Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The etiologic factors responsible for IBD remain only speculative. It does appear that the inappropriate activation of the immune system, whether by immune complex deposition, infectious agents or vascular impairment, is important in the pathogenesis of these diseases. Interaction of certain cytokines known to be produced in human IBD with specific immune cells such as neutrophils and macrophages results in the induction of the enzyme NO. synthase with the concomitant release of large amounts of NO.. Nitric oxide is known to mediate many of the pathophysiological alterations associated with IBD including cell injury, intestinal hyperemia and intestinal smooth muscle dysfunction. In addition, NO. is known to decompose in solution to yield potent N-nitrosating agents which will N-nitrosate certain amines to yield potent carcinogenic nitrosamines. Because antioxidants (including 5-ASA) are potent inhibitors of nitrosamine formation, they may prove useful in attenuating the formation of potentially carcinogenic agents in vivo.
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PMID:Neutrophils, nitrogen oxides, and inflammatory bowel disease. 145 43

Endogenously formed nitrogen and oxygen free radicals are believed to be involved in human cancer etiology. Plasma nitrate/nitrite originates from endogenous nitric oxide production in fasting humans, decrease in superoxide scavenger activity (SSA), and free sulfhydryl groups (SH) reflects the amount of superoxide anion generated, and nitrotyrosine is believed to be formed by the interaction of tyrosine and peroxynitrite in vivo. The aim of the current study was to measure plasma nitrate/ nitrite, SSA, and SH in 69 patients (mean age +/- standard deviation, 66 +/- 11 years) with colorectal carcinoma. Nitrotyrosine was measured from both the plasma and tumor tissues in 32 patients. All patients had adenocarcinoma of the colon or rectum. Twenty-five patients were classified as stage B according to Dukes classification as modified by Astler-Coller, 13 were classified as stage C, and 31 patients were classified as stage D. To determine whether the changes are specific for colorectal cancer, 20 patients with active inflammatory bowel disease (IBD; mean age, 52 +/- 18 years) and 30 healthy volunteers, who served as control subjects (mean age, 48 +/- 11 years), were studied. Plasma nitrate/nitrite was measured by the modified Griess method, SSA was measured by an electron/spin resonance spin trapping method, free SH was measured by Ellman's method, and the presence of nitrotyrosine in the plasma and tumor tissue was detected by high performance liquid chromatography (HPLC) using C- 18-derivatized silica (5 microm) column (C18S, Crestpaque, New York, NY, USA) and at a wavelength of 274 nm. Patients with colorectal carcinoma and with active IBD had a significantly higher plasma nitrate/ nitrite level (51.2 +/- 26.2 microm and 56.0 +/- 14.6 microm versus. 29.6 +/- 6.3 microm; p < 0.01), and a lower SSA level (39 +/- 11.5 U/g protein and 52.0 +/- 18.9 U/g protein versus. 88 +/- 25.1 U/g protein; p < 0.05) and SH level (7.7 +/- 3.89 microm protein and 6.4
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PMID:Evidence of in vivo peroxynitrite formation in patients with colorectal carcinoma, higher plasma nitrate/nitrite levels, and lower protection against oxygen free radicals. 1063 9

The activity of nitric oxide synthase (NOS) was assayed in enterocytes isolated from human duodenal biopsies to determine its role in celiac disease. Patients were categorized into groups with irritable bowel syndrome, iron-deficiency anemia, B(12)/folate deficiency, and treated and untreated celiac disease. Enterocytes isolated from all groups showed 1400W-inhibitable Ca2+-independent NOS activity with a pH level and temperature optimum of 9.4 and 37 degrees C, respectively. Western blotting showed that enterocytes expressed the inducible NOS protein and proteins with nitrated tyrosine residues, the latter being indicative of nitric oxide-driven peroxynitrite and/or free-radical damage. Endothelial NOS was seen only in the lamina propria. Patients with celiac disease had higher NOS activity than other patient groups. Treatment of the condition led to a fall in activity. Enzyme-linked immunosorbent assay demonstrated cGMP production by the enterocyte fraction, but cGMP levels did not correlate with NOS activity. These results suggest that inducible NOS is constitutively expressed in human duodenal enterocytes, is increased in patients with untreated celiac disease, and is partially corrected when such patients are treated. We found no evidence to support a role for nitric oxide in the formation of cGMP within the small intestine. Furthermore, we were unable to demonstrate a role for peroxynitrite/free radical damage in the pathophysiology of celiac disease.
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PMID:Increased activity and expression of iNOS in human duodenal enterocytes from patients with celiac disease. 1212 78

