6-ketoprostaglandin-f1-alpha and Colitis

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) play an important role in inflammatory bowel diseases (IBDs). We investigated the effects of flavocoxid, a dual COX/LOX inhibitor, in experimental colitis induced with either dinitrobenzenesulfonic acid (DNBS) or dextrane sulphate sodium (DSS) In the first model, colitis was induced in rats by a single intra-colonic instillation (25mg in 0.8ml 50% ethanol) of DNBS; after 24h animals were randomized to receive orally twice a day, flavocoxid (10mg/kg), zileuton (50mg/kg), or celecoxib (5mg/kg). Sham animals received 0.8ml of saline by a single intra-colonic instillation. Rats were killed 4 days after induction and samples were collected for analysis. In the second model, colitis was induced in rats by the administration of 8% DSS dissolved in drinking water; after 24h animals were randomized to the same above reported treatments. Sham animals received standard drinking water. Rats were killed 5 days after induction and samples were collected for analysis. Flavocoxid, zileuton and celecoxib improved weight loss, reduced colonic myeloperoxydase activity, macroscopic and microscopic damage, and TNF-α serum levels. Flavocoxid and celecoxib also reduced malondialdheyde, 6-keto PGF1α and PGE-2 levels while flavocoxid and zileuton decreased LTB-4 levels. In addition, flavocoxid treatment improved histological features and apoptosis as compared to zileuton and celecoxib; moreover only flavocoxid reduced TXB2, thus avoiding an imbalance in eicosanoids production. Our results show that flavocoxid has protective effect in IBDs and may represents a future safe treatment for inflammatory bowel diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Body Weight; Catechin; CD3 Complex; Celecoxib; Colitis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drug Combinations; Eating; Gene Expression Regulation; Hydroxyurea; Leukotriene B4; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley; Thromboxane B2; Tumor Necrosis Factor-alpha

The clinical usefulness of celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, for treatment of inflammatory bowel disease (IBD) is controversial in terms of efficacy and toxicity. To overcome these problems, colon-specific drug delivery was adopted, which generally confers therapeutic and toxicological advantages of drugs for treatment of colonic diseases. N-succinylaspart-1-yl celecoxib (SA1C), a colon-specific prodrug of celecoxib, was administered orally to rats with experimental colitis, and the anti-colitic effects and a molecular mechanism were investigated and compared to those of conventional celecoxib. SA1C, which delivered a much greater amount of celecoxib to the inflamed colon, alleviated the colonic injury, lowered myeloperoxidase activity in the inflamed colonic tissues and was much more effective than conventional celecoxib. SA1C but not conventional celecoxib significantly attenuated expression of NFκB target gene products in the inflamed tissues. Consistent with this, SA1C effectively prevented nuclear accumulation of p65 in the inflamed tissues. Moreover, while conventional celecoxib lowered the serum level of 6-keto-PGF1α, an inverse indicator of cardiovascular toxicity, SA1C did not change its serum level. Our data suggest that colonic delivery of celecoxib is a feasible strategy for treatment of IBD with improved therapeutic and toxicological properties.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Celecoxib; Cell Line; Colitis; Colon; Cyclooxygenase 2 Inhibitors; Gene Expression Regulation; Humans; Male; Mice; Prodrugs; Pyrazoles; Rats; Sulfonamides; Trinitrobenzenesulfonic Acid

This study has examined the response of a rabbit model of inflammatory bowel disease to methylprednisolone. Colitis was induced in the colon of rabbits with 40 mg trinitrobenzenesulphonic acid in 25% ethanol (TNBS). The effect of methylprednisolone (0.5 mg/kg/day) on the development of colitis was determined at one week, by examining the colon's macroscopic and microscopic appearance, the distribution of matrix metalloproteinases (MMPs) and by measuring eicosanoid production. Although there was no difference in the area of ulcerated colonic tissue in the treated and untreated TNBS animals, the increase in polymorphonuclear leucocytes was significantly reduced in TNBS rabbits given methylprednisolone. The only difference in the distribution of MMPs was a reduction in the number of polymorphonuclear leucocytes containing gelatinase B. The release of immunoreactive PGE2 and LTB4, but not 6-keto PGF1 alpha, was increased in the TNBS animals and was unchanged by methylprednisolone. These results show that methylprednisolone does not modify the injury produced by TNBS in this model despite reducing the infiltration of polymorphonuclear leucocytes. Hence it suggests that these cells do not contribute to the injury observed, are not the source of the eicosanoids and that gelatinase B is not required in the healing process in this model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Colitis; Colon; Dinoprostone; Disease Models, Animal; Eicosanoids; Leukocyte Count; Leukotriene B4; Metalloendopeptidases; Methylprednisolone; Neutrophils; Rabbits; Random Allocation; Trinitrobenzenesulfonic Acid

Platelet-activating factor (PAF) is an endogenous phospholipid which may be an important mediator of shock and inflammation. Recent evidence suggests that PAF plays a role in the development of ischemic colitis and inflammatory bowel disease. Its effects are mediated by second messengers, including the arachidonic acid metabolites. Using an ex vivo isolated left colon rabbit perfusion model, our aims were to determine whether exogenously administered trinitrobenzene sulfonic acid (TNB), which produces experimental colitis, stimulates both PAF and eicosanoid release in the colon, and if so, whether this effect can be blocked by a PAF antagonist. Colonic inflammation was induced by the intracolonic administration of 0.25 ml of 50% ethanol containing 30 mg of TNB. Tissue and perfusate concentrations of the eicosanoids, [prostaglandin E (PGE2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2), leukotriene B4 (LTB4)] and the autocoid PAF were measured by ELISA. During TNB infusion there was a significant increase in tissue levels of PAF compared to control colons. Additional studies performed pretreating the colons with the PAF receptor antagonist WEB-2170 prior to TNB infusion blocked PAF release. TNB stimulated release of luminal eicosanoids except LTB4 and suppressed release of tissue prostanoids. Pretreatment with WEB-2170 prior to TNB inhibited luminal eicosanoids, and inhibited PGE2 and prostacyclin, but not TX tissue suppression. Inhibition of TNB-stimulated PAF release by WEB-2170 suggests that PAF may play a role in TNB-induced colitis and this phenomenon may mediate tissue injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Azepines; Colitis; Colon; Dinoprostone; Eicosanoids; Gastrointestinal Contents; Leukotriene B4; Platelet Activating Factor; Rabbits; Second Messenger Systems; Thromboxane B2; Triazoles; Trinitrobenzenesulfonic Acid

