Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In rodents colitis can be induced by adding 2% (w/v) carrageenan (CARR) for 4 weeks or 10% (w/v) dextran sulphate sodium (DSS) for 7 days to their drinking water. These models are suitable to test anti-inflammatory drugs used in inflammatory bowel disease in man. Mice were treated with olsalazine (400 mg/kg body wt) starting 7 days before the DSS or CARR administration. Colonic tissues were incubated with [1-14C]-arachidonic acid and stimulated with A23187 and, thereafter, the pattern of eicosanoids was determined by separation on HPLC. DSS and CARR produced a marked diffuse inflammatory response in the colon and a subsequent 5-fold increase of all eicosanoids after DSS, whereas after CARR only a 2-fold increase of PGs was observed. Olsalazine treatment decreased all cyclooxygenase and lipoxygenase products to baseline levels.
 ...
PMID:Experimental colitis in mice: effects of olsalazine on eicosanoid production in colonic tissue. 144 39

Nonsteroidal anti-inflammatory drugs have become increasingly popular, with more than 90 million prescriptions being written annually. These drugs inhibit the intracellular cyclooxygenase enzyme system, thus blocking the production of various prostaglandin compounds. This, in turn, interferes with normal mucosal protective mechanisms, leading to local injury. Gastrointestinal complications of nonsteroidal anti-inflammatory drug use include ulcerations, hemorrhage, perforation, stricture formation, and the exacerbation of inflammatory bowel disease. Treatment involves stopping the drug if at all possible and then instituting more specific therapy depending on the anatomic area that has been injured.
 ...
PMID:Gastrointestinal complications of nonsteroidal anti-inflammatory drugs. 146 53

In the presence of halides, granulocytes generate hypochlorous acid and, subsequently, chlorinated amines (chloramines). These lipophilic, potent reactive oxygen metabolites may contribute to the mucosal pathophysiology associated with inflammatory bowel disease. A common symptom of inflammatory bowel disease is mucosal secretion of fluid and electrolytes, leading to diarrhea. Because acetylcholine (Ach) can stimulate colonic fluid secretion, we determined the effect of monochloramine (NH2Cl) on Ach release by mucosal/submucosal nerves. Mucosa from the rat colon was separated from outer muscle layers and minced before incubation with [14C]choline to label stores of Ach in cholinergic neurons. Release of [14C]Ach was evoked with NH2Cl in the absence and presence of 5-aminosalicylic acid, glutathione, nordihydroguaiarectic acid or the cyclooxygenase inhibitor piroxicam. NH2Cl produced concentration-related increases in [14C] Ach release into the medium; greater than 100% over base line was observed at 0.5 mM. Glutathione inhibited the NH2Cl-evoked release in a concentration-dependent fashion. Release induced by 0.1 mM NH2Cl was abolished by 5-aminosalicylic acid and significantly inhibited by nordihydroguaiarectic acid. Piroxicam also prevented the effect of NH2Cl on release of [14C] Ach. None of these agents alone had any effect on base line [14C]Ach release. Tetrodotoxin (5 microM) did not significantly inhibit the NH2Cl-evoked transmitter release. We conclude that NH2Cl, at concentrations believed to exist in inflamed tissue, causes the release of Ach from mucosal/submucosal nerves primarily through nonspecific neural membrane injury. Endogenous prostaglandins, possibly liberated as a consequence of the injury, may be involved in the Ach release process.
 ...
PMID:Oxidant-evoked release of acetylcholine from enteric neurons of the rat colon. 146 20

Arachidonic acid metabolites formed by both the cyclooxygenase and lipoxygenase pathways may contribute to the clinical diarrhea and colitis of inflammatory bowel disease. Patients with active ulcerative colitis have increased levels of leukotriene B4 in their rectal mucosa, and these levels tend to correlate with severity of the disease. In this study, we evaluated the efficacy of ingestion of fish oil n-3-omega-fatty acids, inhibitors of leukotriene synthesis, in the treatment of ulcerative colitis. Eleven patients with ulcerative colitis of mild to moderate severity were studied in a 8-month, double-blind, placebo-controlled, crossover trial of dietary supplementation with fish oil, which provided about 4.2 g of omega-3- fatty acids per day. A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess efficacy. Mucosal leukotriene B4 production was measured by radioimmunoassay. Mean disease activity index declined 56% for patients receiving fish oil and 4% for patients on placebo (p less than 0.05). There were no statistically significant differences in histopathologic scores or colonic mucosal leukotriene B4 levels. All patients tolerated fish oil ingestion and showed no alteration in routine blood studies. No patient worsened; anti-inflammatory drugs could be reduced or eliminated in eight patients (72%) while receiving fish oil. We conclude that fish oil dietary supplementation results in clinical improvement of active mild to moderate ulcerative colitis but is not associated with significant reduction in mucosal leukotriene B4 production, compared with placebo therapy. Further studies are needed to elucidate the mechanism of action and optimal dose and duration of fish oil supplementation in ulcerative colitis.
 ...
PMID:Fish oil fatty acid supplementation in active ulcerative colitis: a double-blind, placebo-controlled, crossover study. 155 30

