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)

6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are well known for their lymphocytotoxic and bone marrow suppressive effects in the management of patients with leukemia. Although their immunosuppressive properties are mediated by the active AZA antimetabolite 6-thioguanine (6-TG), its mechanism of action is largely unknown. In IBD, a significant inverse correlation has been shown between erythrocyte 6-TG metabolite levels and disease activity, further supporting the proposed immunosuppressive role for 6-TG. Since leukocytes possess quantitatively different purine metabolic pathways compared to erythrocytes, this study aims to measure lymphocyte DNA 6-TG metabolites and correlate levels with the INF-gamma and IL-10 cytokine profile in patients with Crohn's disease (CD). Forty-six adult patients with CD, either naive (17) or on long-term (>4-month) AZA therapy (29), had erythrocyte and lymphocyte DNA 6-TG levels measured by reverse-phase HPLC under UV detection (6-TG, 340 nm). Lymphocyte DNA 6-TG was expressed as picomoles per milligram of DNA. Lymphocyte DNA 6-TG metabolite levels were correlated with INF-gamma and IL-10 cytokine profiles using the OptEIA kit (Pharmigen). Lymphocyte DNA 6-TG metabolite levels correlate with erythrocyte 6-TG levels (P < 0.03) but not total patient leukocyte levels. Erythrocyte 6-TG metabolite levels correlated (P < 0.01) inversely with INF-gamma but not IL-10 cytokine levels. This study suggests a preferential dampening of the TH1 response on exposure to 6-TG and a possible immunosuppressive mechanism of action for AZA. Future studies are needed to determine if cytokine profiles can be used to predict recalcitrant CD to AZA therapy.
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PMID:Peripheral blood mononuclear cell DNA 6-thioguanine metabolite levels correlate with decreased interferon-gamma production in patients with Crohn's disease on AZA therapy. 1499 47

Products of arachidonic acid metabolism are important for mucosal homeostasis, because blockade of this pathway with an NSAID triggers rapid onset of severe colitis in the IL-10 knockout (IL-10(-/-)) model of IBD. Rag mice do not make T or B cells. This study determined whether reconstitution of Rag mice with T cells from IL-10(-/-) mice transferred NSAID colitis susceptibility. Rag mice were reconstituted by intraperitoneal injection with splenocytes from wild-type (WT) or IL-10(-/-) animals. Colitis was induced by using piroxicam and was graded histologically. Isolated lamina propria mononuclear cells (LPMC), lamina propria T cells, and LPMC depleted of T cells from reconstituted Rag mice were studied for cytokine production. Only animals reconstituted with IL-10(-/-) CD4(+) T cells and administered piroxicam developed severe colitis. LPMC from these colitic animals made IFN-gamma, whose production was dependent on T cells. Some IL-10 was produced but only from non-T cells. LPMC from the healthy Rag mice that were reconstituted with WT T cells and were piroxicam resistant made much more IL-10. This was mostly T cell dependent. In conclusion, only CD4(+) T cells from IL-10(-/-) animals leave Rag mice susceptible to NSAID-induced, Th1 colitis. Lamina propria T cells normally make large quantities of IL-10, suggesting that IL-10 from T cells may be protective.
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PMID:CD4+ T cells from IL-10-deficient mice transfer susceptibility to NSAID-induced Rag colitis. 1524 67

Conventional therapy for inflammatory bowel diseases rely on corticosteroids and 5-aminosalicylates combined with immunosuppressive agents for maintenance. These drugs are not always effective and may inflict serious side effects. Other therapies are therefore awaited. Infliximab, a monoclonal antibody against the pro-inflammatory cytokine TNF-alpha has been successfully applied as a treatment for Crohn's disease. The mechanism of action of this drug extends beyond the level of TNF-alpha scavenging and includes induction of apoptosis of effector cells. Numerous anti-TNF antibodies have been developed and are currently evaluated in clinical trials. Other targets for monoclonal antibodies include integrins and cytokines involved in T-cell differentiation and activation. Likewise recombinant proteins that moderate TNF bioactivity and lymphocyte function have been developed. The therapeutic effect of recombinant interleukin-10 seems to be dependent on local delivery of the protein. Antisense therapy targeting lymphocyte migration has also been tested in IBD. Finally, the conventional drug thalidomide and possibly MAP-kinase inhibitors may become novel treatment entities for IBD.
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PMID:New cytokine therapeutics for inflammatory bowel disease. 1558 91

