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PubMed2000

Iron supplementation affects the production of pro-inflammatory cytokines in IL-10 deficient mice.

BACKGROUND: Iron supplements may increase disease activity in inflammatory bowel disease through the production of the hydroxyl radical because of its catalytic activity in the Fenton reaction. The purpose of this study was to assess the effect of dietary and locally administered iron in the IL-10 knock-out (-/-) mouse, a model of chronic inflammatory bowel disease. MATERIALS AND METHODS: IL10-/- and wild-type mice received a standard or a high-iron diet (35 mg kg(-1) ferrosulphate vs. 500 mg kg(-1) ferrosulphate) after weaning. After 4 weeks the mice were sacrificed. Furthermore, a group of adult IL-10 knock-out mice was given three iron-containing enema's (0.2 mL of 1 mM ferrous-ammonium sulphate) or phosphate buffered saline. These mice were sacrificed after 1 week. Production of pro-inflammatory cytokines by colon tissue cultures, haematological parameters and histology was determined to assess inflammatory activity. RESULTS: Oral as well as rectal administration of iron resulted in increased pro-inflammatory cytokine production in IL-10-/- mice. Neutrophil counts in IL10-/- on a high iron diet increased as well. No enhanced colonic inflammation was noted on histology after iron supplementation. CONCLUSION: We conclude that dietary or topical administered iron increases pro-inflammatory cytokine production in the colon of IL10-/- mice. No significant increase of histological intestinal inflammation was observed.

Animals↗
PubMed2004

Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease.

BACKGROUND & AIMS: To investigate the role of inducible costimulator (ICOS), a new member of the CD28 family involved in regulation of T-cell activation and chronic intestinal inflammation, we assessed its expression and functional role in patients with inflammatory bowel disease (IBD). METHODS: Expression of ICOS, CD28, and cytotoxic T-lymphocyte antigen (CTLA) 4 on intestinal lamina propria mononuclear cells (LPMC) from patients with ulcerative colitis (UC), Crohn's disease (CD), and normal controls was determined using flow cytometry and immunohistochemistry. Expressions of the ICOS ligand, B7h, on lamina propria B cells, macrophages, and epithelial cells (EC) in the intestinal mucosa were also determined using flow cytometry. The functional costimulatory effect of ICOS on LPMC was assessed by the proliferative response and cytokine production. RESULTS: CD4(+) LPMC expressing ICOS was significantly increased in the inflamed mucosa of IBD patients but not in inflammatory or normal controls. B7h was also significantly up-regulated on B cells, macrophages, and EC in inflamed mucosa of IBD patients. Proliferative responses of anti-CD3/ICOS costimulation were significantly higher compared with those of anti-CD3 monoclonal antibody (mAb) alone. Anti-CD3/ICOS-stimulated-LPMC from UC secreted significantly increased amounts of interleukin (IL)-5 among the 3 groups. In contrast, anti-CD3/ICOS-stimulated-LPMC from CD secreted significantly increased amounts of interferon (IFN)-gamma in the presence of IL-12. CONCLUSIONS: Highly expressed ICOS in activated CD4(+) LPMC of IBD patients contributes to the dysregulated immune responses in IBD. Because ICOS hyperexpression was limited to inflammatory sites in IBD patients, ICOS would be a feasible therapeutic target for the treatment of IBD.

Antibodies, Monoclonal↗
PubMed2004

Lactic acid bacteria secrete metabolites retaining anti-inflammatory properties after intestinal transport.

