpur, India.

    Science.gov (United States)

    Qadir, S; Dixit, A K; Dixit, P; Sharma, R L

    2011-12-01

    The effect of canine intestinal helminths on the haematological profile of 200 dogs, of both sexes and variable age, visiting university veterinary clinics for routine examination was investigated. The dogs were assigned to parasitized (n = 39) and non-parasitized (n = 161) groups of animals. Coprological examination revealed a 19.5% prevalence of different species of the helminths. Of these animals, 10.25% had mixed infections with Ancylostoma caninum, Toxascaris spp. and Dipylidium caninum. The intensity of A. caninum infection was the highest, with mean egg counts of 951.43 (standard error 88.66), followed by Toxascaris 283.33 (standard error 116.81) and D. caninum. The parasitized animals had significantly lower levels of haemoglobin, packed cell volume and total erythrocyte counts than non-parasitized animals (P < 0.01). Values of other parameters, except for lymphocytes and eosinophils, were not different between the two groups. Analyses of the haematological profile revealed normocytic hypochromic anaemia in the parasitized group of animals.

  7. Attenuative effects of G-CSF in radiation induced intestinal injury

    International Nuclear Information System (INIS)

    Kim, Joong Sun; Gong, Eun Ji; Kim, Sung Dae; Heo, Kyu; Ryoo, Seung Bum; Yang, Kwang Mo

    2011-01-01

    Granulocyte colony stimulating factor (G-CSF) has been reported to protect from radiationinduced myelosuppression. Growing evidence suggests that G-CSF also has many important non-hematopoietic functions in other tissues, including the intestine (Kim et al., 2010; Kim et al., 2011). However, little is known about the influence of G-CSF on intestinal injury. Examination 12 hours after radiation (5 Gy) revealed that the G-CSF treated mice were significantly protected from apoptosis of jejunal crypt, compared with radiation controls. G-CSF treatment attenuated intestinal morphological changes such as decreased survival crypt, the number of villi, villous shortening, crypt depth and length of basal lamina of 10 enterocytes compared with the radiation control 3.5 days after radiation (10 Gy). G-CSF attenuated the change of peripheral blood from radiation-induced myelosuppression and displayed attenuation of mortality in lethally-irradiated (10 Gy) mice. The present results support the suggestion that G-CSF administrated prior to radiation plays an important role in the survival of irradiated mice, possibly due to the protection of hematopoietic cells and intestinal stem cells against radiation. The results indicate that G-CSF protects from radiation-mediated intestinal damage and from hematopoietic injury. G-CSF treatment may be useful clinically in the prevention of injury following radiation.

  8. Inducing effect of clofibric acid on stearoyl-CoA desaturase in intestinal mucosa of rats.

    Science.gov (United States)

    Yamazaki, Tohru; Kadokura, Makiko; Mutoh, Yuki; Sakamoto, Takeshi; Okazaki, Mari; Mitsumoto, Atsushi; Kawashima, Yoichi; Kudo, Naomi

    2014-12-01

    Fibrates have been reported to elevate the hepatic proportion of oleic acid (18:1n-9) through inducing stearoyl-CoA desaturase (SCD). Despite abundant studies on the regulation of SCD in the liver, little is known about this issue in the small intestine. The present study aimed to investigate the effect of clofibric acid on the fatty acid profile, particularly monounsaturated fatty acids (MUFA), and the SCD expression in intestinal mucosa. Treatment of rats with a diet containing 0.5% (w/w) clofibric acid for 7 days changed the MUFA profile of total lipids in intestinal mucosa; the proportion of 18:1n-9 was significantly increased, whereas those of palmitoleic (16:1n-7) and cis-vaccenic (18:1n-7) acids were not changed. Upon the treatment with clofibric acid, SCD was induced and the gene expression of SCD1, SCD2, and fatty acid elongase (Elovl) 6 was up-regulated, but that of Elovl5 was unaffected. Fat-free diet feeding for 28 days increased the proportions of 16:1n-7 and 18:1n-7, but did not effectively change that of 18:1n-9, in intestinal mucosa. Fat-free diet feeding up-regulated the gene expression of SCD1, but not that of SCD2, Elovl6, or Elovl5. These results indicate that intestinal mucosa significantly changes its MUFA profile in response to challenges by clofibric acid and a fat-free diet and suggest that up-regulation of the gene expression of SCD along with Elovl6 is indispensable to elevate the proportion of 18:1n-9 in intestinal mucosa.

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

    Science.gov (United States)

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

    2009-05-01

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

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

    Directory of Open Access Journals (Sweden)

    Taketomo Kido

    2014-01-01

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

  11. Differential effect of immune cells on non-pathogenic Gram-negative bacteria-induced nuclear factor-kappaB activation and pro-inflammatory gene expression in intestinal epithelial cells

    DEFF Research Database (Denmark)

    Haller, D.; Holt, L.; Parlesak, Alexandr

    2004-01-01

    stimulation, interleukin-8 (IL-8) mRNA accumulation is strongly induced in Escherichia coli- but not Bacteroides vulgatus-stimulated IEC cocultured with peripheral blood (PBMC) and lamina propria mononuclear cells (LPMC). The presence of PBMC triggered both E. coli- and B. vulgatus-induced mRNA expression...... in the presence of PBMC. Interestingly, B. vulgatus- and E. coli-derived lipopolysaccharide-induced similar IL-8 mRNA expression in epithelial cells after basolateral stimulation of HT-29/PBMC cocultures. Although luminal enteric bacteria have adjuvant and antigenic properties in chronic intestinal inflammation...

  12. Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids.

    Science.gov (United States)

    Choi, Sun Ju; Kim, Francis; Schwartz, Michael W; Wisse, Brent E

    2010-06-01

    Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1-7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFalpha, as judged by induction of IkappaBalpha (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IkappaBalpha protein, and TNFalpha pretreatment reduced insulin-mediated p-Akt activation by 30% (P fatty acid (100, 250, or 500 microM for neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.

  13. 18F-F.D.G. PET imaging of infection and inflammation: intestinal, prosthesis replacements, fibrosis, sarcoidosis, tuberculosis.

    International Nuclear Information System (INIS)

    Fernandez, A.; Cortes, M.; Caresia, A.P.; Juan, R. de; Vidaller, A.; Mana, J.; Martinez-Yelamos, S.; Gamez, C.

    2008-01-01

    Nuclear medicine plays an important role in the evaluation of infection and inflammation. A variety of diagnostic methods are available for imaging this inflammation and infection, most notably computed tomography, 68 Ga scintigraphy or radionuclide labeled leucocytes. Fluorine 18 fluorodeoxyglucose ( 18 F-F.D.G.) is a readily available radiotracer that offers rapid, exquisitely sensitive high-resolution images by positron emission tomography (PET). Inflammation can be acute or chronic, the former showing predominantly neutrophilic granulocyte infiltrates, whereas in the latter, macrophages predominate. F.D.G. uptake in infection is based on the fact that mononuclear cells and granulocytes use large quantities of glucose by way of the hexose monophosphate shunts. 18 F-F.D.G. PET accurately helps diagnose spinal osteomyelitis, diabetic foot and in inflammatory conditions such as sarcoidosis and tuberculosis.(it appears to be useful for defining the extent of disease and monitoring response to treatment). 18 F-F.D.G. PET can also help localize the source of fever of undetermined origin, thereby guiding additional testing. 18 F-F.D.G. PET may be of limited usefulness in postoperative patients and in patients with a failed joint prosthesis or bowel inflammatory disease. In this review, we will focus on the role of 18 F-F.D.G. PET in the management of patients with inflammation or suspected or confirmed infection

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

    Science.gov (United States)

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

    2016-01-01

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

  15. Docosahexaenoic acid inhibits monocrotaline-induced pulmonary hypertension via attenuating endoplasmic reticulum stress and inflammation.

    Science.gov (United States)

    Chen, Rui; Zhong, Wei; Shao, Chen; Liu, Peijing; Wang, Cuiping; Wang, Zhongqun; Jiang, Meiping; Lu, Yi; Yan, Jinchuan

    2018-02-01

    Endoplasmic reticulum (ER) stress and inflammation contribute to pulmonary hypertension (PH) pathogenesis. Previously, we confirmed that docosahexaenoic acid (DHA) could improve hypoxia-induced PH. However, little is known about the link between DHA and monocrotaline (MCT)-induced PH. Our aims were, therefore, to evaluate the effects and molecular mechanisms of DHA on MCT-induced PH in rats. Rat PH was induced by MCT. Rats were treated with DHA daily in the prevention group (following MCT injection) and the reversal group (after MCT injection for 2 wk) by gavage. After 4 wk, mean pulmonary arterial pressure (mPAP), right ventricular (RV) hypertrophy index, and morphological and immunohistochemical analyses were evaluated. Rat pulmonary artery smooth muscle cells (PASMCs) were used to investigate the effects of DHA on cell proliferation stimulated by platelet-derived growth factor (PDGF)-BB. DHA decreased mPAP and attenuated pulmonary vascular remodeling and RV hypertrophy, which were associated with suppressed ER stress. DHA blocked the mitogenic effect of PDGF-BB on PASMCs and arrested the cell cycle via inhibiting nuclear factor of activated T cells-1 (NFATc1) expression and activation and regulating cell cycle-related proteins. Moreover, DHA ameliorated inflammation in lung and suppressed macrophage and T lymphocyte accumulation in lung and adventitia of resistance pulmonary arteries. These findings suggest that DHA could protect against MCT-induced PH by reducing ER stress, suppressing cell proliferation and inflammation.

  16. Relation between radiation-induced tissue injury and its carcinogenesis of the rat small intestine

    Energy Technology Data Exchange (ETDEWEB)

    Tsubouchi, S [Aichi Cancer Center, Nagoya (Japan). Research Inst.; Matsuzawa, T

    1975-06-01

    This study was undertaken to make clear the relationships between radiation-induced tissue injury and its carcinogenesis in the rat small intestine. The abdomens of Wistar rats were irradiated locally with 1000 to 2000 rads. Approximately 2 months following irradiation, visible nodules were found in the intestines of the groups receiving irradiation. Nodule incidence was 80 to 100% in groups that received 1750 or 2000 rads, 50% in the 1500-rad groups, and 3% in the 1000-rad groups, respectively. The histology of the nodules within 70 days postirradiation, revealed adenomatous hyperplasia, including invasion of submucosa, muscle layers, and serosa of the small intestine accompanied by an area of fibrous tissue resulting from desmoplastic reaction by irradiation injury. The nodule within 140 to 300 days postirradiation induced advanced tissue injuried, that is, a polypoid lesion in histology and intestinal nodular adhesion in macroscopic anatomy. Running parallel with the advance of the above mentioned tissue injuries, the nodules in 3 out of 18 rat during 200 to 300 days postirradiation showed mucoid adenocarcinoma.

  17. Campylobacter jejuni induces transcytosis of commensal bacteria across the intestinal epithelium through M-like cells

    Science.gov (United States)

    2010-01-01

    Background Recent epidemiological analyses have implicated acute Campylobacter enteritis as a factor that may incite or exacerbate inflammatory bowel disease (IBD) in susceptible individuals. We have demonstrated previously that C. jejuni disrupts the intestinal barrier function by rapidly inducing epithelial translocation of non-invasive commensal bacteria via a transcellular lipid raft-mediated mechanism ('transcytosis'). To further characterize this mechanism, the aim of this current study was to elucidate whether C. jejuni utilizes M cells to facilitate transcytosis of commensal intestinal bacteria. Results C. jejuni induced translocation of non-invasive E. coli across confluent Caco-2 epithelial monolayers in the absence of disrupted transepithelial electrical resistance or increased permeability to a 3 kDa dextran probe. C. jejuni-infected monolayers displayed increased numbers of cells expressing the M cell-specific marker, galectin-9, reduced numbers of enterocytes that stained with the absorptive enterocyte marker, Ulex europaeus agglutinin-1, and reduced activities of enzymes typically associated with absorptive enterocytes (namely alkaline phosphatase, lactase, and sucrase). Furthermore, in Campylobacter-infected monolayers, E. coli were observed to be internalized specifically within epithelial cells displaying M-like cell characteristics. Conclusion These data indicate that C. jejuni may utilize M cells to promote transcytosis of non-invasive bacteria across the intact intestinal epithelial barrier. This mechanism may contribute to the inflammatory immune responses against commensal intestinal bacteria commonly observed in IBD patients. PMID:21040540

  18. Campylobacter jejuni induces transcytosis of commensal bacteria across the intestinal epithelium through M-like cells

    Directory of Open Access Journals (Sweden)

    Kalischuk Lisa D

    2010-11-01

    Full Text Available Abstract Background Recent epidemiological analyses have implicated acute Campylobacter enteritis as a factor that may incite or exacerbate inflammatory bowel disease (IBD in susceptible individuals. We have demonstrated previously that C. jejuni disrupts the intestinal barrier function by rapidly inducing epithelial translocation of non-invasive commensal bacteria via a transcellular lipid raft-mediated mechanism ('transcytosis'. To further characterize this mechanism, the aim of this current study was to elucidate whether C. jejuni utilizes M cells to facilitate transcytosis of commensal intestinal bacteria. Results C. jejuni induced translocation of non-invasive E. coli across confluent Caco-2 epithelial monolayers in the absence of disrupted transepithelial electrical resistance or increased permeability to a 3 kDa dextran probe. C. jejuni-infected monolayers displayed increased numbers of cells expressing the M cell-specific marker, galectin-9, reduced numbers of enterocytes that stained with the absorptive enterocyte marker, Ulex europaeus agglutinin-1, and reduced activities of enzymes typically associated with absorptive enterocytes (namely alkaline phosphatase, lactase, and sucrase. Furthermore, in Campylobacter-infected monolayers, E. coli were observed to be internalized specifically within epithelial cells displaying M-like cell characteristics. Conclusion These data indicate that C. jejuni may utilize M cells to promote transcytosis of non-invasive bacteria across the intact intestinal epithelial barrier. This mechanism may contribute to the inflammatory immune responses against commensal intestinal bacteria commonly observed in IBD patients.