Eicosanoids, as modulators of inflammation, may be involved in the pathogenesis of inflammatory bowel disease. We investigated their potential role in a rat model of chronic granulomatous colonic inflammation induced by trinitrobenzene sulphonic acid. Luminal eicosanoid release was quantified in vivo using a dialysis bag placed into the distal colon. We tested the effect of drugs known to modify inflammatory activity or arachidonic acid metabolism. Three days after intracolonic injection of trinitrobenzene sulphonic acid at different dose levels, the dialysates showed a highly significant increase of prostaglandin E2, 6-keto-prostaglandin F1 alpha, thromboxane B2 (TXB2), and leukotriene B4, compared with levels in controls not subjected to the toxic agent. Remarkably, the release of TXB2 continued to increase during the stage of chronic inflammation (up to day 21), whereas the levels of the remainder eicosanoids declined. Treatment with prednisone or 5-aminosalicylic acid reduced TXB2 levels in the chronic stage of the inflammatory disease and improved the morphological damage as assessed macroscopically and histologically. Moreover, two selective thromboxane synthetase inhibitors, OKY 1581 and R70416, significantly reduced the development of chronic inflammatory lesions in the colon while inhibiting the release of TXB2. Our results indicate that (1) luminal release of thromboxane increases in the chronic stage of colonic inflammation, (2) anti-inflammatory treatment reduces tissue damage and thromboxane release, and (3) selective thromboxane synthetase inhibition improves the course of the disease in our experimental model.

Topics: 6-Ketoprostaglandin F1 alpha; Aminosalicylic Acids; Animals; Colitis; Dinoprostone; Indomethacin; Leukotriene B4; Male; Mesalamine; Methacrylates; Pentanoic Acids; Prednisone; Pyridines; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxane-A Synthase; Trinitrobenzenesulfonic Acid

The role of leukotrienes in the pathogenesis of chronic colitis was investigated using a rat model. Ulceration and inflammation of the distal colon was initiated by the intracolonic administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol. Leukotriene B4 synthesis increased significantly within 4 h after induction of damage, with the greatest increase observed 24-72 h after administration of the hapten. The increase in leukotriene B4 synthesis correlated well (r = 0.88) with an increase in colonic myeloperoxidase activity, a biochemical marker of neutrophil infiltration. Daily intracolonic treatment with a specific 5-lipoxygenase inhibitor, L651,392, during the first 4 days after initiation of colitis, resulted in significant reductions of colonic leukotriene B4 synthesis, colonic damage score, and colon wet weight. When examined 2 wk after initiation of colitis, the group treated with L651,392 (for the first 4 days) showed significantly less colonic damage (assessed macroscopically and histologically) and colonic inflammation (assessed histologically and by measurement of myeloperoxidase activity). The healing produced by treatment with L651,392 was comparable to that observed after treatment with 5-aminosalicylic acid in a similar manner. Although a reduction of colonic damage could be produced in this model by intracolonic pretreatment with a prostaglandin E1 analogue (rioprostil), the mechanism of action of L651,392 did not appear to be through prevention of the initial injury induced by the hapten and ethanol solution. These results demonstrate that inhibition of leukotriene synthesis results in a marked acceleration of the healing of colonic ulcers and resolution of colonic inflammation in this animal model of chronic colitis. The results are therefore consistent with the hypothesis that leukotrienes play an important role in the pathogenesis of intestinal inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Aminosalicylic Acids; Animals; Chronic Disease; Colitis; Colon; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mesalamine; Peroxidase; Phenothiazines; Prostaglandins E; Rats; Rats, Inbred Strains; Rioprostil

1. The effects of anti-inflammatory drugs on eicosanoid formation and colonic damage in a chronic model of inflammatory bowel disease (IBD) in the rat were investigated. 2. A single colonic instillation of the hapten, trinitrobenzene sulphonic acid (TNB) resulted in ulceration and inflammation which persisted for 3 weeks. 3. The macroscopic colonic damage, present 3 weeks after TNB, was correlated with an increase in immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene B4 (LTB4) synthesis by the rat colon. 4. Anti-inflammatory drugs were administered 2 weeks after TNB, when there was substantial colonic damage, and continued for a week. The experimental drug BW755C inhibited the increased formation of 6-keto-PGF1 alpha and LTB4 by the inflamed colon. Indomethacin and aspirin markedly inhibited prostanoid formation in both inflamed and control colon. Sulphasalazine or prednisolone also inhibited the formation of 6-keto-PGF1 alpha but the effects were less marked. 5. None of the anti-inflammatory drugs significantly reduced the colonic damage induced by TNB. 6. The results suggest that eicosanoids, including LTB4, have only a minor role in maintaining the chronic macroscopic damage induced in the rat colon by TNB. The role of such eicosanoids in the underlying infiltration and activity of inflammatory cells in this model of IBD, however, is not known.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Colitis; Eicosanoic Acids; In Vitro Techniques; Leukotriene B4; Male; Radioimmunoassay; Rats; Rats, Inbred Strains