BACKGROUND: Probiotic bacteria have a beneficial effect on intestinal inflammation. In this study, we have examined the effect of lactic acid and commensal Gram positive (+) bacteria conditioned media (CM) on tumour necrosis factor alpha (TNF-alpha) release and the mechanisms involved. METHODS: Lipopolysaccharide (LPS) induced TNF-alpha secretion by peripheral blood mononuclear cells or the THP-1 cell line was monitored in the presence or absence of bacteria CM obtained from two probiotic strains, Bifidobacterium breve (Bb) and Streptococcus thermophilus (St), and three commensal bacterial strains (Bifidobacterium bifidum, Ruminococcus gnavus, and unidentified Streptococcus). Bb and St bacteria CM were allowed to cross filter grown intestinal epithelial cell monolayers (HT29-19A) to assess intestinal transport of active bacterial products. These products were characterised and their effect on LPS binding to THP-1 cells and nuclear factor kappa B (NF kappa B) activation assessed. RESULTS: Dose dependent inhibition of LPS induced TNF-alpha secretion was noted for both probiotic bacteria CM (64% and 71% inhibition for Bb and St, respectively) and to a lesser extent commensal bacteria CM (21-32% inhibition). Active products from Bb and St were resistant to digestive enzymes and had a molecular mass <3000 Da. Their inhibitory effect was preserved after transepithelial transport across intestinal cell monolayers, mainly in inflammatory conditions. LPS-FITC binding to THP-1 cells and NF kappa B activation were significantly inhibited by Bb and St CM. CONCLUSION: B breve and S thermophilus release metabolites exerting an anti-TNF-alpha effect capable of crossing the intestinal barrier. Commensal bacteria also display a TNF-alpha inhibitory capacity but to a lesser extent. These results underline the beneficial effect of commensal bacteria in intestinal homeostasis and may explain the role of some probiotic bacteria in alleviating digestive inflammation.

Bifidobacterium↗
PubMedDate not supplied

Role of commensal bacteria in chronic experimental colitis: lessons from the HLA-B27 transgenic rat.

Rats on Lewis or Fischer background, transgenic for human HLA-B27 and beta(2)-microglobulin genes spontaneously develop colitis, gastritis, arthritis, dermatitis, orchitis, epididymitis, carditis, alopecia and nail changes. Disease susceptibility correlates with the gene copy number and is influenced by the genetic background. The pathomechanism in this model is still not completely understood. Cell transfer experiments indicate an essential role of HLA-B27 expression in bone marrow-derived cells. On Fischer background the onset of colitis occurs at 2 months of age, peaks at 3 months of age, and plateaus. Histologic findings include inflammatory cell infiltration, mostly limited to the mucosa, crypt hyperplasia, reduction of goblet cells, occasionally crypt abscesses and early ulcers. There is evidence that normal luminal bacteria play an essential role in initiating and perpetuating chronic colitis and gastritis in HLA-B27 transgenic rats: Transgenic rats raised under germ-free conditions do not develop gastrointestinal disease, whereas transgenic littermates exposed to specific pathogen-free bacteria develop colitis and gastritis within 2-4 weeks. Obligate anaerobic bacteria, especially Bacteroides spp., may play a predominant role since metronidazole prevents colitis and transgenic germ-free rats contaminated with a cocktail of six obligate and facultative anaerobic bacteria develop colitis and gastritis only in the presence of Bacteroides vulgatus. Luminal bacteria may also be involved in trafficking and homing of inflammatory cells into remote organs, since varying cecal bacterial composition does not only alter local inflammation but also influences gastritis. Lymphocyte transfer experiments indicate a specific response to luminal bacteria. In summary, this animal model is suitable for investigating the influence of normal luminal bacteria on the cellular immune mechanism in chronic intestinal inflammation.

Animals↗
PubMed2005

Protein microarray analysis of disease activity in pediatric inflammatory bowel disease demonstrates elevated serum PLGF, IL-7, TGF-beta1, and IL-12p40 levels in Crohn's disease and ulcerative colitis patients in remission versus active disease.