  19. Relation between radiation-induced tissue injury and its carcinogenesis of the rat small intestine

    International Nuclear Information System (INIS)

    Tsubouchi, Susumu; Matsuzawa, Taiju.

    1975-01-01

    This study was undertaken to make clear the relationships between radiation-induced tissue injury and its carcinogenesis in the rat small intestine. The abdomens of Wistar rats were irradiated locally with 1000 to 2000 rads. Approximately 2 months following irradiation, visible nodules were found in the intestines of the groups receiving irradiation. Nodule incidence was 80 to 100% in groups that received 1750 or 2000 rads, 50% in the 1500-rad groups, and 3% in the 1000-rad groups, respectively. The histology of the nodules within 70 days postirradiation, revealed adenomatous hyperplasia, including invasion of submucosa, muscle layers, and serosa of the small intestine accompanied by an area of fibrous tissue resulting from desmoplastic reaction by irradiation injury. The nodule within 140-300 days postirradiation induced advanced tissue injuried, that is, a polypoid lesion in histology and intestinal nodular adhesion in macroscopic anatomy. Running parallel with the advance of the above mentioned tissue injuries, the nodules in 3 out of 18 rat during 200-300 days postirradiation showed mucoid adenocarcinoma. (author)

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

    Science.gov (United States)

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

    2010-12-01

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

  1. Splenectomy attenuates severe thermal trauma-induced intestinal barrier breakdown in rats.

    Science.gov (United States)

    Liu, Xiang-dong; Chen, Zhen-yong; Yang, Peng; Huang, Wen-guang; Jiang, Chun-fang

    2015-12-01

    The severe local thermal trauma activates a number of systemic inflammatory mediators, such as TNF-α, NF-κB, resulting in a disruption of gut barrier. The gastrointestinal tight junction (TJ) is highly regulated by membrane-associated proteins including zonula occludens protein-1 (ZO-1) and occludin, which can be modulated by inflammatory cytokines. As splenectomy has been shown to reduce secretion of cytokines, we hypothesized that (1) severe scald injury up-regulates TNF-α and NF-κB, meanwhile down-regulates expression of ZO-1 and occludin, leading to the increased intestinal permeability, and (2) splenectomy can prevent the burn-induced decrease in ZO-1 and occludin expression, resulting in improved intestinal barrier. Wistar rats undergoing a 30% total body surface area (TBSA) thermal trauma were randomized to receive an accessorial splenectomy meanwhile or not. Intestinal injury was assessed by histological morphological analysis, and serum endotoxin levels, TNF-α, NF-κB, ZO-1 and occludin levels were detected by Western blotting in the terminal ileum mucosal tissue. 30% TBSA burn caused a significant increase in serum endotoxin levels, but NF-κB, and TNF-α, and the average intestinal villus height and mucosal thickness were decreased significantly. Burn injury could also markedly decrease the levels of ZO-1 and occludin in terminal ileum mucosal tissue (all PSplenectomy at 7th day after burn significantly reversed the burn-induced breakdown of ZO-1 and occludin (all PSplenectomy may provide a therapeutic benefit in restoring burn-induced intestinal barrier by decreasing the release of inflammatory cytokines and recovering TJ proteins.

  2. Memory Deficits Induced by Inflammation Are Regulated by α5-Subunit-Containing GABAA Receptors

    Directory of Open Access Journals (Sweden)

    Dian-Shi Wang

    2012-09-01

    Full Text Available Systemic inflammation causes learning and memory deficits through mechanisms that remain poorly understood. Here, we studied the pathogenesis of memory loss associated with inflammation and found that we could reverse memory deficits by pharmacologically inhibiting α5-subunit-containing γ-aminobutyric acid type A (α5GABAA receptors and deleting the gene associated with the α5 subunit. Acute inflammation reduces long-term potentiation, a synaptic correlate of memory, in hippocampal slices from wild-type mice, and this reduction was reversed by inhibition of α5GABAA receptor function. A tonic inhibitory current generated by α5GABAA receptors in hippocampal neurons was increased by the key proinflammatory cytokine interleukin-1β through a p38 mitogen-activated protein kinase signaling pathway. Interleukin-1β also increased the surface expression of α5GABAA receptors in the hippocampus. Collectively, these results show that α5GABAA receptor activity increases during inflammation and that this increase is critical for inflammation-induced memory deficits.

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

    Directory of Open Access Journals (Sweden)

    Lieberman AR

    2006-01-01

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

  4. Chemotherapy induced intestinal mucositis; from bench to bed

    NARCIS (Netherlands)

    B.A.E. Koning, de (Barbara)

    2008-01-01

    textabstractPart 1 focuses primarily on the pathophysiology of mucositis, in order to gain more insight different experimental mouse models were used. Chapter 2 describes mucositis induced by high dose doxorubicin (DOX)- treatment. DOX is a frequently used cytostatic drug in childhood cancer,

  5. Exogenous HIV-1 Nef upsets the IFN-γ-induced impairment of human intestinal epithelial integrity.

    Directory of Open Access Journals (Sweden)

    Maria Giovanna Quaranta

    Full Text Available The mucosal tissues play a central role in the transmission of HIV-1 infection as well as in the pathogenesis of AIDS. Despite several clinical studies reported intestinal dysfunction during HIV infection, the mechanisms underlying HIV-induced impairments of mucosal epithelial barrier are still unclear. It has been postulated that HIV-1 alters enterocytic function and HIV-1 proteins have been detected in several cell types of the intestinal mucosa. In the present study, we analyzed the effect of the accessory HIV-1 Nef protein on human epithelial cell line.We used unstimulated or IFN-γ-stimulated Caco-2 cells, as a model for homeostatic and inflamed gastrointestinal tracts, respectively. We investigated the effect of exogenous recombinant Nef on monolayer integrity analyzing its uptake, transepithelial electrical resistance, permeability to FITC-dextran and the expression of tight junction proteins. Moreover, we measured the induction of proinflammatory mediators. Exogenous Nef was taken up by Caco-2 cells, increased intestinal epithelial permeability and upset the IFN-γ-induced reduction of transepithelial resistance, interfering with tight junction protein expression. Moreover, Nef inhibited IFN-γ-induced apoptosis and up-regulated TNF-α, IL-6 and MIP-3α production by Caco-2 cells while down-regulated IL-10 production. The simultaneous exposure of Caco-2 cells to Nef and IFN-γ did not affect cytokine secretion respect to untreated cells. Finally, we found that Nef counteracted the IFN-γ induced arachidonic acid cascade.Our findings suggest that exogenous Nef, perturbing the IFN-γ-induced impairment of intestinal epithelial cells, could prolong cell survival, thus allowing for accumulation of viral particles. Our results may improve the understanding of AIDS pathogenesis, supporting the discovery of new therapeutic interventions.

  6. Intermedin attenuates LPS-induced inflammation in the rat testis.

    Directory of Open Access Journals (Sweden)

    Lei Li

    Full Text Available First reported as a vasoactive peptide in the cardiovascular system, intermedin (IMD, also known as adrenomedullin 2 (ADM2, is a hormone with multiple potent roles, including its antioxidant action on the pulmonary, central nervous, cardiovascular and renal systems. Though IMD may play certain roles in trophoblast cell invasion, early embryonic development and cumulus cell-oocyte interaction, the role of IMD in the male reproductive system has yet to be investigated. This paper reports our findings on the gene expression of IMD, its receptor components and its protein localization in the testes. In a rat model, bacterial lippolysaccharide (LPS induced atypical orchitis, and LPS treatment upregulated the expression of IMD and one of its receptor component proteins, i.e. receptor activity modifying protein 2 (RAMP2. IMD decreased both plasma and testicular levels of reactive oxygen species (ROS production, attenuated the increase in the gene expression of the proinflammatory cytokines tumor necrosis factor alpha (TNFα, interleukin 6 (IL6 and interleukin 1 beta (IL1β, rescued spermatogenesis, and prevented the decrease in plasma testosterone levels caused by LPS. The restorative effect of IMD on steroidogenesis was also observed in hydrogen peroxide-treated rat primary Leydig cells culture. Our results indicate IMD plays an important protective role in spermatogenesis and steroidogenesis, suggesting therapeutic potential for IMD in pathological conditions such as orchitis.

  7. Pre-treatment with Bifidobacterium breve UCC2003 modulates Citrobacter rodentium-induced colonic inflammation and organ specificity.

    Science.gov (United States)

    Collins, James W; Akin, Ali R; Kosta, Artemis; Zhang, Ning; Tangney, Mark; Francis, Kevin P; Frankel, Gad

    2012-11-01

    Citrobacter rodentium, which colonizes the gut mucosa via formation of attaching and effacing (A/E) lesions, causes transmissible colonic hyperplasia. The aim of this study was to evaluate whether prophylactic treatment with Bifidobacterium breve UCC2003 can improve the outcome of C. rodentium infection. Six-week-old albino C57BL/6 mice were pre-treated for 3 days with B. breve, challenged with bioluminescent C. rodentium and administered B. breve or PBS-C for 8 days post-infection; control mice were either administered B. breve and mock-infected with PBS, or mock-treated with PBS-C and mock-infected with PBS. C. rodentium colonization was monitored by bacterial enumeration from faeces and by a combination of both 2D bioluminescence imaging (BLI) and composite 3D diffuse light imaging tomography with µCT imaging (DLIT-µCT). At day 8 post-infection, colons were removed and assessed for crypt hyperplasia, histology by light microscopy, bacterial colonization by immunofluorescence, and A/E lesion formation by electron microscopy. Prophylactic administration of B. breve did not prevent C. rodentium colonization or A/E lesion formation. However, this treatment did alter C. rodentium distribution within the large intestine and significantly reduced colonic crypt hyperplasia at the peak of bacterial infection. These results show that B. breve could not competitively exclude C. rodentium, but reduced pathogen-induced colonic inflammation.

  8. Transient infection of the zebrafish notochord with E. coli induces chronic inflammation

    Directory of Open Access Journals (Sweden)

    Mai Nguyen-Chi

    2014-07-01

    Full Text Available Zebrafish embryos and larvae are now well-established models in which to study infectious diseases. Infections with non-pathogenic Gram-negative Escherichia coli induce a strong and reproducible inflammatory response. Here, we study the cellular response of zebrafish larvae when E. coli bacteria are injected into the notochord and describe the effects. First, we provide direct evidence that the notochord is a unique organ that is inaccessible to leukocytes (macrophages and neutrophils during the early stages of inflammation. Second, we show that notochord infection induces a host response that is characterised by rapid clearance of the bacteria, strong leukocyte recruitment around the notochord and prolonged inflammation that lasts several days after bacteria clearance. During this inflammatory response, il1b is first expressed in macrophages and subsequently at high levels in neutrophils. Moreover, knock down of il1b alters the recruitment of neutrophils to the notochord, demonstrating the important role of this cytokine in the maintenance of inflammation in the notochord. Eventually, infection of the notochord induces severe defects of the notochord that correlate with neutrophil degranulation occurring around this tissue. This is the first in vivo evidence that neutrophils can degranulate in the absence of a direct encounter with a pathogen. Persistent inflammation, neutrophil infiltration and restructuring of the extracellular matrix are defects that resemble those seen in bone infection and in some chondropathies. As the notochord is a transient embryonic structure that is closely related to cartilage and bone and that contributes to vertebral column formation, we propose infection of the notochord in zebrafish larvae as a new model to study the cellular and molecular mechanisms underlying cartilage and bone inflammation.

  9. Transient infection of the zebrafish notochord with E. coli induces chronic inflammation.

    Science.gov (United States)

    Nguyen-Chi, Mai; Phan, Quang Tien; Gonzalez, Catherine; Dubremetz, Jean-François; Levraud, Jean-Pierre; Lutfalla, Georges

    2014-07-01

    Zebrafish embryos and larvae are now well-established models in which to study infectious diseases. Infections with non-pathogenic Gram-negative Escherichia coli induce a strong and reproducible inflammatory response. Here, we study the cellular response of zebrafish larvae when E. coli bacteria are injected into the notochord and describe the effects. First, we provide direct evidence that the notochord is a unique organ that is inaccessible to leukocytes (macrophages and neutrophils) during the early stages of inflammation. Second, we show that notochord infection induces a host response that is characterised by rapid clearance of the bacteria, strong leukocyte recruitment around the notochord and prolonged inflammation that lasts several days after bacteria clearance. During this inflammatory response, il1b is first expressed in macrophages and subsequently at high levels in neutrophils. Moreover, knock down of il1b alters the recruitment of neutrophils to the notochord, demonstrating the important role of this cytokine in the maintenance of inflammation in the notochord. Eventually, infection of the notochord induces severe defects of the notochord that correlate with neutrophil degranulation occurring around this tissue. This is the first in vivo evidence that neutrophils can degranulate in the absence of a direct encounter with a pathogen. Persistent inflammation, neutrophil infiltration and restructuring of the extracellular matrix are defects that resemble those seen in bone infection and in some chondropathies. As the notochord is a transient embryonic structure that is closely related to cartilage and bone and that contributes to vertebral column formation, we propose infection of the notochord in zebrafish larvae as a new model to study the cellular and molecular mechanisms underlying cartilage and bone inflammation. © 2014. Published by The Company of Biologists Ltd.

  10. Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain

    Science.gov (United States)

    Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N.