The inflammatory bowel diseases (IBD; Crohn's disease, ulcerative colitis) are a collection of chronic idiopathic inflammatory disorders of the intestine and/or colon. Although the pathophysiology of IBD is not known with certainty, a growing body of experimental and clinical data suggests that chronic gut inflammation may result from a dysregulated immune response to normal bacterial antigens. This uncontrolled immune system activation results in the sustained overproduction of reactive metabolites of oxygen and nitrogen. It is thought that some of the intestinal and/or colonic injury and dysfunction observed in IBD is due to elaboration of these reactive species. This review summarizes the current state-of-knowledge of the role of reactive oxygen species and nitric oxide in the pathophysiology of IBD.
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PMID:Role of reactive metabolites of oxygen and nitrogen in inflammatory bowel disease. 1212 53

Distinguishing patients with inflammatory bowel disease from those with irritable bowel syndrome can be difficult. A simple and reliable test that detects intestinal inflammation would therefore be very useful in the clinic. If such a test parameter correlated with the intensity of the inflammatory reaction it could also be used to monitor disease activity. Calprotectin, lactoferrin and nitric oxide are produced and released locally in much greater quantities in the inflamed gut than in the noninflamed gut. These compounds can be readily measured in fecal samples (calprotectin and lactoferrin) or directly in the intestinal lumen (nitric oxide gas). Here, we discuss what is known about these markers, how they could be used in clinical practice and how they can complement existing techniques used for the diagnosis and monitoring of inflammatory bowel disease.
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PMID:Technology insight: calprotectin, lactoferrin and nitric oxide as novel markers of inflammatory bowel disease. 1626 27

Irritable bowel syndrome (IBS) is one of the most common disorders and a heterogeneous condition in view of symptoms and underlying mechanisms. Though underlying causes of pathophysiologic changes remain unclear, low grade mucosal inflammation and abnormal intestinal motility are accepted mechanisms which alter gut function and generate symptoms of IBS. First, before 1980s, abnormal colonic and rectal motor functions were regarded as the main pathophysiology of IBS, but only 25-75% of IBS patients have apparent motor abnormalities which differ from the motor functions in normal controls. So, various gastrointestinal motility tests were not indicated for the diagnosis of IBS. The high-amplitude propagating contractions of colon in IBS patients may be related to the visceral pain perception. Second, the low grade mucosal inflammation may be involved in the pathophysiology of visceral hypersensitivity. Post infectious IBS (PI-IBS) occupied 6-17% of the total IBS and some previous prospective studies reported that 7-33% of acute bacterial enteritis patients developed IBS after 6-12 months of infection. The relative risk of IBS in the gastroenteritis cohort was 11.9 and the strongest risk factor is the duration of diarrhea. After enteritis event, the increased number of immunocytes, mast cells and large amount of lymphocytes infiltration were revealed in mucosa and enteric nervous system of the gut. Beside the inflammatory cells, enterochromaffin cells, cytokines and inducible nitric oxide may be related to the pathophysiologic mechanism of PI-IBS. Lastly, the abnormalities in the gastrointestinal autonomic nervous system can induce constipation or motor disorders, but further research should elucidate it.
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PMID:[The pathophysiology of irritable bowel syndrome: inflammation and motor disorder]. 1649 75

The maintenance of gastrointestinal mucosal integrity depends on the rapid alarm of protective mechanisms in the face of pending injury. To this end, the gastric mucosa is innervated by intrinsic sensory neurons and two populations of extrinsic sensory neurons: vagal and spinal afferents. Extrinsic afferent neurons constitute an emergency system that is called into operation when the gastrointestinal mucosa is endangered by noxious chemicals. The function of these chemoceptive afferents can selectively be manipulated and explored with the use of capsaicin which acts via a cation channel termed TRPV1. Many of the homeostatic actions of spinal afferents are brought about by transmitter release from their peripheral endings. When stimulated by noxious chemicals, these afferents enhance gastrointestinal blood flow and activate hyperaemia-dependent and hyperaemia-independent mechanisms of protection and repair. In the rodent foregut these local regulatory roles of sensory neurons are mediated by calcitonin gene-related peptide and nitric oxide. The pathophysiological potential of the neural emergency system is best portrayed by the gastric hyperaemic response to acid back-diffusion, which is governed by spinal afferent nerve fibres. This mechanism limits damage to the surface of the mucosa and creates favourable conditions for rapid restitution and healing of the wounded mucosa. Other extrinsic afferent neurons, particularly in the vagus nerve, subserve gastrointestinal homeostasis by signalling noxious events in the foregut to the central nervous system and eliciting autonomic, emotional-affective and neuroendocrine reactions. Under conditions of inflammation and injury, chemoceptive afferents are sensitized to peripheral stimuli and in this functional state contribute to the hyperalgesia associated with functional dyspepsia and irritable bowel syndrome. Thus, if GI pain is to be treated by sensory neuron-directed drugs it needs to be considered that these drugs do not inhibit nociception at the expense of GI mucosal vulnerability.
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PMID:Efferent-like roles of afferent neurons in the gut: Blood flow regulation and tissue protection. 1654 83