OBJECTIVES: Cytokines and growth factors play a major role in the dysregulated immune response in inflammatory bowel disease (IBD). We hypothesized that significant differences exist between the serum cytokine and growth factor profiles of pediatric IBD patients with active disease (AD) and those in remission, and that levels of some of these soluble mediators may be used to define regulators in IBD and determine disease activity. METHODS: Eighty-eight consecutive patients with confirmed Crohn's disease (CD) and ulcerative colitis (UC) seen at the Duke Children's Hospital were prospectively enrolled and a serum sample was obtained. Data were recorded at the time of serum collection to calculate disease activity indices. The relative expression of 78 cytokines, growth factors, and soluble receptors was determined using proprietary antibody-based protein microarrays amplified by rolling circle amplification. SPSS 8 (SPSS Inc., Chicago, IL) was used to compare protein profiles for CD and UC patients in clinical remission (CR) versus AD. RESULTS: Sixty-five CD patients and 23 UC patients were enrolled. Forty-one CD patients had available samples and PCDAI results. Twenty-two patients were in remission PCDAI < or = 12.5 (median 5), 19 patients had disease activity >15 (median 30). Univariate analysis revealed that PLGF, IL-7, IL-12p40, and TGF-beta1 cytokine levels were significantly elevated for patients in CR versus AD (p < 0.01). Twelve UC serum samples had Seo/Truelove Witt AI for analysis. Five patients were in remission by TW AI and Seo AI < or =110 and 7 patients had active mild-to-severe disease by TW and Seo AI >110. Only one cytokine, IL12p40, showed significance between CR versus AD (p < 0.02). CONCLUSIONS: Surprisingly, we found no differences in circulating levels of proinflammatory cytokines but found that pediatric IBD patients in remission compared to those with AD had higher levels of specific circulating cytokines, including the regulatory cytokines IL-12p40 and TGF-beta1. It may be that these cytokines directly regulate intestinal inflammation in IBD or reflect the activity of T regulatory cells in negatively regulating the inflammatory response. Further studies will be needed to validate our results to define the molecular pathways involved in the intestinal immune response in man.

Adolescent↗
PubMed2006

Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice.

Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) are noninvasive bacterial pathogens that infect their hosts' intestinal epithelium, causing severe diarrheal disease. These infections also cause intestinal inflammation, although the mechanisms underlying the inflammatory response, as well as its potential role in host defense, are unclear. Since these bacteria are gram-negative, Toll-like receptor 4 (TLR4), the innate receptor for bacterial lipopolysaccharide may contribute to the host response; however, the role of TLR4 in the gastrointestinal tract is poorly understood, and its impact has yet to be tested against this family of enteric bacterial pathogens. Since EPEC and EHEC are human specific, we infected mice with Citrobacter rodentium, a mouse-adapted attaching and effacing (A/E) bacterium that infects colonic epithelial cells, causing colitis and epithelial hyperplasia, using a similar array of virulence proteins as EPEC and EHEC. We demonstrated that C. rodentium activates TLR4 and rapidly induced NF-kappaB nuclear translocation in host cells in a partially TLR4-dependent manner. Infection of TLR4-deficient mice revealed that TLR4-dependent responses mediate much of the inflammation and tissue pathology seen during infection, including the induction of the chemokines MIP-2 and MCP-1, as well as the recruitment of macrophages and neutrophils into the infected intestine. Surprisingly, spread of C. rodentium through the colon was delayed in TLR4-deficient mice, whereas the duration of the infection was unaffected, indicating that TLR4-mediated responses against this A/E pathogen are not host protective and are ultimately maladaptive to the host, contributing to both the morbidity and the pathology seen during infection.

Active Transport, Cell Nucleus↗
PubMedDate not supplied

Direct evidence of monocyte recruitment to inflammatory bowel disease mucosa.

Alterations in phenotype and function of intestinal macrophages occur in inflammatory bowel disease (IBD) but it is unclear whether these changes result from the recruitment of circulating monocytes to the intestine or from proliferation of resident intestinal macrophages. We sought to demonstrate the arrival of blood monocytes, the precursors of macrophages, in IBD mucosa. Peripheral blood mononuclear cells were isolated from 23 patients with clinically active intestinal inflammation (13 Crohn's disease, eight ulcerative colitis, two infective colitis), then radiolabelled with 99mtechnetium (Tc)-stannous colloid (n = 13) or 111indium (In)-oxine (n = 10) before re-injection and abdominal scanning. Four patients had demonstrable intestinal monocyte uptake using [99mTc]-stannous colloid, while six [111In]-oxine-labelled monocyte scans were positive. Uptake sites correlated with actively inflamed regions. Patients demonstrating monocyte uptake had been treated with corticosteroids for a significantly (P < 0.02) shorter duration (median 3 vs 20 days) than those with negative scans. There was no significant difference between positive and negative scans for disease category, clinical or histological disease, activity, or radioisotope used. Biopsies of inflamed mucosa from two patients suffering ulcerative colitis who had positive scans showed a high proportion of CD14-positive macrophages, 4-9% of which contained autoradiographic grains. These results demonstrate that blood monocytes are recruited to the mucosa of actively inflamed bowel, and suggest that this process may be inhibited by corticosteroids. Moreover, the phenotype of the recently-arrived monocytes indicates their susceptibility to stimulation by lipopolysaccharide, and suggests a mechanism for the continuing inflammation in the bacterial product-rich milieu of IBD.