    2014-01-01

    The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

  11. The hexane fraction of Ardisia crispa Thunb. A. DC. roots inhibits inflammation-induced angiogenesis

    Science.gov (United States)

    2013-01-01

    Background Ardisia crispa (Myrsinaceae) is used in traditional Malay medicine to treat various ailments associated with inflammation, including rheumatism. The plant’s hexane fraction was previously shown to inhibit several diseases associated with inflammation. As there is a strong correlation between inflammation and angiogenesis, we conducted the present study to investigate the anti-angiogenic effects of the plant’s roots in animal models of inflammation-induced angiogenesis. Methods We first performed phytochemical screening and high-performance liquid chromatography (HPLC) fingerprinting of the hexane fraction of Ardisia crispa roots ethanolic extract (ACRH) and its quinone-rich fraction (QRF). The anti-inflammatory properties of ACRH and QRF were tested using the Miles vascular permeability assay and the murine air pouch granuloma model following oral administration at various doses. Results Preliminary phytochemical screening of ACRH revealed the presence of flavonoids, triterpenes, and tannins. The QRF was separated from ACRH (38.38% w/w) by column chromatography, and was isolated to yield a benzoquinonoid compound. The ACRH and QRF were quantified by HPLC. The LD50 value of ACRH was 617.02 mg/kg. In the Miles vascular permeability assay, the lowest dose of ACRH (10 mg/kg) and all doses of QRF significantly reduced vascular endothelial growth factor (VEGF)-induced hyperpermeability, when compared with the vehicle control. In the murine air pouch granuloma model, ACRH and QRF both displayed significant and dose-dependent anti-inflammatory effects, without granuloma weight. ACRH and QRF significantly reduced the vascular index, but not granuloma tissue weight. Conclusions In conclusion, both ACRH and QRF showed potential anti-inflammatory properties in a model of inflammation-induced angiogenesis model, demonstrating their potential anti-angiogenic properties. PMID:23298265

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

    Science.gov (United States)

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

    2015-08-01

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

  13. Preventive Intra Oral Treatment of Sea Cucumber Ameliorate OVA-Induced Allergic Airway Inflammation.

    Science.gov (United States)

    Lee, Da-In; Park, Mi-Kyung; Kang, Shin Ae; Choi, Jun-Ho; Kang, Seok-Jung; Lee, Jeong-Yeol; Yu, Hak Sun

    2016-01-01

    Sea cucumber extracts have potent biological effects, including anti-viral, anti-cancer, antibacterial, anti-oxidant, and anti-inflammation effects. To understand their anti-asthma effects, we induced allergic airway inflammation in mice after 7 oral administrations of the extract. The hyper-responsiveness value in mice with ovalbumin (OVA)-alum-induced asthma after oral injection of sea cucumber extracts was significantly lower than that in the OVA-alum-induced asthma group. In addition, the number of eosinophils in the lungs of asthma-induced mice pre-treated with sea cucumber extract was significantly decreased compared to that of PBS pre-treated mice. Additionally, CD4[Formula: see text]CD25[Formula: see text]Foxp3[Formula: see text]T (regulatory T; Treg) cells significantly increased in mesenteric lymph nodes after 7 administrations of the extract. These results suggest that sea cucumber extract can ameliorate allergic airway inflammation via Treg cell activation and recruitment to the lung.

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

    Science.gov (United States)

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

    2012-01-01

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

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

    Directory of Open Access Journals (Sweden)

    José F. González-Benítez

    2008-01-01

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

  16. Bradykinin-induced lung inflammation and bronchoconstriction: role in parainfluenze-3 virus-induced inflammation and airway hyperreactivity.

    Science.gov (United States)

    Broadley, Kenneth J; Blair, Alan E; Kidd, Emma J; Bugert, Joachim J; Ford, William R

    2010-12-01

    Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B(2) kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 μM, 20 min) and are therefore mediated via B(2) kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B(2) antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B(2) receptor antagonist MEN16132 and H-(4-chloro)DPhe-2'(1-naphthylalanine)-(3-aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR.

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

    Directory of Open Access Journals (Sweden)

    Stavros Selemidis

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

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

    DEFF Research Database (Denmark)

    Genster, Ninette; Østrup, Olga; Schjalm, Camilla

    2017-01-01

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

  19. Kampo medicine "Dai-kenchu-to" prevents CPT-11-induced small-intestinal injury in rats.

    Science.gov (United States)

    Chikakiyo, Motoya; Shimada, Mitsuo; Nakao, Toshihiro; Higashijima, Jun; Yoshikawa, Kozo; Nishioka, Masanori; Iwata, Takashi; Kurita, Nobuhiro

    2012-01-01

    The key anticancer agent, CPT-11 (irinotecan hydrochloride), induces severe diarrhea clinically. We investigated the effect of a Kampo medicine, Dai-kenchu-to (DKT), on CPT-11-induced intestinal injuries in rats. Twenty-four male Wistar rats were divided into three groups: a control group; a CPT-11 group, given CPT-11 150 mg/kg intraperitoneally for 2 days; and a DKT group, given DKT 300 mg/kg orally for 5 days with CPT-11 150 mg/kg intraperitoneally on days 4 and 5. The rats were killed on day 6. Interleukin (IL)-1β, IL-12, interferon (IFN)-γ, and tumor necrosis factor-α expression in the small intestine of the CPT-11 group was significantly higher than that of the control group. Interleukin-1β and IFN-γ expression was improved significantly by DKT (P DKT (P DKT suppressed CPT-11 induced inflammatory cytokines and apoptosis in the intestinal mucosa and maintained the mucosal integrity.

  20. Combined compared to dissociated oral and intestinal sucrose stimuli induce different brain hedonic processes

    Science.gov (United States)

    Clouard, Caroline; Meunier-Salaün, Marie-Christine; Meurice, Paul; Malbert, Charles-Henri; Val-Laillet, David

    2014-01-01

    The characterization of brain networks contributing to the processing of oral and/or intestinal sugar signals in a relevant animal model might help to understand the neural mechanisms related to the control of food intake in humans and suggest potential causes for impaired eating behaviors. This study aimed at comparing the brain responses triggered by oral and/or intestinal sucrose sensing in pigs. Seven animals underwent brain single photon emission computed tomography (99mTc-HMPAO) further to oral stimulation with neutral or sucrose artificial saliva paired with saline or sucrose infusion in the duodenum, the proximal part of the intestine. Oral and/or duodenal sucrose sensing induced differential cerebral blood flow changes in brain regions known to be involved in memory, reward processes and hedonic (i.e., pleasure) evaluation of sensory stimuli, including the dorsal striatum, prefrontal cortex, cingulate cortex, insular cortex, hippocampus, and parahippocampal cortex. Sucrose duodenal infusion only and combined sucrose stimulation induced similar activity patterns in the putamen, ventral anterior cingulate cortex and hippocampus. Some brain deactivations in the prefrontal and insular cortices were only detected in the presence of oral sucrose stimulation. Finally, activation of the right insular cortex was only induced by combined oral and duodenal sucrose stimulation, while specific activity patterns were detected in the hippocampus and parahippocampal cortex with oral sucrose dissociated from caloric load. This study sheds new light on the brain hedonic responses to sugar and has potential implications to unravel the neuropsychological mechanisms underlying food pleasure and motivation. PMID:25147536

  1. Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation.

    Science.gov (United States)

    Bailey-Downs, Lora C; Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2013-07-01

    Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet-fed obese C57BL/6 mice. High-fat diet-induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet-induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals.

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

    Science.gov (United States)

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

    2016-05-01

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

  3. Resolution of LPS-induced airway inflammation and goblet cell hyperplasia is independent of IL-18

    Directory of Open Access Journals (Sweden)

    Lyons C Rick

    2007-03-01

    Full Text Available Abstract Background The resolution of inflammatory responses in the lung has not been described in detail and the role of specific cytokines influencing the resolution process is largely unknown. Methods The present study was designed to describe the resolution of inflammation from 3 h through 90 d following an acute injury by a single intratracheal instillation of F344/N rats with LPS. We documented the inflammatory cell types and cytokines found in the bronchoalveolar lavage fluid (BALF, and epithelial changes in the axial airway and investigated whether IL-18 may play a role in the resolution process by reducing its levels with anti-IL-18 antibodies. Results Three major stages of inflammation and resolution were observed in the BALF during the resolution. The first stage was characterized by PMNs that increased over 3 h to 1 d and decreased to background levels by d 6–8. The second stage of inflammation was characterized by macrophage influx reaching maximum numbers at d 6 and decreasing to background levels by d 40. A third stage of inflammation was observed for lymphocytes which were elevated over d 3–6. Interestingly, IL-18 and IL-9 levels in the BALF showed a cyclic pattern with peak levels at d 4, 8, and 16 while decreasing to background levels at d 1–2, 6, and 12. Depletion of IL-18 caused decreased PMN numbers at d 2, but no changes in inflammatory cell number or type at later time points. Conclusion These data suggest that IL-18 plays a role in enhancing the LPS-induced neutrophilic inflammation of the lung, but does not affect the resolution of inflammation.

  4. Intestinal metaplasia induced by x-irradiation in different strains of rats

    International Nuclear Information System (INIS)

    Watanabe, Hiromitsu; Naito, Masashi; Kawashima, Kengo; Ito, Akihiro

    1985-01-01

    Attempts were made to examine strain differences in the susceptibility of rats to intestinal metaplasia induced by X-irradiation. The gastric regions of 4 inbred male rats (SHR, F344, WKY, and LEW strains) in 5-week-old and 2 random bred male rats (SD, and WIS strains) were irradiated with a total dose of 20 Gy X-ray given in two equal fractions separated by three days. Upon sacrifice at 6 months after the last irradiation, the number of intestinal metaplastic crypts with positive reaction to alkaline phosphatase (ALP) appeared highest in the SHR and lowest in the WIS rats. Morphologically, the number of crypts with intestinal metaplasia in whole glandular stomachs of SHR, WIS, F344, and SD rats were higher than those in WKY and LEW rats. In the pyloric gland, it was highest in WIS rats, while in the fundic gland it was highest in SHR rats. The results show that the appearance and location of intestinal metaplasia by X-irradiation are greatly influenced by the strain of the rat. (author)

  5. High-density lipoproteins inhibit urate crystal-induced inflammation in mice

    OpenAIRE

    Scanu Anna; Luisetto Roberto; Oliviero Francesca; Gruaz Lyssia; Sfriso Paolo; Burger Danielle; Punzi Leonardo

    2015-01-01

    Objectives To investigate the effects and mechanisms of action of high density lipoproteins (HDL) in monosodium urate (MSU) crystal induced inflammation—that is gouty inflammation in vivo. Methods Air pouches raised on the backs of mice were injected with MSU crystals or tumour necrosis factor (TNF) in the presence or absence of HDL and/or interleukin (IL) 1 receptor antagonist (IL 1Ra) for 3 h. Leucocyte count and neutrophil percentage in pouch fluids were measured using a haemocytometer an...

  6. Pomegranate polyphenolics reduce inflammation and ulceration in intestinal colitis-involvement of the miR-145/p70S6K1/HIF1α axis in vivo and in vitro.

    Science.gov (United States)

    Kim, Hyemee; Banerjee, Nivedita; Sirven, Maritza A; Minamoto, Yasushi; Markel, Melissa E; Suchodolski, Jan S; Talcott, Stephen T; Mertens-Talcott, Susanne U

    2017-05-01

    This study investigated the potential role of the p70S6K1/HIF1α axis in the anti-inflammatory activities of pomegranate (Punica granatum L.) polyphenolics in dextran sodium sulfate (DSS)-induced colitis in Sprague-Dawley rats and in lipopolysaccharide (LPS)-treated CCD-18Co colon-myofibroblastic cells. Rats were administered either control (CT) or pomegranate beverage (PG), containing ellagic acid and ellagitannins, then exposed to three cycles of 3% DSS followed by a 2-week recovery period. PG protected against DSS-induced colon inflammation and ulceration (50% and 66.7%, P=.05 and .045, respectively), and decreased the Ki-67 proliferative index in the central and basal regions compared to the control. PG also significantly reduced the expression of proinflammatory cytokines (TNF-α and IL-1β), COX-2, and iNOS at mRNA and protein levels. In addition, the expression of p70S6K1 and HIF1α was reduced, while the tumor suppressor miR-145 was induced by PG. The intestinal microbiota of rats treated with PG showed a significant increase in Ruminococcaceae that include several butyrate producing bacteria (P=.03). In vitro, PG reduced the expression of p70S6K1 and HIF1α and induced miR-145 in a dose-dependent manner. The involvement of miR-145/p70S6K1 was confirmed by treating LPS-treated CCD-18Co cells with miR-145 antagomiR, where the pomegranate polyphenolics reversed the effects of the antagomiR for p70S6K1 mRNA and protein levels. These results suggest that pomegranate polyphenols attenuated DSS-induced colitis by modulating the miR-145/p70S6K/HIF1α axis, indicating potential use in therapeutic treatment of ulcerative colitis. Copyright © 2017 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2014-02-01

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

  8. HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Varun Chandrashekaran

    2017-10-01

    Full Text Available Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1 as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4 activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA, AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.

  9. High fructose intake fails to induce symptomatic adaptation but may induce intestinal carriers

    Directory of Open Access Journals (Sweden)

    Debra Heilpern

    2010-01-01

    Full Text Available Fructose has several interactions in man, including intolerance and promotion of some diseases. However, fructose in fruits and in prebiotics may be associated with benefits. Adaptation to regular fructose ingestion as defined for lactose could support a beneficial rather than a deleterious effect. This study was undertaken to evaluate symptomatic response and potential underlying mechanisms of fecal bacterial change and breath hydrogen response to short term regular fructose supplementation. Forty-five participants were recruited for a 3 day recall diet questionnaire and a 50 g fructose challenge. Breath hydrogen was measured for 4.5 hrs and symptoms were recorded. Thirty-eight subjects provided stool samples for analysis by selective culture of 4 groups of bacteria, including bifidobacteria and lactobacilli. Intolerant subjects returned a second time 15 days later. Ten of these served as controls and 16 received 30 g fructose twice a day. Ten of the latter returned 27 days later, after stopping fructose for a third challenge test. Student’s paired, unpaired t-tests and Pearson correlations were used. Significance was accepted at P<0.05. After fructose rechallenge there were no significant reductions in symptoms scores in volunteers in either the fructose supplemented or non supplemented groups. However, total breath hydrogen was reduced between test 1 and test 2 (P=0.03 or test 3 (P=0.04 in the group given fructose then discontinued, compared with controls. There were no statistically significant changes in bacterial numbers between test 2 and 1. This study shows that regular consumption of high dose fructose does not follow the lactose model of adaptation. Observed changes in hydrogen breath tests raise the possibility that intestinal carriers of fructose may be induced potentially aggravating medical problems attributed to fructose.