Large numbers of polymorphonuclear leukocytes which generate reactive oxygen metabolites are found in mucosa and submucosa of the intestinal wall of subjects suffering from inflammatory bowel disease. We have, therefore, examined the relative influences of hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and N-chloramines such as NH2Cl, on the neurally stimulated and nonstimulated guinea pig ileum. In separate experiments the oxidants were tested in the presence and absence of the cyclooxygenase inhibitor piroxicam and the antioxidant glutathione. All three oxidants, in concentrations produced by activated neutrophils, increased the muscle tone (concentration-dependent, peak at 0.3 mM for NH2Cl and H2O2 and 1 mM for HOCl). Tetrodotoxin (0.5 microM) inhibited the NH2Cl and H2O2 effects by 50% and 70%, respectively. Piroxicam (5 microM) partially blocked maximal contractions induced by all three oxidants. The contractile response to carbachol (10 microM) was blocked by 0.3 mM NH2Cl, but not by H2O2 and HOCl. In electrically stimulated ileum the oxidants produced a concentration-dependent biphasic response (transient enhancement of neurally mediated twitch contraction followed by marked inhibition). This response was not modified by piroxicam, hexamethonium, atropine and pyrilamine. The inhibition of twitch contraction was irreversible for NH2Cl and HOCl, in contrast to H2O2, which was reversed by repeated washing. Neither the contractile effect nor the effects on nerve stimulation-induced contraction were affected by preincubation of the tissue with glutathione, whereas prior combination of NH2Cl with glutathione prevented the effects of NH2Cl. Oxidant-induced contraction of guinea pig ileum appears to be via release of prostaglandins and one or more neurotransmitters. High concentrations of reactive oxygen metabolites may alter receptor function.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Differential effects of reactive oxygen metabolites on neurally stimulated and nonstimulated guinea pig ileum. 167 Oct 95

Polyethylene glycol 400 (PEG 400) is a clinically useful intestinal permeability probe whose rate of intestinal permeation is influenced in part by solvent drag. As mucosal prostanoids are increased in inflammatory bowel disease and affect water transport we examined the possible relationship between prostaglandin E2 (PGE2) and the inhibitors of endogenous prostaglandins--the non-steroidal anti-inflammatory drugs (NSAIDS)--on PEG 400 absorption in vivo using segmental perfusion of rat small intestine. We found that the addition of exogenous PGE2 in concentrations of 0.5, 1.0, and 1.5 micrograms/ml significantly (p less than 0.01) decreased PEG 400 and water absorption. Addition of 5 mmol/l of the cyclooxygenase inhibitors acetylsalicylic acid (ASA) or indomethacin in concentrations 2.5 or 5.0 mmol/l to the perfusate significantly (p less than 0.01) increased PEG 400 and water absorption. The simultaneous addition of 1.0 micrograms/ml of exogenous PGE2 to the perfusate with 5 mmol/l of ASA or with 2.5 mmol/l of indomethacin reversed the increase of PEG 400 and water transport (p less than 0.01). There were no differences in PEG 400 and water absorption when PGE2 was given alone or in combination with ASA or indomethacin. This study suggests that endogenous or exogenous prostanoids play an important role in the regulation of PEG 400 permeation. PGE2 and NSAIDS modify PEG 400 permeation in parallel with changes in water transport indicating that their effect on permeability is through changes in solvent drag. These findings provide a mechanism which might explain the increase in PEG 400 intestinal permeability in Crohn's disease patients and the increase in intestinal permeability found in patients receiving NSAIDS.
 ...
PMID:Regulation of polyethylene glycol 400 intestinal permeability by endogenous and exogenous prostanoids. Influence of non-steroidal anti-inflammatory drugs. 233 66

Different layers of rabbit large and small intestine display different peptide sensitivity and different profiles of eicosanoid release. Isolated perfused mesenteric pedicle alone, with muscularis/submucosa or with muscularis and mucosa from normal small bowel, normal colon, or inflamed colon were stimulated with bradykinin (BK) or n-formyl-methionyl-leucyl-phenylalanine (fMLP). Released prostaglandin (PG)E2, thromboxane (Tx)B2, and leukotriene (LT)B4 were assayed using extensively validated radioimmunoassays. In rabbit colon, PGE2 arises primarily from the mesentery, while in small intestine the muscularis/mucosa releases 70-80% of the total PGE2. BK releases no significant thromboxane from healthy colon, although both muscularis/submucosa and mucosa respond in inflamed colon. In contrast, fMLP stimulates thromboxane from muscularis/submucosa and mucosa of even healthy colon, while release is greatly potentiated in inflammation. Lipoxygenase in the colon is regulated differently than cyclooxygenase; it is not stimulated by BK in either healthy or inflamed colon. fMLP releases equal amounts of LTB4 from healthy and inflamed colon, but release was primarily from healthy colonic mucosa, whereas it was distributed throughout mesenteric pedicle, muscularis, and mucosa in inflamed colon. The ability of normal colonic mucosa to release proinflammatory LTB4 in response to a chemotactic factor (fMLP) produced by enteric bacteria suggests a possible role for these compounds as a stimulus for inflammation in some patients with inflammatory bowel disease.
 ...
PMID:Tissue origin of peptide-responsive eicosanoid production in rabbit intestine. 261 Feb 59