Recent studies have shown that mucosal serotonin (5-HT) transporter (SERT) expression is decreased in animal models of colitis, as well as in the colonic mucosa of humans with ulcerative colitis and irritable bowel syndrome. Altered SERT function or expression may underlie the altered motility, secretion, and sensation seen in these inflammatory gut disorders. In an effort to elucidate possible mediators of SERT downregulation, we treated cultured colonic epithelial cells (Caco2) with conditioned medium from activated human lymphocytes. Application of the conditioned medium caused a decrease in fluoxetine-sensitive [(3)H]5-HT uptake. Individual proinflammatory agents were then tested for their ability to affect uptake. Cells were treated for 48 or 72 h with PGE(2) (10 microM), IFN-gamma (500 ng/ml), TNF-alpha (50 ng/ml), IL-12 (50 ng/ml), or the nitric oxide-releasing agent S-nitrosoglutathione (GSNO; 100 microM). [(3)H]5-HT uptake was then measured. Neither PGE nor IL-12 had any effect on [(3)H]5-HT uptake, and GSNO increased uptake. However, after 3-day incubation, both TNF-alpha and IFN-gamma elicited significant decreases in SERT function. Neither TNF-alpha nor IFN-gamma were cytotoxic when used for this period of time and at these concentrations. These two cytokines also induced decreases in SERT mRNA and protein levels. By altering SERT expression, TNF-alpha and IFN-gamma could contribute to the altered motility and expression seen in vivo in ulcerative colitis or irritable bowel syndrome.
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PMID:IFN-gamma and TNF-alpha decrease serotonin transporter function and expression in Caco2 cells. 1717 25

Nitric oxide (.NO) generation from conversion of l-arginine to citrulline by nitric oxide synthase isoforms plays a critical role in vascular homeostasis. Loss of .NO is linked to vascular pathophysiology and is decreased in chronically inflamed gut blood vessels in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). Mechanisms underlying decreased .NO production in IBD gut microvessels are not fully characterized. Loss of .NO generation may result from increased arginase (AR) activity, which enzymatically competes with nitric oxide synthase for the common substrate l-arginine. We characterized AR expression in IBD microvessels and endothelial cells and its contribution to decreased .NO production. AR expression was assessed in resected gut tissues and human intestinal microvascular endothelial cells (HIMEC). AR expression significantly increased in both ulcerative colitis and Crohn's disease microvessels and submucosal tissues compared with normal. TNF-alpha/lipopolysaccharide increased AR activity, mRNA and protein expression in HIMEC in a time-dependent fashion. RhoA/ROCK pathway, a negative regulator of .NO generation in endothelial cells, was examined. The RhoA inhibitor C3 exoenzyme and the ROCK inhibitor Y-27632 both attenuated TNF-alpha/lipopolysaccharide-induced MAPK activation and blocked AR expression in HIMEC. A significantly higher AR activity and increased RhoA activity were observed in IBD submucosal tissues surrounding microvessels compared with normal control gut tissue. Functionally, inhibition of AR activity decreased leukocyte binding to HIMEC in an adhesion assay. Loss of .NO production in IBD microvessels is linked to enhanced levels of AR in intestinal endothelial cells exposed to chronic inflammation in vivo.
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PMID:Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease. 1721 73

Chronic active colitis (including inflammatory bowel disease - IBD) is maintained by a variety of pro-inflammatory mediators. Certain intestinal bacterial strains may induce colitis, whereas some strains (e.g. Lactobacillus spp.) show a protective effect in colitis owing to their anti-inflammatory activity. In this study, we have examined the production of selected inflammatory cytokines, reactive oxygen species (ROS), nitric oxide (NO) and the expression of haeme oxygenase-1 (HO-1) by murine peritoneal macrophages stimulated in vitro by the intestinal bacterial strains, isolated from mice with colitis. Lactobacillus strains (Lactobacillus reuteri, L. johnsonii, L. animalis/murinus) and two potentially pathogenic bacteria (Escherichia coli and Enterococcus faecalis) induced the production of substantial amounts of cytokines with a strain specific profile. Despite some interstrain differences, all lactobacilli induced production of anti-inflammatory cytokines (IL-10(high), IL-6(low), IL-12p70(low)). Conversely, E. faecalis and E. coli induced the production of proinflammatory cytokines (TNF-alpha, IL-12p70), the cytokines essential for chronic IBD. Macrophages released comparably substantial amounts of ROS in response to all Lactobacillus strains tested, while E. coli and E. faecalis ability to induce generation of ROS was negligible. In contrast to ROS, the production of NO/NO(2) (-) by macrophages activated with all bacterial strains tested was similar. Moreover, for the first time, it has been shown that intestinal bacteria differed in their ability to induce expression of HO-1, a stress-inducible enzyme with antioxidant and anti-inflammatory properties. The beneficial immunoregulatory properties of candidate probiotic bacteria for the treatment of IBD are discussed.
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PMID:Differential inflammatory mediator response in vitro from murine macrophages to lactobacilli and pathogenic intestinal bacteria. 1750 45


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