  10. Protective effect of Arbutus unedo aqueous extract in carrageenan-induced lung inflammation in mice.

    Science.gov (United States)

    Mariotto, Sofia; Esposito, Emanuela; Di Paola, Rosanna; Ciampa, Anna; Mazzon, Emanuela; de Prati, Alessandra Carcereri; Darra, Elena; Vincenzi, Simone; Cucinotta, Giovanni; Caminiti, Rocco; Suzuki, Hisanori; Cuzzocrea, Salvatore

    2008-02-01

    In the present study, we show that an aqueous extract of Arbutus unedo L. (AuE), a Mediterranean endemic plant widely employed as an astringent, diuretic and urinary anti-septic, in vitro down-regulates the expression of some inflammatory genes, such as those encoding inducible nitric oxide synthase (iNOS) and intracellular adhesion molecule-(ICAM)-1, exerting a inhibitory action on both IFN-gamma-elicited STAT1 activation and IL-6-elicited STAT3 activation. To evaluate further the effect of AuE in animal models of acute inflammation, we examined whether AuE administration attenuates inflammatory response of murine induced by intrapleural injection of carrageenan. For this purpose we studied: (1) STAT1/3 activation, (2) TNF-alpha, IL-1beta and IL-6 production in pleural exudate, (3) lung iNOS, COX-2 and ICAM-1 expression, (4) neutrophil infiltration, (5) the nitration of cellular proteins by peroxynitrite, (6) lipid peroxidation, (7) prostaglandin E2 and nitrite/nitrate levels and (8) lung injury. We show that AuE strongly down-regulates STAT3 activation induced in the lung by carrageenan with concomitant attenuation of all parameters examined associated with inflammation, suggesting that STAT3 should be a new molecular target for anti-inflammatory treatment. This study demonstrates that acute lung inflammation is significantly attenuated by the treatment with AuE.

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

    Directory of Open Access Journals (Sweden)

    Inge Van Hove

    2016-11-01

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

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

    Science.gov (United States)

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

    2015-09-01

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

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

    Directory of Open Access Journals (Sweden)

    Yue Jing

    2017-01-01

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

  14. Inhibition of IKKβ in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality.

    Science.gov (United States)

    Dominguez, Jessica A; Samocha, Alexandr J; Liang, Zhe; Burd, Eileen M; Farris, Alton B; Coopersmith, Craig M

    2013-10-01

    Nuclear factor-κB is a critical regulator of cell-survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase. Prospective, randomized controlled study. Animal laboratories in university medical centers. Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkβ) and wild-type mice were subjected to sham laparotomy or cecal ligation and puncture. Animals were killed at 24 hours or followed 7 days for survival. Septic wild-type mice had decreased villus length compared with sham mice, whereas villus atrophy was further exacerbated in septic Vil-Cre/Ikkβ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared with sham mice, which was further exacerbated in Vil-Cre/Ikkβ mice. Sepsis induced intestinal hyperpermeability in wild-type mice compared with sham mice, which was further exacerbated in septic Vil-Cre/Ikkβ mice. This was associated with increased intestinal expression of claudin-2 in septic wild-type mice, which was further increased in septic Vil-Cre/Ikkβ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following cecal ligation and puncture, and interleukin 10 and monocyte chemoattractant protein-1 levels were higher in septic Vil-Cre/Ikkβ mice than in septic wild-type mice. All septic mice were bacteremic, but no differences in bacterial load were identified between wild-type and Vil-Cre/Ikkβ mice. To determine the functional significance of these results, animals were followed for survival. Septic wild-type mice had lower mortality than septic Vil-Cre/Ikkβ mice (47% vs 80%, p<0.05). Antitumor necrosis factor administration decreased intestinal apoptosis, permeability, and mortality in wild-type septic mice, and a similar improvement in intestinal integrity and survival were seen when antitumor necrosis factor was given to Vil-Cre/Ikkβ mice. Enterocyte

  15. Inhibition of IKKß in enterocytes exacerbates sepsis-induced intestinal injury and worsens mortality

    Science.gov (United States)

    Dominguez, Jessica A.; Samocha, Alexandr J.; Liang, Zhe; Burd, Eileen M.; Farris, Alton B.; Coopersmith, Craig M.

    2013-01-01

    Objective NF-kB is a critical regulator of cell survival genes and the host inflammatory response. The purpose of this study was to investigate the role of enterocyte-specific NF-kB in sepsis through selective ablation of IkB kinase (IKK)-ß. Design Prospective, randomized, controlled study. Setting Animal laboratories in university medical centers. Subjects and Interventions Mice lacking functional NF-kB in their intestinal epithelium (Vil-Cre/Ikkßf/Δ) and wild type (WT) mice were subjected to sham laparotomy or cecal ligation and puncture (CLP). Animals were sacrified at 24 hours or followed seven days for survival. Measurements and Main Results Septic WT mice had decreased villus length compared to sham mice while villus atrophy was further exacerbated in septic Vil-Cre/Ikkßf/Δ mice. Sepsis induced an increase in intestinal epithelial apoptosis compared to sham mice which was further exacerbated in Vil-Cre/Ikkßf/Δ mice. Sepsis induced intestinal hyperpermeability in WT mice compared to sham mice, which was further exacerbated in septic Vil-Cre/Ikkßf/Δ mice. This was associated with increased intestinal expression of claudin-2 in septic WT mice, which was further increased in septic Vil-Cre/Ikkßf/Δ mice. Both, pro-inflammatory and anti-inflammatory cytokines were increased in serum following CLP, and IL-10 and MCP-1 levels were higher in septic Vil-Cre/Ikkßf/Δ mice than septic WT mice. All septic mice were bacteremic, but no differences in bacterial load were identified between WT and Vil-Cre/Ikkßf/Δ mice. To determine the functional significance of these results, animals were followed for survival. Septic WT mice had lower mortality than septic Vil-Cre/Ikkßf/Δ mice (47% vs. 80%, p<0.05). Anti-TNF administration decreased intestinal apoptosis, permeability and mortality in WT septic mice and a similar improvement in intestinal integrity and survival were seen when anti-TNF was given to Vil-Cre/Ikkßf/Δ mice. Conclusions Enterocyte-specific NF

  16. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    International Nuclear Information System (INIS)

    Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15 ml/kg). In CCl 4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl 4 -induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl 4 -induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  17. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Da-Gang [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Wang, Jun-Xian [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Lu, Yan; Tao, Li; Wang, Jian-Qing [Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei 230032 (China)

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  18. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.

    Science.gov (United States)

    Lammers, Karen M; Lu, Ruliang; Brownley, Julie; Lu, Bao; Gerard, Craig; Thomas, Karen; Rallabhandi, Prasad; Shea-Donohue, Terez; Tamiz, Amir; Alkan, Sefik; Netzel-Arnett, Sarah; Antalis, Toni; Vogel, Stefanie N; Fasano, Alessio

    2008-07-01

    Celiac disease is an immune-mediated enteropathy triggered by gliadin, a component of the grain protein gluten. Gliadin induces an MyD88-dependent zonulin release that leads to increased intestinal permeability, a postulated early element in the pathogenesis of celiac disease. We aimed to establish the molecular basis of gliadin interaction with intestinal mucosa leading to intestinal barrier impairment. Alpha-gliadin affinity column was loaded with intestinal mucosal membrane lysates to identify the putative gliadin-binding moiety. In vitro experiments with chemokine receptor CXCR3 transfectants were performed to confirm binding of gliadin and/or 26 overlapping 20mer alpha-gliadin synthetic peptides to the receptor. CXCR3 protein and gene expression were studied in intestinal epithelial cell lines and human biopsy specimens. Gliadin-CXCR3 interaction was further analyzed by immunofluorescence microscopy, laser capture microscopy, real-time reverse-transcription polymerase chain reaction, and immunoprecipitation/Western blot analysis. Ex vivo experiments were performed using C57BL/6 wild-type and CXCR3(-/-) mouse small intestines to measure intestinal permeability and zonulin release. Affinity column and colocalization experiments showed that gliadin binds to CXCR3 and that at least 2 alpha-gliadin 20mer synthetic peptides are involved in this binding. CXCR3 is expressed in mouse and human intestinal epithelia and lamina propria. Mucosal CXCR3 expression was elevated in active celiac disease but returned to baseline levels following implementation of a gluten-free diet. Gliadin induced physical association between CXCR3 and MyD88 in enterocytes. Gliadin increased zonulin release and intestinal permeability in wild-type but not CXCR3(-/-) mouse small intestine. Gliadin binds to CXCR3 and leads to MyD88-dependent zonulin release and increased intestinal permeability.

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

    Directory of Open Access Journals (Sweden)

    António M. Santos

    2015-01-01

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

  20. Exercise protects against high-fat diet-induced hypothalamic inflammation.

    Science.gov (United States)

    Yi, Chun-Xia; Al-Massadi, Omar; Donelan, Elizabeth; Lehti, Maarit; Weber, Jon; Ress, Chandler; Trivedi, Chitrang; Müller, Timo D; Woods, Stephen C; Hofmann, Susanna M

    2012-06-25

    Hypothalamic inflammation is a potentially important process in the pathogenesis of high-fat diet-induced metabolic disorders that has recently received significant attention. Microglia are macrophage-like cells of the central nervous system which are activated by pro-inflammatory signals causing local production of specific interleukins and cytokines, and these in turn may further promote systemic metabolic disease. Whether or how this microglial activation can be averted or reversed is unknown. Since running exercise improves systemic metabolic health and has been found to promote neuronal survival as well as the recovery of brain functions after injury, we hypothesized that regular treadmill running may blunt the effect of western diet on hypothalamic inflammation. Using low-density lipoprotein receptor deficient (l dlr-/-) mice to better reflect human lipid metabolism, we first confirmed that microglial activation in the hypothalamus is severely increased upon exposure to a high-fat, or "western", diet. Moderate, but regular, treadmill running exercise markedly decreased hypothalamic inflammation in these mice. Furthermore, the observed decline in microglial activation was associated with an improvement of glucose tolerance. Our findings support the hypothesis that hypothalamic inflammation can be reversed by exercise and suggest that interventions to avert or reverse neuronal damage may offer relevant potential in obesity treatment and prevention. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Intestine-Specific Mttp Deletion Decreases Mortality and Prevents Sepsis-Induced Intestinal Injury in a Murine Model of Pseudomonas aeruginosa Pneumonia

    Science.gov (United States)

    Dominguez, Jessica A.; Xie, Yan; Dunne, W. Michael; Yoseph, Benyam P.; Burd, Eileen M.; Coopersmith, Craig M.; Davidson, Nicholas O.

    2012-01-01

    Background The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the “motor” of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO), which exhibit a block in chylomicron assembly together with lipid malabsorption. Methodology/Principal Findings Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomonas aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0%) dying compared to 5/17 (29%) control mice (p<0.05). This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL) levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice. Conclusions/Significance These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by

  2. Intestine-specific Mttp deletion decreases mortality and prevents sepsis-induced intestinal injury in a murine model of Pseudomonas aeruginosa pneumonia.

    Directory of Open Access Journals (Sweden)

    Jessica A Dominguez

    Full Text Available The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the "motor" of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO, which exhibit a block in chylomicron assembly together with lipid malabsorption.Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomonas aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0% dying compared to 5/17 (29% control mice (p<0.05. This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice.These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by metabolic and physiological adaptations in both intestinal and

  3. Voltage dependent potassium channel remodeling in murine intestinal smooth muscle hypertrophy induced by partial obstruction.

    Science.gov (United States)

    Liu, Dong-Hai; Huang, Xu; Guo, Xin; Meng, Xiang-Min; Wu, Yi-Song; Lu, Hong-Li; Zhang, Chun-Mei; Kim, Young-chul; Xu, Wen-Xie

    2014-01-01

    Partial obstruction of the small intestine causes obvious hypertrophy of smooth muscle cells and motility disorder in the bowel proximate to the obstruction. To identify electric remodeling of hypertrophic smooth muscles in partially obstructed murine small intestine, the patch-clamp and intracellular microelectrode recording methods were used to identify the possible electric remodeling and Western blot, immunofluorescence and immunoprecipitation were utilized to examine the channel protein expression and phosphorylation level changes in this research. After 14 days of obstruction, partial obstruction caused obvious smooth muscle hypertrophy in the proximally located intestine. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed, their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized compared with normal and sham animals. The current density of voltage dependent potassium channel (KV) was significantly decreased in the hypertrophic smooth muscle cells and the voltage sensitivity of KV activation was altered. The sensitivity of KV currents (IKV) to TEA, a nonselective potassium channel blocker, increased significantly, but the sensitivity of IKv to 4-AP, a KV blocker, stays the same. The protein levels of KV4.3 and KV2.2 were up-regulated in the hypertrophic smooth muscle cell membrane. The serine and threonine phosphorylation levels of KV4.3 and KV2.2 were significantly increased in the hypertrophic smooth muscle cells. Thus this study represents the first identification of KV channel remodeling in murine small intestinal smooth muscle hypertrophy induced by partial obstruction. The enhanced phosphorylations of KV4.3 and KV2.2 may be involved in this process.

  4. Voltage dependent potassium channel remodeling in murine intestinal smooth muscle hypertrophy induced by partial obstruction.