Our understanding of the etiology and pathogenesis of IBD has improved extensively over the past years. At the center of the pathogenesis seems to be an excessive pro-inflammatory immune reaction towards normal intestinal flora. The different factors involved in this concept will form the focus of this review. The initial phase of antigen processing and presentation can be influenced by either modulation of the intestinal flora via antibiotics or probiotics or by direct stimulation of macrophages through GM-CSF treatment. Antigen recognition and activation of T-cells can be down-regulated by immunosuppressives such as azathioprine, CsA or methotrexate thus building the basis for current treatment in IBD. The pro-inflammatory character of the immune reaction is defined by the predominance of certain T-cell subpopulations. By targeting cytokines the disbalance of these subpopulation should be reconstituted. Here we will focus first on preliminary clinical as well as experimental data for the pro-inflammatory mediators IL-12 and IL-18 as well as for the anti-inflammatory cytokine IL-10. Second, the clinical data for the TNFalpha antibody that has been proven to be efficacious in Crohn's disease and the associated risks will be discussed. Last, recent clinical and experimental data on targeting cell adhesion as well as intracellular signaling pathways will be presented. In summary, with regard to this review, treatments, which intervene as early as possible in the initiation of the pathological immune reaction and simultaneously have a favorable side-effect profile, must be the focus of future research.
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PMID:Therapeutic approaches in inflammatory bowel disease based on the immunopathogenesis. 1563 10

Therapeutic interventions in the case of gastrointestinal disease are based on the understanding of the role of different inflammatory mediators. Reactive O2 and N2 metabolites are involved in IBD. Pro-inflammatory cytokines, apoptosis signalling and redox-response transcription factors are depended on free radicals. NO activates COX enzymes. PGE2 negatively modulates induction of NO synthase by interleukins and therefore regulation of gastric mucosal integrity by endogenous NO depends on arachidonic acid cascade. PG-s have pro-inflammatory and anti-inflammatory effects on the immune system. Dietary PUFA-s and eicosanoids have potential effects on the modulation of inflammatory processes and immune cells. The cholesterol level lowering activity of several cytokines and colony stimulating factor can be observed. Therapeutic efficacy of N-3 PUFA is described in cases of patients with chronic gastrointestinal disorders, but N-3 PUFA-s only delay early relapse of ulcerative colitis in remission. TNF is known as a pleiotropic cytokine. Strategies for TNF in IBD is very important part of therapeutical approaches. Therapy with infliximab and related ones are encouraging in critical cases. It is also believed recently, that NF-kappaB also may be a target of IBD treatment. It became known, that oxidized LDL can inhibit LPS-induced binding of the NF-kappaB to DNA and the subsequent expression of TNF-alpha and interleukin-1beta in macrophages as well as oxidized LDL modulates activation of NF-kappaB in mononuclear phagocytes by altering the degradation of I-kappaBs. 15-d-PGJ2 inhibits multiple steps in the NF-kappaB signaling pathway. 15-d-PGJ2 metabolite binds PPAR-gamma promotes adipocyte differentiation. PPAR-gamma ligand inhibits growth of cells through induction of apoptosis. Several nutritional polyphenols (the secondary metabolites of plants) are COX2 and/or LOX inhibitors and iNOS activators. The moderate nutritional customs with natural antioxidants can help restore to normal function of gastrointestinal tract, but the immoderate consumption of vitamins and polyphenol type antioxidant molecules is contraindicated.
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PMID:[Cytokines, prostaglandins, nutritive and non-nuitritive factors in inflammatory bowel diseases]. 1566 52