Adolescent↗
PubMed2004

Oral RDP58 allows CPT-11 dose intensification for enhanced tumor response by decreasing gastrointestinal toxicity.

Cancer patients undergoing triple therapy (CPT-11, 5-fluorouracil, and leucovorin) often present with severe delayed diarrhea as a result of chemotherapy-induced gastrointestinal (GI) toxicity and inflammation. RDP58 is a novel, anti-inflammatory, D-amino acid decapeptide that inhibits the production of tumor necrosis factor alpha, IFN-gamma, and interleukin 12, and has been shown to effectively inhibit clinical symptoms and intestinal inflammation in several rodent models of chemically induced colitis, nonhuman primates with spontaneous colitis, and humans with mild to moderate ulcerative colitis. We evaluated RDP58 as a potential protective agent in chemotherapy-induced GI inflammation. Oral administration of RDP58 significantly decreased the incidence of diarrhea and improved the survival rates of mice treated with toxic doses of CPT-11 or 5-fluorouracil. Histological analysis showed that RDP58 significantly reduced the destruction of the intestinal mucosa by inhibiting local overproduction of tumor necrosis factor alpha, IFN-gamma, and interleukin 12 in vivo. Furthermore, RDP58 administration allowed the maximum tolerated dose of CPT-11 to be doubled in tumor-bearing mice resulting in significantly enhanced primary tumor responses and prolongation of time to relapse without a concomitant increase in GI toxicity. Our results suggest that RDP58 may have clinical utility in cancer therapy by preventing treatment-associated GI toxicity and potentially increasing the effectiveness of chemotherapy.

Administration, Oral↗
PubMed2003

Determining small bowel integrity following drug treatment.

Intestinal integrity is maintained by a delicate balance between mucosal defence and luminal aggressors that cause damage if exposed to the mucosa. The intestinal barrier function appears to be the gatekeeper for controlling this balance. It is becoming increasingly clear that if the intestinal barrier is disrupted the consequences are low grade intestinal inflammation which carry with it the risk of significant blood and protein loss both of which may cause clinical management problems. We review the strength and weaknesses of methods for assessing small bowel function that are useful for assessing drug-induced intestinal toxicity. There are a number of imaging methods for assessing intestinal integrity but these do not provide functional information. Intestinal permeability measurements have been optimized for specificity and there are now ways of measuring intestinal permeability regionally, but marker analyses continue to be cumbersome. Recent developments of faecal inflammatory markers make it a matter of routine to assess this in any routine chemical pathology laboratory. Bleeding, protein loss and other complications of inflammation can also be measured with good specificity, but again the methods are cumbersome. Using a combination of functional and imaging techniques it is now possible to characterize and define with precision, the small bowel side-effects of drugs, the best example being the small bowel side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Expression of 4C8 antigen, a novel transendothelial migration-associated molecule on activated T lymphocytes, in inflammatory bowel disease.