    Directory of Open Access Journals (Sweden)

    Dong-Hai Liu

    Full Text Available Partial obstruction of the small intestine causes obvious hypertrophy of smooth muscle cells and motility disorder in the bowel proximate to the obstruction. To identify electric remodeling of hypertrophic smooth muscles in partially obstructed murine small intestine, the patch-clamp and intracellular microelectrode recording methods were used to identify the possible electric remodeling and Western blot, immunofluorescence and immunoprecipitation were utilized to examine the channel protein expression and phosphorylation level changes in this research. After 14 days of obstruction, partial obstruction caused obvious smooth muscle hypertrophy in the proximally located intestine. The slow waves of intestinal smooth muscles in the dilated region were significantly suppressed, their amplitude and frequency were reduced, whilst the resting membrane potentials were depolarized compared with normal and sham animals. The current density of voltage dependent potassium channel (KV was significantly decreased in the hypertrophic smooth muscle cells and the voltage sensitivity of KV activation was altered. The sensitivity of KV currents (IKV to TEA, a nonselective potassium channel blocker, increased significantly, but the sensitivity of IKv to 4-AP, a KV blocker, stays the same. The protein levels of KV4.3 and KV2.2 were up-regulated in the hypertrophic smooth muscle cell membrane. The serine and threonine phosphorylation levels of KV4.3 and KV2.2 were significantly increased in the hypertrophic smooth muscle cells. Thus this study represents the first identification of KV channel remodeling in murine small intestinal smooth muscle hypertrophy induced by partial obstruction. The enhanced phosphorylations of KV4.3 and KV2.2 may be involved in this process.

  5. Motorcycle exhaust particles induce airway inflammation and airway hyperresponsiveness in BALB/C mice.

    Science.gov (United States)

    Lee, Chen-Chen; Liao, Jiunn-Wang; Kang, Jaw-Jou

    2004-06-01

    A number of large studies have reported that environmental pollutants from fossil fuel combustion can cause deleterious effects to the immune system, resulting in an allergic reaction leading to respiratory tract damage. In this study, we investigated the effect of motorcycle exhaust particles (MEP), a major pollutant in the Taiwan urban area, on airway inflammation and airway hyperresponsiveness in laboratory animals. BALB/c mice were instilled intratracheally (i.t.) with 1.2 mg/kg and 12 mg/kg of MEP, which was collected from two-stroke motorcycle engines. The mice were exposed 3 times i.t. with MEP, and various parameters for airway inflammation and hyperresponsiveness were sequentially analyzed. We found that MEP would induce airway and pulmonary inflammation characterized by infiltration of eosinophils, neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid (BALF) and inflammatory cell infiltration in lung. In addition, MEP treatment enhanced BALF interleukin-4 (IL-4), IL-5, and interferon-gamma (IFN-gamma) cytokine levels and serum IgE production. Bronchial response measured by unrestrained plethysmography with methacholine challenge showed that MEP treatment induced airway hyperresponsiveness (AHR) in BALB/c mice. The chemical components in MEP were further fractionated with organic solvents, and we found that the benzene-extracted fraction exerts a similar biological effect as seen with MEP, including airway inflammation, increased BALF IL-4, serum IgE production, and induction of AHR. In conclusion, we present evidence showing that the filter-trapped particles emitted from the unleaded-gasoline-fueled two-stroke motorcycle engine may induce proinflammatory and proallergic response profiles in the absence of exposure to allergen.

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

    Directory of Open Access Journals (Sweden)

    Jie Wang

    2017-12-01

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

  7. Grain dust-induced lung inflammation is reduced by Rhodobacter sphaeroides diphosphoryl lipid A.

    Science.gov (United States)

    Jagielo, P J; Quinn, T J; Qureshi, N; Schwartz, D A

    1998-01-01

    To further determine the importance of endotoxin in grain dust-induced inflammation of the lower respiratory tract, we evaluated the efficacy of pentaacylated diphosphoryl lipid A derived from the lipopolysaccharide of Rhodobacter sphaeroides (RsDPLA) as a partial agonist of grain dust-induced airway inflammation. RsDPLA is a relatively inactive compound compared with lipid A derived from Escherichia coli (LPS) and has been demonstrated to act as a partial agonist of LPS-induced inflammation. To assess the potential stimulatory effect of RsDPLA in relation to LPS, we incubated THP-1 cells with RsDPLA (0.001-100 micrograms/ml), LPS (0.02 microgram endotoxin activity/ml), or corn dust extract (CDE; 0.02 microgram endotoxin activity/ml). Incubation with RsDPLA revealed a tumor necrosis factor (TNF)-alpha stimulatory effect at 100 micrograms/ml. In contrast, incubation with LPS or CDE resulted in TNF-alpha release at 0.02 microgram/ml. Pretreatment of THP-1 cells with varying concentrations of RsDPLA before incubation with LPS or CDE (0.02 microgram endotoxin activity/ml) resulted in a dose-dependent reduction in the LPS- or CDE-induced release of TNF-alpha with concentrations of RsDPLA of up to 10 micrograms/ml but not at 100 micrograms/ml. To further understand the role of endotoxin in grain dust-induced airway inflammation, we utilized the unique LPS inhibitory property of RsDPLA to determine the inflammatory response to inhaled CDE in mice in the presence of RsDPLA. Ten micrograms of RsDPLA intratracheally did not cause a significant inflammatory response compared with intratracheal saline. However, pretreatment of mice with 10 micrograms of RsDPLA intratracheally before exposure to CDE (5.4 and 0.2 micrograms/m3) or LPS (7.2 and 0.28 micrograms/m3) resulted in significant reductions in the lung lavage concentrations of total cells, neutrophils, and specific proinflammatory cytokines compared with mice pretreated with sterile saline. These results confirm the LPS

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

    Directory of Open Access Journals (Sweden)

    Takeshi Tohyama

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

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

    Science.gov (United States)

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

    2018-01-01

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

  10. Orally delivered β-glucans aggravate dextran sulfate sodium (DSS)-induced intestinal inflammation

    NARCIS (Netherlands)

    Heinsbroek, Sigrid E. M.; Williams, David L.; Welting, Olaf; Meijer, Sybren L.; Gordon, Siamon; de Jonge, Wouter J.

    2015-01-01

    β-Glucans have beneficial health effects due to their immune modulatory properties. Oral administration of β-glucans affects tumour growth, microbial infection, sepsis, and wound healing. We hypothesized that pre-treatment with orally delivered soluble and particulate β-glucans could ameliorate the

  11. protective and therapeutic effects of anaerobic bacteria sonicate on experimentally induced intestinal inflammation

    Czech Academy of Sciences Publication Activity Database

    Sokol, Dan; Rossmann, Pavel; Jelen, P.; Hudcovic, Tomáš; Horáková, Dana; Jelínková, Lenka; Tučková, Ludmila; Tlaskalová, Helena

    2003-01-01

    Roč. 87, č. 1 (2003), s. 87 ISSN 0165-2478. [European Immunology Congress /15./. Rhodes, 08.06.2003-12.06.2003] Institutional research plan: CEZ:AV0Z5020903 Keywords : anacrobic * bacteria * sonicate Subject RIV: EE - Microbiology, Virology Impact factor: 1.710, year: 2003

  12. Transient, heat-induced thermal resistance in the small intestine of mouse

    International Nuclear Information System (INIS)

    Hume, S.P.; Marigold, J.C.L.

    1980-01-01

    Heat-induced thermal resistance has been investigated in mouse jejunum by assaying crypt survival 24 h after treatment. Hyperthermia was achieved by immersing an exteriorized loop of intestine in a bath of Krebs-Ringer solution. Two approaches have been used. In the first, thermal survival curves were obtained following single hyperthermal treatments at temperatures in the range 42 to 44 0 C. Transient thermal resistance, inducted by a plateau in the crypt survival curve, developed during heating at temperatures around 42.5 0 C after 60 to 80 min. In the second series of experiments, a priming heat treatment (40.0, 41.0, 41.5, or 42.0 0 C for 60 min) was followed at varying intervals by a test treatment at 43.0 0 C. A transient resistance to the second treatment was induced, the extent and time of development being dependent upon the priming treatment. Crypt survival curves for thermally resistant intestine showed an increase in thermal D 0 and a decrease in n compared with curves from previously unheated intestine

  13. κ-Carrageenan Enhances Lipopolysaccharide-Induced Interleukin-8 Secretion by Stimulating the Bcl10-NF-κB Pathway in HT-29 Cells and Aggravates C. freundii-Induced Inflammation in Mice

    Directory of Open Access Journals (Sweden)

    Wei Wu

    2017-01-01

    Full Text Available Background. The dietary usage of carrageenan as common food additive has increased observably over the last 50 years. But there is substantial controversy about its safety. Methods. We investigated whether the κ-carrageenan could enhance lipopolysaccharide-induced IL-8 expression by studying its actions on the TLR4-NF-κB pathway. The aggravating effect of κ-carrageenan on Citrobacter freundii DBS100-induced intestinal inflammation was also investigated in a mouse model. Results. Our data show that κ-carrageenan pretreatment promoted LPS-induced IL-8 expression in HT-29 cells. Although CD14, MD-2, and TLR4 were upregulated, the binding of LPS was not enhanced. However, the pathway of Bcl10-NF-κB was triggered. Interestingly, κ-carrageenan competitively blocked the binding of FITC-LPS. Furthermore, pretreatment with κ-carrageenan for one week previous to gavage with C. freundii DBS100 markedly aggravated weight loss, mortality, and colonic damage. The secretion of cytokines was unbalanced and the ratio of Tregs was decreased significantly. In addition, κ-carrageenan, together with C. freundii DBS100, enhanced the transcription and secretion of TLR4 and NF-κB. Conclusions. κ-Carrageenan can synergistically activate LPS-induced inflammatory through the Bcl10-NF-κB pathway, as indicated by its aggravation of C. freundii DBS100-induced colitis in mice. General Significance. Our results suggest that κ-carrageenan serves as a potential inflammatory agent that magnifies existing intestinal inflammation.

  14. Delivery of Human EV71 Receptors by Adeno-Associated Virus Increases EV71 Infection-Induced Local Inflammation in Adult Mice

    Directory of Open Access Journals (Sweden)

    Hung-Bo Hsiao

    2014-01-01

    Full Text Available Enterovirus71 (EV71 is now recognized as an emerging neurotropic virus in Asia and one major causative agent of hand-foot-mouth diseases (HFMD. However potential animal models for vaccine development are limited to young mice. In this study, we used an adeno-associated virus (AAV vector to introduce the human EV71 receptors P-selectin glycoprotein ligand-1 (hPSGL1 or a scavenger receptor class-B member-2 (hSCARB2 into adult ICR mice to change their susceptibility to EV71 infection. Mice were administered AAV-hSCARB2 or AAV-hPSGL1 through intravenous and oral routes. After three weeks, expression of human SCARB2 and PSGL1 was detected in various organs. After infection with EV71, we found that the EV71 viral load in AAV-hSCARB2- or AAV-hPSGL1-transduced mice was higher than that of the control mice in both the brain and intestines. The presence of EV71 viral particles in tissues was confirmed using immunohistochemistry analysis. Moreover, inflammatory cytokines were induced in the brain and intestines of AAV-hSCARB2- or AAV-hPSGL1-transduced mice after EV71 infection but not in wild-type mice. However, neurological disease was not observed in these animals. Taken together, we successfully infected adult mice with live EV71 and induced local inflammation using an AAV delivery system.

  15. Systemic N-terminal fragments of adrenocorticotropin reduce inflammation- and stress-induced anhedonia in rats.

    Science.gov (United States)

    Markov, Dmitrii D; Yatsenko, Ksenia A; Inozemtseva, Lyudmila S; Grivennikov, Igor A; Myasoedov, Nikolai F; Dolotov, Oleg V

    2017-08-01

    Emerging evidence implicates impaired self-regulation of the hypothalamic-pituitary-adrenal (HPA) axis and inflammation as important and closely related components of the pathophysiology of major depression. Antidepressants show anti-inflammatory effects and are suggested to enhance glucocorticoid feedback inhibition of the HPA axis. HPA axis activity is also negatively self-regulated by the adrenocorticotropic hormone (ACTH), a potent anti-inflammatory peptide activating five subtypes of melanocortin receptors (MCRs). There are indications that ACTH-mediated feedback can be activated by noncorticotropic N-terminal ACTH fragments such as a potent anti-inflammatory MC1/3/4/5R agonist α-melanocyte-stimulating hormone (α-MSH), corresponding to ACTH(1-13), and a MC3/5R agonist ACTH(4-10). We investigated whether intraperitoneal administration of rats with these peptides affects anhedonia, which is a core symptom of depression. Inflammation-related anhedonia was induced by a single intraperitoneal administration of a low dose (0.025mg/kg) of lipopolysaccharide (LPS). Stress-related anhedonia was induced by the chronic unpredictable stress (CUS) procedure. The sucrose preference test was used to detect anhedonia. We found that ACTH(4-10) pretreatment decreased LPS-induced increase in serum corticosterone and tumor necrosis factor (TNF)-α, and a MC3/4R antagonist SHU9119 blocked this effect. Both α-MSH and ACTH(4-10) alleviated LPS-induced anhedonia. In the CUS model, these peptides reduced anhedonia and normalized body weight gain. The data indicate that systemic α-MSH and ACTH(4-10) produce an antidepressant-like effect on anhedonia induced by stress or inflammation, the stimuli that trigger the release of ACTH and α-MSH into the bloodstream. The results suggest a counterbalancing role of circulating melanocortins in depression and point to a new approach for antidepressant treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Claudin-3 expression in radiation-exposed rat models: A potential marker for radiation-induced intestinal barrier failure

    Energy Technology Data Exchange (ETDEWEB)

    Shim, Sehwan; Lee, Jong-geol; Bae, Chang-hwan; Lee, Seung Bum [National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Jang, Won-Suk; Lee, Sun-Joo [Laboratory of Experimental Pathology, Korea Cancer Center Hospital, Seoul (Korea, Republic of); Lee, Seung-Sook [National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Department of Pathology, Korea Cancer Center Hospital, Seoul (Korea, Republic of); Park, Sunhoo, E-mail: sunhoo@kcch.re.kr [National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Department of Pathology, Korea Cancer Center Hospital, Seoul (Korea, Republic of)

    2015-01-02

    Highlights: • Irradiation increased intestinal bacterial translocation, accompanied by claudin protein expression in rats. • Neurotensin decreased the bacterial translocation and restored claudin-3 expression. • Claudin-3 can be used as a marker in evaluating radiation induced intestinal injury. - Abstract: The molecular events leading to radiation-induced intestinal barrier failure are not well known. The influence of the expression of claudin proteins in the presence and absence of neurotensin was investigated in radiation-exposed rat intestinal epithelium. Wistar rats were randomly divided into control, irradiation, and irradiation + neurotensin groups, and bacterial translocation to the mesenteric lymph node and expression of claudins were determined. Irradiation led to intestinal barrier failure as demonstrated by significant bacterial translocation. In irradiated terminal ilea, expression of claudin-3 and claudin-4 was significantly decreased, and claudin-2 expression was increased. Administration of neurotensin significantly reduced bacterial translocation and restored the structure of the villi as seen by histologic examination. Among the three subtype of claudins, only claudin-3 expression was restored. These results suggest that the therapeutic effect of neurotensin on the disruption of the intestinal barrier is associated with claudin-3 alteration and that claudin-3 could be used as a marker in evaluating radiation-induced intestinal injury.