Non-steroid, anti-inflammatory drug (NSAID)-induced lesions in the gut are common, but so far most focus has been placed on the gastroduodenal mucosa. However, an increasing number of reports describe deleterious effects on the distal gut as well. Findings range from asymptomatic mucosal inflammation to stricture and obstruction, perforations, and major hemorrhages. Induction and exacerbation of inflammatory bowel disease has also been noted for most of the commercially available NSAIDs. Although final proof of a causal relationship is lacking, the indices present strongly suggest such a connection. The mechanism is largely unknown, although inhibition of cyclooxygenase with subsequent depletion of endogenous prostanoid synthesis has been suggested as a mediator. If surgery can be avoided, stopping the NSAID therapy is often sufficient to obtain lasting remission. The main point is knowledge of this facet of NSAID use, so that the pertinent drug history is obtained. Determination of the distal gut effects should probably also be included in the evaluation of present and future NSAIDs.
 ...
PMID:Non-steroidal anti-inflammatory drug-induced disease in the distal ileum and large bowel. 268 28

Inflammatory bowel disease affects millions of people, some with fatal consequences. Little is known about the factors which contribute to its pathogenesis particularly regarding cytokine production and action. In this paper we summarize our recent findings using the rabbit model for immune complex-generated experimental colitis, a model which is similar to ulcerative colitis in humans. Recombinant human IL-1 was perfused through rabbit colons and we observed elevated levels of PGE2, TxB2 and 6-keto-PGF1 alpha, the stable metabolite of PGI2. Using radioimmunoassays specific for rabbit IL-1 alpha and IL-1 beta, we induced immune complex colitis and measured the generation of these IL-1's in various tissues. Markedly elevated levels of IL-1 were detected only in inflamed tissues. The levels of IL-1 correlated with the degree of inflammation as judged by a blinded assessment of pathological changes. Similar to other disease models in which small doses of the agonist can afford protection or result in a state of "desensitization" when administered prior to the onset of the disease, we accordingly injected rabbits with a single, small (300 ng/kg) dose of IL-1 and observed a significant reduction in the inflammatory index and necrosis of immune complex colitis. However, unlike other models of IL-1-induced protection, in this model cyclooxygenase products were required since we prevented the IL-1-induced protection with a single dose of ibuprofen given at the same time as the IL-1. This correlated with the reduction in IL-1-induced PGE2. These results demonstrate that IL-1 plays a key role in the pathogenesis of inflammatory bowel disease in the rabbit and that the protection afforded by a low dose of IL-1 24 hours before the onset of the colitis requires IL-1-induced cyclooxygenase products.
 ...
PMID:Interleukin-1 in the pathogenesis of and protection from inflammatory bowel disease. 270 50

Despite the extensive use of sulfasalazine (SAS) and/or 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease and, more recently, rheumatoid arthritis, their mode of action has not been elucidated so far. None of the numerous pharmacological and biochemical effects described, including immunosuppressive, antifolate, and modulatory actions on lymphocyte and leukocyte functions, could be defined unequivocally as mediating their beneficial activity. Recently, interest has focused on actions of SAS and 5-ASA on the various enzymes of the arachidonic acid cascade. Mucosa of patients with inflammatory bowel disease generates excessive amounts of cyclooxygenase products such as prostaglandins (PG) as well as 5-lipoxygenase products such as leukotriene (LT) B4 and sulfidopeptide-LT. Both PG and LT exert proinflammatory actions and are potentially important mediators of mucosal inflammation. SAS and 5-ASA, however, have been found to inhibit PG synthesis under certain experimental conditions only, while increasing PG formation under other conditions. While SAS was found to inhibit colonic LTB4 synthesis, 5-ASA was reported to selectively affect the cyclooxygenase pathway of arachidonate metabolism in this tissue. Our results demonstrate that, like the parent compound, the metabolite 5-ASA in a dose-dependent manner inhibits release of LTB4 and sulfidopeptide-LT from normal human colonic mucosa (IC50 3.5 and 3.7 mmol/liter, respectively). Indomethacin, which has no efficacy in the treatment of patients with inflammatory bowel disease, on the other hand, selectively inhibited PGE2 formation in normal and inflamed colonic mucosa (IC50 1.7 and 1.0 mmol/liter, respectively) without reducing synthesis of LTB4 or sulfidopeptide-LT.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Possible mode of action of 5-aminosalicylic acid. 289 68


1 2 3 4 5 6 7 8 Next >>