Recruitment of peripheral leukocytes to intestine is an essential process for intestinal inflammation. This study examined the localization of a novel molecule, 4C8 antigen, in inflammatory bowel disease; this molecule is involved in the transendothelial migration of T lymphocytes. Surgical specimens of human intestine were obtained from nine patients with ulcerative colitis, 13 with Crohn's disease, and eight controls. Immunohistological staining was performed using antibodies against 4C8 antigen, and CD3, CD4, CD8, CD20, CD68, CD45RA, CD45RO, CD11a, and CD62 (E- and P-selectin) by the peroxidase method. Immunological double staining was subsequently performed for the same specimens stained with anti-4C8 antibody using the alkaline phosphatase method. In normal controls, 4C8-positive cells were mainly found in lamina propria. 4C8-positive cells were increased in lamina propria and submucosa of specimens with Crohn's disease. Accumulation of 4C8-positive cells surrounding CD62-positive vessels was found in the submucosa of specimens with inflammatory bowel disease, but not in controls. Immunohistological double staining revealed that the major subsets of 4C8-positive cells were positive for CD3, CD4, CD45RO, and CD11a. 4C8-positive cells in human intestine belong to the subset of helper/inducer memory T cells newly recruited from the peripheral pool. Inhibition of the 4C8-ligand system could have potentially uses in the treatment of inflammatory bowel disease.

Adult↗
PubMed1997

Xanthine oxidase decreases production of gut wall nitric oxide.

Multiorgan failure is often the lethal outcome of intratracheal aspiration of acidic gastric juice. The pathogenesis of multiorgan failure may involve a systemic imbalance between pro-inflammatory and anti-inflammatory factors. In an anesthetized rat model, intratracheal instillation of HCl elicited intestinal inflammation which was exaggerated by xanthine oxidase (XO) and attenuated by nitric oxide (NO). We hypothesized that XO may mediate injury in part by suppression of NO formation. Therefore, we measured intestinal tissue concentrations of the stable NO oxidative metabolites (NO2- and NO3-) following intratracheal (IT) instillation of NaCl or HCl alone or in combination with interventions aimed at increasing or decreasing XO activity. Compared with IT NaCl (control treatment) jejunal tissue NO2- and NO2- + NO3- concentrations were increased by allopurinol pretreatment, which inhibits XO, and were decreased by systemically administered XO, as well as by IT HCl. The decreased NO2- and NO2- + NO3- concentrations found following IT HCl were completely reversed by either allopurinol or by systemically administered L-arginine (the precursor of NO). We conclude that manipulation of the pro-inflammatory XO system has a reciprocal effect on the intestinal anti-inflammatory NO system in either the undamaged or the endobronchially acidified lung model.

Animals↗
PubMed2005

Dislocation of tight junction proteins without F-actin disruption in inactive Crohn's disease.

Crohn's disease is associated with increased permeability of the intestinal barrier even in quiescent patients. Increased intestinal permeability may cause dysregulated immunological responses in the intestinal mucosa that leads to chronic intestinal inflammation. We have studied the expression of tight junction proteins (occludin and zonula occludens), alpha2-smooth muscle actin, TGF-beta with a cytoskeletal protein (F-actin) in the intestinal epithelium of patients with inflammatory bowel disease. Surgical samples were obtained from 6 controls (individuals without inflammatory bowel disease), 8 patients with ulcerative colitis and 7 patients with Crohn's disease. F-actin was visualized with fluorescein phalloidin. Tight junction proteins, alpha2 smooth muscle actin, and TGFbeta were visualized by the immunofluorescent method. Occludin and zonula occludens found in apical tight junctions in normal epithelium were dislocated to the basolateral position and in the lamina propria extracellular matrix in patients with Crohn's disease, while the structure of F-actin was maintained in inactive or minimally inflamed mucosa. TGF-beta positive inflammatory cells were increased in ulcerative colitis and Crohn's disease mucosa. Subepithelial myofibroblasts were constitutively found in controls, ulcerative colitis, and Crohn's disease mucosa. Latent dislocation of tight junction proteins, without disturbance of the cytoskeleton in the inactive mucosa of patients with Crohn's disease, may permit the invasion of gut antigens because the functional disruption of tight junctions could initiate an altered immune response.

Actins↗
PubMed1996

Nonsteroidal antiinflammatory drug-induced enteropathy and severe chronic anemia in a patient with rheumatoid arthritis.