  17. Aeromonas caviae strain induces Th1 cytokine response in mouse intestinal tract

    Energy Technology Data Exchange (ETDEWEB)

    Hayes, S L; Lye, D J; McKinstry, Craig A.; Vesper, Sephen J.

    2010-01-01

    Aeromonas caviae has been associated with human gastrointestinal disease. Strains of this species typically lack virulence factors (VFs) such as enterotoxins and hemolysins that are produced by other human pathogens of the Aeromonas genus. Microarray profiling of murine small intestinal extracts, 24 hours after oral infection with an A. caviae strain, provides evidence of a Th1 type immune response. A large number of gamma-interferon (γ-IFN) induced genes are up-regulated as well as several tumor necrosis factor-alpha (TNF-α) transcripts. A. caviae has always been considered as opportunistic pathogen because it lacks obvious virulence factors. This current effort suggests that an A. caviae strain can colonize the murine intestinal tract and cause what has been described by others as a dysregulatory cytokine response. This response could explain why a number of diarrheal waterborne disease cases have been attributed to A. caviae even though it lacks obvious enteropathogenic properties.

  18. Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

    Science.gov (United States)

    Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

    2013-08-01

    To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

  19. Enteric Virome Sensing-Its Role in Intestinal Homeostasis and Immunity.

    Science.gov (United States)

    Metzger, Rebecca N; Krug, Anne B; Eisenächer, Katharina

    2018-03-23

    Pattern recognition receptors (PRRs) sensing commensal microorganisms in the intestine induce tightly controlled tonic signaling in the intestinal mucosa, which is required to maintain intestinal barrier integrity and immune homeostasis. At the same time, PRR signaling pathways rapidly trigger the innate immune defense against invasive pathogens in the intestine. Intestinal epithelial cells and mononuclear phagocytes in the intestine and the gut-associated lymphoid tissues are critically involved in sensing components of the microbiome and regulating immune responses in the intestine to sustain immune tolerance against harmless antigens and to prevent inflammation. These processes have been mostly investigated in the context of the bacterial components of the microbiome so far. The impact of viruses residing in the intestine and the virus sensors, which are activated by these enteric viruses, on intestinal homeostasis and inflammation is just beginning to be unraveled. In this review, we will summarize recent findings indicating an important role of the enteric virome for intestinal homeostasis as well as pathology when the immune system fails to control the enteric virome. We will provide an overview of the virus sensors and signaling pathways, operative in the intestine and the mononuclear phagocyte subsets, which can sense viruses and shape the intestinal immune response. We will discuss how these might interact with resident enteric viruses directly or in context with the bacterial microbiome to affect intestinal homeostasis.

  20. Enteric Virome Sensing—Its Role in Intestinal Homeostasis and Immunity

    Directory of Open Access Journals (Sweden)

    Rebecca N. Metzger

    2018-03-01

    Full Text Available Pattern recognition receptors (PRRs sensing commensal microorganisms in the intestine induce tightly controlled tonic signaling in the intestinal mucosa, which is required to maintain intestinal barrier integrity and immune homeostasis. At the same time, PRR signaling pathways rapidly trigger the innate immune defense against invasive pathogens in the intestine. Intestinal epithelial cells and mononuclear phagocytes in the intestine and the gut-associated lymphoid tissues are critically involved in sensing components of the microbiome and regulating immune responses in the intestine to sustain immune tolerance against harmless antigens and to prevent inflammation. These processes have been mostly investigated in the context of the bacterial components of the microbiome so far. The impact of viruses residing in the intestine and the virus sensors, which are activated by these enteric viruses, on intestinal homeostasis and inflammation is just beginning to be unraveled. In this review, we will summarize recent findings indicating an important role of the enteric virome for intestinal homeostasis as well as pathology when the immune system fails to control the enteric virome. We will provide an overview of the virus sensors and signaling pathways, operative in the intestine and the mononuclear phagocyte subsets, which can sense viruses and shape the intestinal immune response. We will discuss how these might interact with resident enteric viruses directly or in context with the bacterial microbiome to affect intestinal homeostasis.

  1. Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice.

    Science.gov (United States)

    Wood, Tyler T; Winden, Duane R; Marlor, Derek R; Wright, Alex J; Jones, Cameron M; Chavarria, Michael; Rogers, Geraldine D; Reynolds, Paul R

    2014-11-15

    The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time. Copyright © 2014 the American Physiological Society.

  2. Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

    Science.gov (United States)

    Monin, Leticia; Griffiths, Kristin L.; Lam, Wing Y.; Gopal, Radha; Kang, Dongwan D.; Ahmed, Mushtaq; Rajamanickam, Anuradha; Cruz-Lagunas, Alfredo; Zúñiga, Joaquín; Babu, Subash; Kolls, Jay K.; Mitreva, Makedonka; Rosa, Bruce A.; Ramos-Payan, Rosalio; Morrison, Thomas E.; Murray, Peter J.; Rangel-Moreno, Javier; Pearce, Edward J.; Khader, Shabaana A.

    2015-01-01

    Parasitic helminth worms, such as Schistosoma mansoni, are endemic in regions with a high prevalence of tuberculosis (TB) among the population. Human studies suggest that helminth coinfections contribute to increased TB susceptibility and increased rates of TB reactivation. Prevailing models suggest that T helper type 2 (Th2) responses induced by helminth infection impair Th1 immune responses and thereby limit Mycobacterium tuberculosis (Mtb) control. Using a pulmonary mouse model of Mtb infection, we demonstrated that S. mansoni coinfection or immunization with S. mansoni egg antigens can reversibly impair Mtb-specific T cell responses without affecting macrophage-mediated Mtb control. Instead, S. mansoni infection resulted in accumulation of high arginase-1–expressing macrophages in the lung, which formed type 2 granulomas and exacerbated inflammation in Mtb-infected mice. Treatment of coinfected animals with an antihelminthic improved Mtb-specific Th1 responses and reduced disease severity. In a genetically diverse mouse population infected with Mtb, enhanced arginase-1 activity was associated with increased lung inflammation. Moreover, in patients with pulmonary TB, lung damage correlated with increased serum activity of arginase-1, which was elevated in TB patients coinfected with helminths. Together, our data indicate that helminth coinfection induces arginase-1–expressing type 2 granulomas, thereby increasing inflammation and TB disease severity. These results also provide insight into the mechanisms by which helminth coinfections drive increased susceptibility, disease progression, and severity in TB. PMID:26571397

  3. Effect of Gmelina arborea Roxb in experimentally induced inflammation and nociception

    Directory of Open Access Journals (Sweden)

    Yogesh A Kulkarni

    2013-01-01

    Full Text Available Background: Gmelina arborea Roxb (Verbenaceae, also known as "Gambhari", is an important medicinal plant in the Ayurveda. There are no meticulous scientific reports on effect of the plant on inflammation and pain. Objective: To study the anti-inflammatory and anti-nociceptive properties of aqueous extracts (AE and methanol extracts (ME of G. arborea. Materials and Methods: The AE and ME of stembark of G. arborea was prepared by cold maceration and Soxhlet extraction technique respectively. Anti-inflammatory activity was determined in Wistar albino rats in a model of acute plantar inflammation induced by carrageenan. The anti-nociceptive activity was evaluated by using hot plate test and writhing test in Swiss albino mice. Significant differences between the experimental groups were assessed by analysis of variance. Results: AE and ME at dose of 500 mg/kg showed maximum inhibition in carrageenan induced inflammation up to 30.15 and 31.21% respectively. In hot plate test, the AE and ME showed the maximum response of 8.8 ± 0.97 (P < 0.01 and 8.2 ± 1.24 (P < 0.01 respectively at dose of 500 mg/kg when compared with control. AE showed maximum inhibition of writhing response (84.3% as compared to ME (77.9% in writhing test at a dose of 500 mg/kg. Conclusion: The findings suggested that G. arborea possess significant anti-inflammatory and anti-nociceptive activities.

  4. Traditional Herbal Medicine, Rikkunshito, Induces HSP60 and Enhances Cytoprotection of Small Intestinal Mucosal Cells as a Nontoxic Chaperone Inducer

    Directory of Open Access Journals (Sweden)

    Kumiko Tamaki

    2012-01-01

    Full Text Available Increasing incidence of small intestinal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs has become a topic with recent advances of endoscopic technology. However, the pathogenesis and therapy are not fully understood. The aim of this study is to examine the effect of Rikkunshito (TJ-43, a traditional herbal medicine, on expression of HSP60 and cytoprotective ability in small intestinal cell line (IEC-6. Effect of TJ-43 on HSP60 expression in IEC-6 cells was evaluated by immunoblot analysis. The effect of TJ-43 on cytoprotective abilities of IEC-6 cells against hydrogen peroxide or indomethacin was studied by MTT assay, LDH-release assay, caspase-8 activity, and TUNEL. HSP60 was significantly induced by TJ-43. Cell necrosis and apoptosis were significantly suppressed in IEC-6 cells pretreated by TJ-43 with overexpression of HSP60. Our results suggested that HSP60 induced by TJ-43 might play an important role in protecting small intestinal epithelial cells from apoptosis and necrosis in vitro.

  5. Attenuation of Oxidative Stress and Inflammation by Portulaca oleracea in Streptozotocin-Induced Diabetic Rats.

    Science.gov (United States)

    Samarghandian, Saeed; Borji, Abasalt; Farkhondeh, Tahereh

    2017-10-01

    The present study was designed to investigate the protective effect of the aqueous extract of Portulaca oleracea against hyperglycemic, oxidative damage and inflammation in the serum of streptozotocin (STZ)-induced diabetic rats. In the present study, the rats were divided into the following groups of 8 animals each: control, untreated diabetic, 3 Portulaca oleracea (100, 200, 400 mg/kg/d)-treated diabetic groups. At the end of the 4-week period, glucose, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), glutathione (GSH), and total antioxidant status (TAS) levels were measured. STZ caused an elevation in the serum levels of glucose, MDA, IL-6, and TNF-α with reduction in the levels of GSH and TAS ( P Portulaca oleracea ameliorated glucose, MDA, IL-6, TNF-α, GSH, and TAS levels in diabetic groups versus to the untreated groups ( P Portulaca oleracea prevented hyperglycemia by preventing the oxidative stress and inflammation.

  6. Role of leukotrienes in NSAID induced gastric ulceration and inflammation in wistar rats

    Directory of Open Access Journals (Sweden)

    Maulik N Gandhi

    2012-06-01

    Full Text Available Objective: To evaluate the effects of Montelukast and Curcumin against indomethacin induced gastric damage in rats in order to assess the role of leukotriene (LTs if any, in non steroidal antiinflammatory drug (NSAID induced gastroinflammation. Methods: The effects of Montelukast (10 mg/kg and Curcumin (100 mg/kg were observed on gastric lesion induced by Indomethacin. The blood samples were analyzed for neutrophil adhesion and lipid peroxide levels in gastric tissue measured spectrophotometrically. The skin vascular permeability study was performed by using compound 48/80 induced vascular permeability model. Results: Montelukast and Curcumin significantly reduced Indomethacin induced gastric lesion score. Pretreatment with Montelukast and Curcumin significantly counteracted Indomethacin induced gastropathy by a combination of its effect on inhibition of neutrophil adherence, through decrease in related production of free radicals that disrupts integrity of stomach mucosa and decrease in vascular permeability as compared to Indomethacin group. The results of the present study further indicates the role of 5-LOX metabolites in NSAIDs induced gastro inflammation and suggests that Montelukast and Curcumin counteracted the Indomethacin induced gastropathy by a combination of its effect on inhibition of neutrophil adherence and through decrease in related production of free radicals that disrupts integrity of stomach mucosa. Conclusions: Experimental data clearly demonstrated the role of LTs was indomethacin induced gastric ulcers. However, inhibition of ulcerogenic events by Montelukast and Curcumin is suggestive of an important balance between COX and 5-LOX products.

  7. Murine P-glycoprotein deficiency alters intestinal injury repair and blunts lipopolysaccharide-induced radioprotection.