Inflammatory bowel diseases are chronic inflammatory disorders of the gastrointestinal tract. Vasoactive intestinal peptide (VIP) is a neuropeptide with known anti-inflammatory activity. We have demonstrated previously that administration of VIP inhibits leucocyte migration in a murine model of delayed-type hypersensitivity, and anti-inflammatory efficacy is supported by other studies. The aim of this study was to investigate the VIP effects in a murine model of intestinal inflammation. Colitis was induced in BALB/c mice by a 2.5 mg enema of 2,4,6-trinitrobenzenesulphonic acid (TNBS) and the mice were killed on day 7. Mice were administered either a 3-day (therapeutic) or 7-day (prophylactic) constant infusion of VIP by subcutaneously implanted mini-osmotic pumps, or intraperitoneal (i.p.) injection of VIP on alternate days over 7 days. Clinical disease scores, weight changes, histopathology of colon tissues, plasma VIP levels, cytokine levels and chemotaxis of peripheral blood mononuclear cells were evaluated. After administration of TNBS, mice quickly developed severe colitis accompanied by dramatic body weight loss (20% by day 6) and high mortality (30%). Prophylactic treatment using high-dose VIP abrogated leucocyte chemotaxis; however, it failed to ameliorate the weight loss and mortality. Moreover, VIP delivered either by constant infusion or i.p. failed to modify the clinical, histological or cytokine markers of disease. Our studies show that, despite an ability to inhibit chemokine-induced chemotaxis of mononuclear cells, VIP was unable to modulate TNBS-induced colitis. This contrasts with the efficacy of VIP in models of mild inflammatory disease and suggests that VIP is unlikely to provide a useful model for novel anti-IBD therapy.
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PMID:Vasoactive intestinal peptide impairs leucocyte migration but fails to modify experimental murine colitis. 1573 Mar 86

Our understanding of irritable bowel syndrome and the functional GI disorders has grown considerably over the last 15 years. In part this relates changes in their classification and definition from being due solely to motility disturbances, to being symptom based (eg, Rome criteria). This opened the door to the study of many other factors that contribute to the clinical expression of these disorders, including visceral hypersensitivity, sensitization, altered mucosal immunity, and dysfunction in brain-gut regulatory processes. New knowledge has been gained in areas of genetics, central nervous system and enteric nervous system neurotransmitters of motility, sensitivity and secretion, the effect of altered mucosal inflammation on cytokine and paracrine activation, and neural sensitization, postinfectious disorders, the influence of psychologic stress on gut functioning via alterations in regulatory pathways (eg, hypothalamic-pituitary adrenal axis, or pain regulatory system like the cingulate cortex), improved accuracy of diagnosis using Rome II criteria plus "red flags" the institution of behavioral treatments, and the use of new pharmacologic treatments both at the gut and brain level. Future research will improve upon this new knowledge via basic and translational studies of neuropeptide signaling with new neurotransmitters, new knowledge on the mechanisms for central nervous system-enteric nervous system communication and dysfunction, and more advanced clinical research on education, communication skills and their effects on outcome, genetics, pharmacogenetics and genetic epidemiology, better understanding as to how certain psychosocial domains (eg, catastrophizing, abuse) affect symptom behavior and outcome, newer pharmacologic treatments, and the use of combined pharmacologic and behavioral treatment packages. I am pleased to have the opportunity to provide a personal perspective on what the future will be for irritable bowel syndrome and the other functional GI disorders. Having been involved in this field for almost 30 years, I have been fortunate to witness tremendous changes. The focus of this presentation is to address the advances that have recently occurred that set the stage for proposing future research to help move the field along and ultimately to help our patients.
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PMID:What does the future hold for irritable bowel syndrome and the functional gastrointestinal disorders? 1579 93

Enteral nutrition therapy with liquid diet has been shown to be effective in achieving clinical remission in intestinal Crohn's disease. The mechanism of action of this therapy, however, is still poorly understood. As part of our assessment of the action of 3 related polymeric enteral therapies, we have used a variety of techniques to document the histological and cytokine responses, in the mucosa and, systemically, to these treatments. The feeds studied (AL110, Modulen IBD and ACD004 [Nestle, Vevey, Switzerland]) all have casein as the protein source, are lactose free and are rich in transforming growth factor beta (TGF-beta). They have all been shown to induce clinical remission associated with mucosal healing. In the case of Modulen IBD, as well as mucosal macroscopic and histological healing there was a fall in mucosal proinflammatory cytokines: interleukin-1 mRNA in colonic and ileal, interleukin-8 mRNA in the colon and interferon gamma mRNA in the ileum, but a rise in the regulatory cytokine TGF-beta mRNA in the ileum. These results indicate that these formulas are influencing the disease process itself, and thus suggest that the clinical remission achieved is a result of a reduction in inflammation, rather than a consequence of some other nutrition effect.
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PMID:Control of systemic and local inflammation with transforming growth factor beta containing formulas. 1598 Feb 74