This report describes the case of a woman who was admitted to the hospital with severe anemia and refractory rheumatoid arthritis. She had been transfusion dependent for 8 years and was receiving a combination of indomethacin and naproxen. An indium-111 white blood cell scan revealed small bowel inflammation. Salsalate was substituted for her previous nonsteroidal antiinflammatory drugs (NSAIDs), and metronidazole was initiated. This resulted in maintenance of a normal hemoglobin level for at least 1 year after discharge. Small intestine inflammation and bleeding (enteropathy) due to NSAIDs must be considered in the evaluation of anemia in patients with arthritis.

Aged↗
PubMed2003

CCR6 has a non-redundant role in the development of inflammatory bowel disease.

Antigen-loaded tissues such as the intestinal mucosa must simultaneously elicit appropriate immune response to innocuous bacteria and food proteins, and to potentially harmful antigens. Impairment of the mechanisms controlling this response may mediate the excessive immune reaction that can lead to tissue destruction and inflammatory intestinal diseases, including inflammatory bowel disease. The intestinal epithelium influences local immune responses through the expression of adhesion molecules, costimulatory factors, cytokines and chemokines. CCL20, a beta-chemokine expressed in epithelia from colon and other intestinal tissue, plays a role in immune responses of intestinal mucosa, as deduced from the defects in intestinal leukocyte homeostasis shown by mice lacking CCR6, the CCL20 receptor. We studied the response of CCR6-deficient mice in two models of inflammatory bowel disease. The data show that absence of CCR6 resulted in less severe intestinal pathology in animals treated with dextran sodium sulfate. Conversely, CCR6 deficiency alters leukocyte homeostasis and the cytokine environment in the intestinal mucosa; these changes are sufficient to confer susceptibility to trinitrobenzene sulfonic acid-induced intestinal inflammation in the otherwise resistant C57BL/6J mouse strain. These results suggest that the CCR6/CCL20 axis has a critical, non-redundant role in the in vivo control of immune responses in the intestine.

Animals↗
PubMed2005

Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis.

BACKGROUND AND AIMS: The imbalance between effector and regulatory T cells plays a central role in the pathogenesis of inflammatory bowel diseases. In addition to the thymus, CD4+CD25+ regulatory T cells can be induced in the periphery from a population of CD25- T cells by treatment with transforming growth factor beta (TGF-beta). Here, we analysed the in vivo function of TGF-beta induced regulatory T (Ti-Treg) cells in experimental colitis. METHODS: Ti-Treg cells were generated in cell culture in the presence or absence of TGF-beta and tested for their regulatory potential in experimental colitis using the CD4+CD62L+ T cell transfer model. RESULTS: Ti-Treg cells significantly suppressed Th1 mediated colitis on CD4+CD62L+ T cell transfer in vivo, as shown by high resolution endoscopy, histology, immunohistochemistry, and cytokine analysis. Further analysis of in vivo and in vitro expanded Ti-Treg cells showed that exogenous interleukin 2 (IL-2) was crucial for survival and expansion of these cells. CONCLUSION: Our data suggest that regulatory Ti-Treg cells expand by TGF-beta and exogenous IL-2 derived from effector T cells at the site of inflammation. In addition to Tr1 and thymic CD4+CD25+ T cells, peripheral Ti-Treg cells emerge as a class of regulatory T cells with therapeutic potential in T cell mediated chronic intestinal inflammation.

Adoptive Transfer↗
PubMed2006

Mechanism of glucocorticoid regulation of the intestinal tight junction barrier.