    Science.gov (United States)

    Staley, Elizabeth M; Yarbrough, Vanisha R; Schoeb, Trenton R; Daft, Joseph G; Tanner, Scott M; Steverson, Dennis; Lorenz, Robin G

    2012-09-01

    P-glycoprotein (P-gp) has been reported to increase stem cell proliferation and regulate apoptosis. Absence of P-gp results in decreased repair of intestinal epithelial cells after chemical injury. To further explore the mechanisms involved in the effects of P-gp on intestinal injury and repair, we used the well-characterized radiation injury model. In this model, injury repair is mediated by production of prostaglandins (PGE(2)) and lipopolysaccharide (LPS) has been shown to confer radioprotection. B6.mdr1a(-/-) mice and wild-type controls were subjected to 12 Gy total body X-ray irradiation and surviving crypts in the proximal jejunum and distal colon were evaluated 3.5 days after irradiation. B6.mdr1a(-/-) mice exhibited normal baseline stem cell proliferation and COX dependent crypt regeneration after irradiation. However, radiation induced apoptosis was increased and LPS-induced radioprotection was blunted in the C57BL6.mdr1a(-/-) distal colon, compared to B6 wild-type controls. The LPS treatment induced gene expression of the radioprotective cytokine IL-1α, in B6 wild-type controls but not in B6.mdr1a(-/-) animals. Lipopolysaccharid-induced radioprotection was absent in IL-1R1(-/-) animals, indicating a role for IL-1α in radioprotection, and demonstrating that P-gp deficiency interferes with IL-1α gene expression in response to systemic exposure to LPS.

  8. Bovine lactoferrin decreases cholera-toxin-induced intestinal fluid accumulation in mice by ganglioside interaction.

    Directory of Open Access Journals (Sweden)

    Fulton P Rivera

    Full Text Available Secretory diarrhea caused by cholera toxin (CT is initiated by binding of CT's B subunit (CTB to GM1-ganglioside on the surface of intestinal cells. Lactoferrin, a breast milk glycoprotein, has shown protective effect against several enteropathogens. The aims of this study were to determine the effect of bovine-lactoferrin (bLF on CT-induced intestinal fluid accumulation in mice, and the interaction between bLF and CT/CTB with the GM1-ganglioside receptor. Fluid accumulation induced by CT was evaluated in the mouse ileal loop model using 56 BALB/c mice, with and without bLF added before, after or at the same time of CT administration. The effect of bLF in the interaction of CT and CTB with GM1-ganglioside was evaluated by a GM1-enzyme-linked immunosorbent assay. bLF decreased CT-induced fluid accumulation in the ileal loop of mice. The greatest effect was when bLF was added before CT (median, 0.066 vs. 0.166 g/cm, with and without bLF respectively, p<0.01. We conclude that bLF decreases binding of CT and CTB to GM1-ganglioside, suggesting that bLF suppresses CT-induced fluid accumulation by blocking the binding of CTB to GM1-ganglioside. bLF may be effective as adjunctive therapy for treatment of cholera diarrhea.

  9. A Comparative Uptake Study of Multiplexed PET Tracers in Mice with Turpentine-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Tingting Huang

    2012-11-01

    Full Text Available The potential value of multiplexed positron emission tomography (PET tracers in mice with turpentine-induced inflammation was evaluated and compared with 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG for glucose metabolism imaging. These PET tracers included [18F]fluoromethylcholine ([18F]FCH for choline metabolism imaging, (S-[11C]methyl-D-cysteine ([11C]DMCYS for amino acid metabolism imaging, [11C]bis(zinc(II-dipicolylamine ([11C]DPA-Zn2+ for apoptosis imaging, 2-(4-N-[11C]-methylaminophenyl-6-hydroxybenzothiazole ([11C]PIB for β amyloid binding imaging, and [18F]fluoride (18F− for bone metabolism imaging. In mice with turpentine-induced inflammation mice, the biodistribution of all the tracers mentioned above at 5, 15, 30, 45, and 60 min postinjection was determined. Also, the time-course curves of the tracer uptake ratios for inflammatory thigh muscle (IM to normal uninflammatory thigh muscle (NM, IM to blood (BL, IM to brain (BR, and IM to liver (LI were acquired, respectively. Moreover, PET imaging with the tracers within 60 min postinjection on a clinical PET/CT scanner was also conducted. [18F]FDG and 18F− showed relatively higher uptake ratios for IM to NM, IM to BL, IM to BR, and IM to LI than [18F]FCH, [11C]DPA-Zn2+, [11C]DMCYS and [11C]PIB, which were highly consistent with the results delineated in PET images. The results demonstrate that 18F− seems to be a potential PET tracer for inflammation imaging. [18F]FCH and [11C]DMCYS, with lower accumulation in inflammatory tissue than [18F]FDG, are not good PET tracers for inflammation imaging. As a promising inflammatory tracer, the chemical structure of [11C]DPA-Zn2+ needs to be further optimized.

  10. Time course of polyhexamethyleneguanidine phosphate-induced lung inflammation and fibrosis in mice.

    Science.gov (United States)

    Song, Jeongah; Kim, Woojin; Kim, Yong-Bum; Kim, Bumseok; Lee, Kyuhong

    2018-04-15

    Pulmonary fibrosis is a chronic progressive disease with unknown etiology and has poor prognosis. Polyhexamethyleneguanidine phosphate (PHMG-P) causes acute interstitial pneumonia and pulmonary fibrosis in humans when it exposed to the lung. In a previous study, when rats were exposed to PHMG-P through inhalation for 3 weeks, lung inflammation and fibrosis was observed even after 3 weeks of recovery. In this study, we aimed to determine the time course of PHMG-P-induced lung inflammation and fibrosis. We compared pathological action of PHMG-P with that of bleomycin (BLM) and investigated the mechanism underlying PHMG-P-induced lung inflammation and fibrosis. PHMG-P (0.9 mg/kg) or BLM (1.5 mg/kg) was intratracheally administered to mice. At weeks 1, 2, 4 and 10 after instillation, the levels of inflammatory and fibrotic markers and the expression of inflammasome proteins were measured. The inflammatory and fibrotic responses were upregulated until 10 and 4 weeks in the PHMG-P and BLM groups, respectively. Immune cell infiltration and considerable collagen deposition in the peribronchiolar and interstitial areas of the lungs, fibroblast proliferation, and hyperplasia of type II epithelial cells were observed. NALP3 inflammasome activation was detected in the PHMG-P group until 4 weeks, which is suspected to be the main reason for the persistent inflammatory response and exacerbation of fibrotic changes. Most importantly, the pathological changes in the PHMG-P group were similar to those observed in humidifier disinfectant-associated patients. A single exposure of PHMG-P led to persistent pulmonary inflammation and fibrosis for at least 10 weeks. Copyright © 2018. Published by Elsevier Inc.

  11. Haemophilus influenzae from Patients with Chronic Obstructive Pulmonary Disease Exacerbation Induce More Inflammation than Colonizers

    Science.gov (United States)

    Chin, Cecilia L.; Manzel, Lori J.; Lehman, Erin E.; Humlicek, Alicia L.; Shi, Lei; Starner, Timothy D.; Denning, Gerene M.; Murphy, Timothy F.; Sethi, Sanjay; Look, Dwight C.

    2005-01-01

    Rationale: Airway infection with Haemophilus influenzae causes airway inflammation, and isolation of new strains of this bacteria is associated with increased risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine whether strains of H. influenzae associated with exacerbations cause more inflammation than strains that colonize the airways of patients with COPD. Methods: Exacerbation strains of H. influenzae were isolated from patients during exacerbation of clinical symptoms with subsequent development of a homologous serum antibody response and were compared with colonization strains that were not associated with symptom worsening or an antibody response. Bacterial strains were compared using an in vivo mouse model of airway infection and in vitro cell culture model of bacterial adherence and defense gene and signaling pathway activation in primary human airway epithelial cells. Results: H. influenzae associated with exacerbations caused more airway neutrophil recruitment compared with colonization strains in the mouse model of airway bacterial infection. Furthermore, exacerbation strains adhered to epithelial cells in significantly higher numbers and induced more interleukin-8 release after interaction with airway epithelial cells. This effect was likely mediated by increased activation of the nuclear factor-κB and p38 mitogen-activated protein kinase signaling pathways. Conclusions: The results indicate that H. influenzae strains isolated from patients during COPD exacerbations often induce more airway inflammation and likely have differences in virulence compared with colonizing strains. These findings support the concept that bacteria infecting the airway during COPD exacerbations mediate increased airway inflammation and contribute to decreased airway function. PMID:15805181

  12. Asthma causes inflammation of human pulmonary arteries and decreases vasodilatation induced by prostaglandin I2 analogs.

    Science.gov (United States)

    Foudi, Nabil; Badi, Aouatef; Amrane, Mounira; Hodroj, Wassim

    2017-12-01

    Asthma is a chronic inflammatory disease associated with increased cardiovascular events. This study assesses the presence of inflammation and the vascular reactivity of pulmonary arteries in patients with acute asthma. Rings of human pulmonary arteries obtained from non-asthmatic and asthmatic patients were set up in organ bath for vascular tone monitoring. Reactivity was induced by vasoconstrictor and vasodilator agents. Protein expression of inflammatory markers was detected by western blot. Prostanoid releases and cyclic adenosine monophosphate (cAMP) levels were quantified using specific enzymatic kits. Protein expression of cluster of differentiation 68, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and cyclooxygenase-2 was significantly increased in arteries obtained from asthmatic patients. These effects were accompanied by an alteration of vasodilatation induced by iloprost and treprostinil, a decrease in cAMP levels and an increase in prostaglandin (PG) E 2 and PGI 2 synthesis. The use of forskolin (50 µmol/L) has restored the vasodilatation and cAMP release. No difference was observed between the two groups in reactivity induced by norepinephrine, angiotensin II, PGE 2 , KCl, sodium nitroprusside, and acetylcholine. Acute asthma causes inflammation of pulmonary arteries and decreases vasodilation induced by PGI 2 analogs through the impairment of cAMP pathway.

  13. Involvement of prostaglandins and histamine in nickel wire-induced acute inflammation in mice.

    Science.gov (United States)

    Hirasawa, Noriyasu; Goi, Yoshiaki; Tanaka, Rina; Ishihara, Kenji; Ohtsu, Hiroshi; Ohuchi, Kazuo

    2010-06-15

    The irritancy of Nickel (Ni) ions has been well documented clinically. However, the chemical mediators involved in the acute inflammation induced by solid Ni are not fully understood. We used the Ni wire-implantation model in mice and examined roles of prostaglandins and histamine in plasma leakage in the acute phase. The subcutaneous implantation of a Ni wire into the back of mice induced plasma leakage from 8 to 24 h and tissue necrosis around the wire at 3 days, whereas the implantation of an aluminum wire induced no such inflammatory responses. An increase in the mRNA for cyclooxygenase (COX)-2 and HDC in cells around the Ni wire was detected 4 h after the implantation. The leakage of plasma at 8 h was inhibited by indomethacin in a dose-dependent manner. Dexamethasone and the p38 MAP kinase inhibitor SB203580 also inhibited the exudation of plasma consistent with the inhibition of the expression of COX-2 mRNA. Furthermore, plasma leakage was partially but siginificantly reduced in histamine H1 receptor knockout mice and histidine decarboxylase (HDC) knockout mice but not in H2 receptor knockout mice. These results suggested that the Ni ions released from the wire induced the expression of COX-2 and HDC, resulting in an increase in vascular permeability during the acute phase of inflammation. (c) 2009 Wiley Periodicals, Inc.

  14. Adiponectin protects palmitic acid induced endothelial inflammation and insulin resistance via regulating ROS/IKKβ pathways.

    Science.gov (United States)

    Zhao, Wenwen; Wu, Chuanhong; Li, Shaojing; Chen, Xiuping

    2016-12-01

    Endothelial inflammation and insulin resistance (IR) has been closely associated with endothelial dysfunction. Adiponectin (APN), an adipocyte-secreted hormone from adipose tissues, showed cardioprotective effects. Here, the protective effect of APN on palmitic acid (PA)-induced endothelial inflammation and IR was investigated. Cultured human umbilical vein endothelial cells (HUVECs) were treated with PA without or without APN pretreatment. The expression of inflammatory cytokines TNF-α, IL-6, adhesion molecule ICAM-1 were determined by western blotting, ELISA, and real-time PCR. The protein expression and protein-protein interaction were determined by western blotting and immunoprecipitation. The intracellular reactive oxygen species (ROS) and nitric oxide (NO) production were monitored with fluorescence probes. PA-induced secretion of TNF-α, IL-6, and expression of ICAM-1 at protein and mRNA levels, which was significantly inhibited by APN. PA treatment caused increase of ROS generation, NOX2, p-IKKβ, p-IκBα, p-p65 expression, and p-IκBα-IKKβ interaction, which were all partly reversed by APN. ROS scavenger N-acetylcysteine (NAC) and NF-κB inhibitor PDTC showed similar effect on PA-induced secretion of TNF-α, IL-6, and expression of ICAM-1. Furthermore, APN and NAC pretreatment restored PA-induced increase of p-IRS-1(S307), decrease of p-IRS-1(Tyr). In addition, insulin-triggered expression of p-IRS-1(Tyr), p-PI3K, p-AKT, p-eNOS and NO generation were inhibited by PA, which were also restored by both APN and NAC. These results suggested that APN ameliorated endothelial inflammation and IR through ROS/IKKβ pathway. This study shed new insights into the mechanisms of APN's cardiovascular protective effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Transcriptional corepressor MTG16 regulates small intestinal crypt proliferation and crypt regeneration after radiation-induced injury.