Transient inflammation is known to alter visceral sensory function and frequently precede the onset of symptoms in a subgroup of patients with irritable bowel syndrome (IBS). Duration and severity of the initial inflammatory stimulus appear to be risk factors for the manifestation of symptoms. Therefore, we aimed to characterize dose-dependent effects of trinitrobenzenesulfonic acid (TNBS)/ethanol on: (1) colonic mucosa, (2) cytokine release and (3) visceral sensory function in a rat model. Acute inflammation was induced in male Lewis rats by single administration of various doses of TNBS/ethanol (total of 0.8, 0.4 or 0.2 ml) in test animals or saline in controls. Assessment of visceromotor response (VMR) to colorectal distensions, histological evaluation of severity of inflammation, and measurement of pro-inflammatory cytokine levels (IL-2, IL-6) using enzyme-linked immunosorbent assay (ELISA) were performed 2h and 3, 14, 28, 31 and 42 days after induction. Increased serum IL-2 and IL-6 levels were evident prior to mucosal lesions 2h after induction of colitis and persist up to 14 days (p<0.05 vs. saline), although no histological signs of inflammation were detected at 14 days. In the acute phase, VMR was only significantly increased after 0.8 ml and 0.4 ml TNBS/ethanol (p<0.05 vs. saline). After 28 days, distension-evoked responses were persistently elevated (p<0.05 vs. saline) in 0.8 and 0.4 ml TNBS/ethanol-treated rats. In 0.2 ml TNBS/ethanol group, VMR was only enhanced after repeated visceral stimulation. Visceral hyperalgesia occurs after a transient colitis. However, even a mild acute but asymptomatic colitis can induce long-lasting visceral hyperalgesia in the presence of additional stimuli.
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PMID:Severity of mucosal inflammation as a predictor for alterations of visceral sensory function in a rat model. 1663 Jun 96

The plasma kallikrein-kinin system (KKS) participates in the pathogenesis of inflammatory reactions involved in cellular injury, coagulation, fibrinolysis, kinin formation, complement activation, cytokine secretion and release of proteases. It has been shown that KKS activation in the systemic inflammatory response syndrome results in decrease of its component plasma proteins. Similar changes have been documented in diabetes, sepsis, children with vasculitis, allograft rejection, disseminated intravascular coagulation, patients with recurrent pregnancy losses, hereditary angioedema, adult respiratory distress syndrome and coronary artery disease. Direct involvement of the KKS in the pathogenesis of experimental acute arthritis and acute and chronic enterocolitis has been documented by previous studies from our laboratory using experimental animal models. It has been found that in HK deficient Lewis rats, experimental IBD was much less severe. We showed a genetic difference in kininogen structure between resistant Buffalo and susceptible Lewis rats, which results in accelerated cleavage of HK and it is responsible for the susceptibility to the inflammatory process in the Lewis rats. It has been demostrated that therapy with a specific plasma kallikrein inhibitor (P8720) modulated the experimental enterocolitis, arthritis and systemic inflammation. Furthermore, it has been shown that a bradykinin 2 receptor (B2R) antagonist attenuates the inflammatory changes in the same animal model. We have showed that a monoclonal antibody targeting HK decreases angiogenesis and arrests tumor growth in a syngeneic animal model. In summary, these results indicate that the plasma KKS plays a central role in the pathogenesis of chronic intestinal inflammation, arthritis and angiogenesis.
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PMID:[High molecular weight kininogen in inflammation and angiogenesis: a review of its properties and therapeutic applications]. 1670 6


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