A defective intestinal epithelial tight junction (TJ) barrier has been proposed as an important pathogenic factor contributing to the intestinal inflammation of Crohn's disease. Glucocorticoids are first-line therapeutic agents for the treatment of moderate to severe Crohn's disease. Glucocorticoid treatment has been shown to induce retightening of the intestinal TJ barrier defect in Crohn's disease patients. However, the mechanisms that mediate the glucocorticoid therapeutic action on intestinal TJ barrier function remain unknown. The aim of this study was to elucidate the mechanism of glucocorticoid modulation of the intestinal epithelial TJ barrier using an in vitro model system. Filter-grown Caco-2 intestinal epithelial cells were used as an in vitro model to examine the effects of glucocorticoids on basal intestinal epithelial TJ barrier function and on TNF-alpha-induced disruption of the TJ barrier. Glucocorticoids (prednisolone and dexamethasone) did not have a significant effect on baseline Caco-2 TJ barrier function but prevented the TNF-alpha-induced increase in Caco-2 TJ permeability. The glucocorticoid protective effect against the TNF-alpha-induced increase in Caco-2 TJ permeability required activation of the glucocorticoid receptor (GR) complex. The activation of the GR complex resulted in GR complex binding to the glucocorticoid response element (GRE) site on DNA and activation of a GR-responsive promoter. Glucocorticoids inhibited the TNF-alpha-induced increase in myosin light chain kinase (MLCK) protein expression, a key process mediating the TNF-alpha increase in intestinal TJ permeability. The glucocorticoid inhibition of the TNF-alpha-induced increase in MLCK protein expression was due to the binding of the GR complex to a GRE binding site on the MLCK promoter region suppressing the TNF-alpha-induced activation. Glucocorticoids inhibit the TNF-alpha-induced increase in Caco-2 TJ permeability. The prednisolone protective action was mediated by binding of activated GR complex to the GRE site on the MLCK promoter, suppressing the TNF-alpha-induced increase in MLCK gene activity, protein expression, and subsequent opening of the intestinal TJ barrier.

Active Transport, Cell Nucleus↗
PubMed2006

Role of the thrombin/protease-activated receptor 1 pathway in intestinal ischemia-reperfusion injury in rats.

CXC chemokines, including human interleukin-8 and rat cytokine-induced neutrophil chemoattractant-1, play a crucial role in the pathogenesis of intestinal inflammation induced by ischemia-reperfusion (I-R). Thrombin and its specific receptor, protease-activated receptor 1 (PAR1), act as important players in inflammation. However, the association between thrombin activation and chemokine production during I-R has not been well studied. We investigated whether thrombin and PAR1 might be involved in the pathophysiology of intestinal I-R, using an in vivo model. Intestinal damage was induced by clamping the superior mesenteric artery for 30 min followed by reperfusion in male Wistar rats. Thrombin-antithrombin complex was measured as an indicator of thrombin activation. PAR1 expression in the intestine was evaluated by real-time PCR. The severity of the intestinal mucosal injury was evaluated on the distal segment of the ileum by several biochemical markers and histological findings. Reperfusion significantly increased the serum levels of thrombin-antithrombin complex and enhanced PAR1 expression in the intestinal mucosa. The levels of both intraluminal hemoglobin and protein were significantly increased in the I-R group. The mucosal myeloperoxidase activity and expressions and/or productions of cytokine-induced neutrophil chemoattractant-1 and TNF-alpha were significantly increased after I-R. These increases were inhibited by the treatment of rat with antithrombin intravenously before I-R at a dose of 30 U/kg. These results suggest that the thrombin/PAR1 pathway plays an important role in the production of these cytokines during I-R and that antithrombin exerts potent anti-inflammatory effects on this injury via inhibition of proinflammatory cytokines.

Animals↗
PubMed2005

[Exploring new therapeutic approaches to the treatment of inflammatory disorders--lipoxins].

The prevalence of inflammatory disorders continues to increase and its optimal treatment still remains a challenge. Lipoxins, endogenous eicosanoids biosynthesised in vivo at inflammatory sites, are potent anti-inflammatory mediators. Therefore, it is of interest to investigate the potential effects of lipoxins that could attenuate chronic inflammation. Currently, only limited data on the effects of lipoxins in clinical investigations are available. Nevertheless, lipoxins caused inhibition of hyper-responsiveness and allergic airway inflammation in asthma. They could also impact the progression of inflammatory arthritides through the reduction of the inflammatory infiltrates and limiting tissue destruction. Lipoxins may play important anti-inflammatory roles in intestinal inflammation as well as in a number of cutaneous inflammatory disorders like psoriasis or atopic dermatitis. Taken together, the available data suggests that lipoxins may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.

Anti-Inflammatory Agents↗