    Science.gov (United States)

    Poindexter, Shenika V; Reddy, Vishruth K; Mittal, Mukul K; Williams, Amanda M; Washington, M Kay; Harris, Elizabeth; Mah, Amanda; Hiebert, Scott W; Singh, Kshipra; Chaturvedi, Rupesh; Wilson, Keith T; Lund, P Kay; Williams, Christopher S

    2015-03-15

    Myeloid translocation genes (MTGs) are transcriptional corepressors implicated in development, malignancy, differentiation, and stem cell function. While MTG16 loss renders mice sensitive to chemical colitis, the role of MTG16 in the small intestine is unknown. Histological examination revealed that Mtg16(-/-) mice have increased enterocyte proliferation and goblet cell deficiency. After exposure to radiation, Mtg16(-/-) mice exhibited increased crypt viability and decreased apoptosis compared with wild-type (WT) mice. Flow cytometric and immunofluorescence analysis of intestinal epithelial cells for phospho-histone H2A.X also indicated decreased DNA damage and apoptosis in Mtg16(-/-) intestines. To determine if Mtg16 deletion affected epithelial cells in a cell-autonomous fashion, intestinal crypts were isolated from Mtg16(-/-) mice. Mtg16(-/-) and WT intestinal crypts showed similar enterosphere forming efficiencies when cultured in the presence of EGF, Noggin, and R-spondin. However, when Mtg16(-/-) crypts were cultured in the presence of Wnt3a, they demonstrated higher enterosphere forming efficiencies and delayed progression to mature enteroids. Mtg16(-/-) intestinal crypts isolated from irradiated mice exhibited increased survival compared with WT intestinal crypts. Interestingly, Mtg16 expression was reduced in a stem cell-enriched population at the time of crypt regeneration. This is consistent with MTG16 negatively regulating regeneration in vivo. Taken together, our data demonstrate that MTG16 loss promotes radioresistance and impacts intestinal stem cell function, possibly due to shifting cellular response away from DNA damage-induced apoptosis and towards DNA repair after injury.

  16. Effects of Saccharomyces cerevisiae or boulardii yeasts on acute stress induced intestinal dysmotility.

    Science.gov (United States)

    West, Christine; Stanisz, Andrew M; Wong, Annette; Kunze, Wolfgang A

    2016-12-28

    To investigate the capacity of Saccharomyces cerevisiae ( S. cerevisiae ) and Saccharomyces boulardii ( S. boulardii ) yeasts to reverse or to treat acute stress-related intestinal dysmotility. Adult Swiss Webster mice were stressed for 1 h in a wire-mesh restraint to induce symptoms of intestinal dysmotility and were subsequently killed by cervical dislocation. Jejunal and colon tissue were excised and placed within a tissue perfusion bath in which S. cerevisiae , S. boulardii , or their supernatants were administered into the lumen. Video recordings of contractility and gut diameter changes were converted to spatiotemporal maps and the velocity, frequency, and amplitude of propagating contractile clusters (PCC) were measured. Motility pre- and post-treatment was compared between stressed animals and unstressed controls. S. boulardii and S. cerevisiae helped to mediate the effects of stress on the small and large intestine. Restraint stress reduced jejunal transit velocity (mm/s) from 2.635 ± 0.316 to 1.644 ± 0.238, P boulardii helped to restore jejunal and colonic velocity towards the unstressed controls; 1.833 ± 0.688 to 2.627 ± 0.664, P boulardii or S. cerevisiae supernatants also helped to restore motility to unstressed values in similar capacity. There is a potential therapeutic role for S. cerevisiae and S. boulardii yeasts and their supernatants in the treatment of acute stress-related gut dysmotility.

  17. Diet-Induced Dysbiosis of the Intestinal Microbiota and the Effects on Immunity and Disease

    Directory of Open Access Journals (Sweden)

    Deanna L. Gibson

    2012-08-01

    Full Text Available The gastrointestinal (GI microbiota is the collection of microbes which reside in the GI tract and represents the largest source of non-self antigens in the human body. The GI tract functions as a major immunological organ as it must maintain tolerance to commensal and dietary antigens while remaining responsive to pathogenic stimuli. If this balance is disrupted, inappropriate inflammatory processes can result, leading to host cell damage and/or autoimmunity. Evidence suggests that the composition of the intestinal microbiota can influence susceptibility to chronic disease of the intestinal tract including ulcerative colitis, Crohn’s disease, celiac disease and irritable bowel syndrome, as well as more systemic diseases such as obesity, type 1 diabetes and type 2 diabetes. Interestingly, a considerable shift in diet has coincided with increased incidence of many of these inflammatory diseases. It was originally believed that the composition of the intestinal microbiota was relatively stable from early childhood; however, recent evidence suggests that diet can cause dysbiosis, an alteration in the composition of the microbiota, which could lead to aberrant immune responses. The role of the microbiota and the potential for diet-induced dysbiosis in inflammatory conditions of the GI tract and systemic diseases will be discussed.

  18. Combined compared to dissociated oral and intestinal sucrose stimuli induce different brain hedonic processes

    Directory of Open Access Journals (Sweden)

    Caroline eClouard

    2014-08-01

    Full Text Available The characterization of brain networks contributing to the processing of oral and/or intestinal sugar signals in a relevant animal model might help to understand the neural mechanisms related to the control of food intake in humans and suggest potential causes for impaired eating behaviors. This study aimed at comparing the brain responses triggered by oral and/or intestinal sucrose sensing in pigs. Seven animals underwent brain single photon emission computed tomography (99mTc-HMPAO further to oral stimulation with neutral or sucrose artificial saliva paired with saline or sucrose infusion in the duodenum, the proximal part of the intestine. Oral and/or duodenal sucrose sensing induced differential cerebral blood flow (CBF changes in brain regions known to be involved in memory, reward processes and hedonic (i.e. pleasure evaluation of sensory stimuli, including the dorsal striatum, prefrontal cortex, cingulate cortex, insular cortex, hippocampus and parahippocampal cortex. Sucrose duodenal infusion only and combined sucrose stimulation induced similar activity patterns in the putamen, ventral anterior cingulate cortex and hippocampus. Some brain deactivations in the prefrontal and insular cortices were only detected in the presence of oral sucrose stimulation. Finally, activation of the right insular cortex was only induced by combined oral and duodenal sucrose stimulation, while specific activity patterns were detected in the hippocampus and parahippocampal cortex with oral sucrose dissociated from caloric load. This study sheds new light on the brain hedonic responses to sugar and has potential implications to unravel the neuropsychological mechanisms underlying food pleasure and motivation.

  19. Aerobic training suppresses exercise-induced lipid peroxidation and inflammation in overweight/obese adolescent girls.

    Science.gov (United States)

    Youssef, Hala; Groussard, Carole; Lemoine-Morel, Sophie; Pincemail, Joel; Jacob, Christophe; Moussa, Elie; Fazah, Abdallah; Cillard, Josiane; Pineau, Jean-Claude; Delamarche, Arlette

    2015-02-01

    This study aimed to determine whether aerobic training could reduce lipid peroxidation and inflammation at rest and after maximal exhaustive exercise in overweight/obese adolescent girls. Thirty-nine adolescent girls (14-19 years old) were classified as nonobese or overweight/obese and then randomly assigned to either the nontrained or trained group (12-week multivariate aerobic training program). Measurements at the beginning of the experiment and at 3 months consisted of body composition, aerobic fitness (VO2peak) and the following blood assays: pre- and postexercise lipid peroxidation (15F2a-isoprostanes [F2-Isop], lipid hydroperoxide [ROOH], oxidized LDL [ox-LDL]) and inflammation (myeloperoxidase [MPO]) markers. In the overweight/ obese group, the training program significantly increased their fat-free mass (FFM) and decreased their percentage of fat mass (%FM) and hip circumference but did not modify their VO2peak. Conversely, in the nontrained overweight/obese group, weight and %FM increased, and VO2peak decreased, during the same period. Training also prevented exercise-induced lipid peroxidation and/or inflammation in overweight/obese girls (F2-Isop, ROOH, ox-LDL, MPO). In addition, in the trained overweight/obese group, exercise-induced changes in ROOH, ox-LDL and F2-Isop were correlated with improvements in anthropometric parameters (waist-to-hip ratio, %FM and FFM). In conclusion aerobic training increased tolerance to exercise-induced oxidative stress in overweight/obese adolescent girls partly as a result of improved body composition.

  20. Anti-inflammation effects of corn silk in a rat model of carrageenin-induced pleurisy.

    Science.gov (United States)

    Wang, Guang-Qiang; Xu, Tao; Bu, Xue-Mei; Liu, Bao-Yi

    2012-06-01

    Pleurisy is an inflammation of the pleural layers that surround the lungs. Despite much research into inflammatory diseases, no drugs with favorable safety profiles are available yet for their treatment. Corn silk has been used in many parts of the world for the treatment of edema, cystitis, gout, kidney stones nephritis, and prostitutes. However, no scientific reports on the anti-inflammatory effects of corn silk were so far available. To test the anti-inflammatory efficacy of corn silk extract (CSEX) in a rat model of carrageenin (Cg)-induced pleurisy, exudate formation, and cellular infiltration, tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), vascular endothelial growth factor alpha (VEGF-α), interleukin-17 (IL-17), C3 and C4 complement protein levels, adhesion molecule (ICAM-1) and inducible nitric oxide synthase (iNOS) levels, nuclear factor kappa B (NF-κB) activation, and total antioxidant activity were studied, respectively. Pretreatment with CSEX reduced Cg-induced pleurisy exudate, number of leukocytes, oxidative stress, C3 protein level, and O (2)(-) levels at the inflammatory site. Pretreatment with CSEX also inhibited TNF-α, IL-1β, VEGF-α, and IL-17A and blocked inflammation-related events (ICAM-1 and iNOS) by activation of NF-κB. Supplementation with CSEX may be a promising treatment for inflammatory diseases that involve oxidative stress.

  1. Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

    Science.gov (United States)

    Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

    2008-12-01

    Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

  2. Autophagy Facilitates IFN-γ-induced Jak2-STAT1 Activation and Cellular Inflammation*

    Science.gov (United States)

    Chang, Yu-Ping; Tsai, Cheng-Chieh; Huang, Wei-Ching; Wang, Chi-Yun; Chen, Chia-Ling; Lin, Yee-Shin; Kai, Jui-In; Hsieh, Chia-Yuan; Cheng, Yi-Lin; Choi, Pui-Ching; Chen, Shun-Hua; Chang, Shih-Ping; Liu, Hsiao-Sheng; Lin, Chiou-Feng

    2010-01-01

    Autophagy is regulated for IFN-γ-mediated antimicrobial efficacy; however, its molecular effects for IFN-γ signaling are largely unknown. Here, we show that autophagy facilitates IFN-γ-activated Jak2-STAT1. IFN-γ induces autophagy in wild-type but not in autophagy protein 5 (Atg5−/−)-deficient mouse embryonic fibroblasts (MEFs), and, autophagy-dependently, IFN-γ induces IFN regulatory factor 1 and cellular inflammatory responses. Pharmacologically inhibiting autophagy using 3-methyladenine, a known inhibitor of class III phosphatidylinositol 3-kinase, confirms these effects. Either Atg5−/− or Atg7−/− MEFs are, independent of changes in IFN-γ receptor expression, resistant to IFN-γ-activated Jak2-STAT1, which suggests that autophagy is important for IFN-γ signal transduction. Lentivirus-based short hairpin RNA for Atg5 knockdown confirmed the importance of autophagy for IFN-γ-activated STAT1. Without autophagy, reactive oxygen species increase and cause SHP2 (Src homology-2 domain-containing phosphatase 2)-regulated STAT1 inactivation. Inhibiting SHP2 reversed both cellular inflammation and the IFN-γ-induced activation of STAT1 in Atg5−/− MEFs. Our study provides evidence that there is a link between autophagy and both IFN-γ signaling and cellular inflammation and that autophagy, because it inhibits the expression of reactive oxygen species and SHP2, is pivotal for Jak2-STAT1 activation. PMID:20592027

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

    Science.gov (United States)

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

    2017-08-09

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

  4. The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

    Directory of Open Access Journals (Sweden)

    Abdulaleem Alnajar

    Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

  5. Inducible nitric oxide expression correlates with the level of inflammation in periapical cysts.

    Science.gov (United States)

    Matsumoto, Mariza Akemi; Ribeiro, Daniel Araki

    2007-10-01

    In an attempt to elucidate if inducible nitric oxide expression (iNOS) is correlated with the level of inflammation in periapical cysts with accuracy, the goal of this study was to evaluate the expression of iNOS in these ones. 30 cases were included in this study being iNOS evaluated by means of immunohistochemistry. Statistical analysis was performed by Kruskal-Wallis non-parametric test followed by the post-hoc Dunn's test. iNOS stain was detected throughout the epithelium, subepithelial fibroblasts and macrophages in all cases, indistinctly. Nevertheless, iNOS immunostaining in periapical cysts was different according to the levels of inflammation, being the strongest effect associated with intense inflammatory infiltrate. Taken together, our results indicate that immunoreactivity of iNOS was expressed in several cellular types present in periapical cyst, being positively correlated with the level of inflammation. Therefore, iNOS expression plays an important role in the pathogenesis of periapical cysts.

  6. HDL inhibit cytokine production in a mouse model of urate crystal-induced inflammation

    OpenAIRE

    L. Punzi; D. Burger; J.M Dayer; P. Sfriso; R. Luisetto; F. Oliviero; A. Scanu

    2011-01-01

    Objectives: To evaluate whether high density lipoproteins (HDL) affect monosodium urate (MSU) crystal-induced inflammation in the murine air pouch model. Methods: MSU crystals were prepared by Denko’s method and sterilized by heating at 180°C for 2 h before each experiment. Human HDL were isolated from peripheral blood of healthy volunteers. MSU crystals (2 mg in 1 ml of PBS) were injected into subcutaneous air pouches in mice in the presence or absence of HDL (0.1 mg). Negative control pouch...

  7. Protection against LPS-induced cartilage inflammation and degradation provided by a biological extract of Mentha spicata

    Directory of Open Access Journals (Sweden)

    Kott Laima S

    2010-05-01

    <