leukotriene-c4 and Colitis

G-protein-coupled receptors (GPCRs) are the molecular target of 40% of marketed drugs and the most investigated structures to develop novel therapeutics. Different members of the GPCRs superfamily can modulate the same cellular process acting on diverse pathways, thus representing an attractive opportunity to achieve multitarget drugs with synergic pharmacological effects. Here, we present a series of compounds with dual activity toward cysteinyl leukotriene receptor 1 (CysLT

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Humans; Leukotriene D4; Macrophages; Mice; Molecular Docking Simulation; Protein Binding; RAW 264.7 Cells; Receptors, G-Protein-Coupled; Receptors, Leukotriene; Structure-Activity Relationship

The cysteinyl leukotrienes (CysLTs), i.e. LTC

Topics: Acetates; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bile Acids and Salts; Colitis; Cyclopropanes; Disease Models, Animal; Gene Expression; Genes, Reporter; HEK293 Cells; Hep G2 Cells; Humans; Leukotriene Antagonists; Leukotriene C4; Leukotriene D4; Leukotriene E4; Luciferases; Mice; Mice, Knockout; Molecular Docking Simulation; Quinolines; RAW 264.7 Cells; Receptors, G-Protein-Coupled; Receptors, Leukotriene; Recombinant Fusion Proteins; Sulfides

The molecular mechanisms underlying inflammatory bowel diseases (IBD) are incompletely characterized. MRP-1, normally expressed in the large and small bowel epithelium, serves as a multidrug resistance protein. In this report we explored the role of MRP1 in IBD. Mrp1-deficient mice (mrp1-/-) were subjected to two different models of IBD. The mrp1-/- mice and wild-type (WT) mice showed equal induction of TNBS colitis, a hapten-induced T-cell mediated disease. However, in DSS colitis more severe disease was observed in mrp1-/- mice. In a survival study, mortality of mrp1-/- mice was higher. In nonlethal DSS colitis, the mean histological colitis score was significantly higher in mrp1-/- mice and showed particularly severe epithelial damage. Although endogenous LTB4 levels were significantly increased in mrp1-/- mice, treatment with a LTB4 antagonist did not reduce disease. We conclude that MRP-1 has an important role in the intestinal epithelial resistance to exogenous injury, but MRP-1 does not affect T-lymphocyte mediated mucosal damage.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Colitis; Colon; Dextran Sulfate; Leukotriene B4; Leukotriene C4; Mice; T-Lymphocytes; Trinitrobenzenesulfonic Acid

Sulfhydryl compounds are essential in maintaining mucosal integrity, and nitric oxide may contribute to tissue injury. The aim of this study was to characterize experimental colitis induced by a sulfhydryl blocker.. Colitis was induced in rats by intracolonic administration of 0.1 mL 3% iodoacetamide with and without addition of 0.1 mg/mL NG-nitro-L-arginine methyl ester (L-NAME) to the drinking water. After death, the distal colonic segment was resected and weighed, and mucosal inflammatory mediator, myeloperoxidase, and NO synthase activities were determined.. Iodoacetamide induced multifocal mucosal erosions and ulceration that were present for up to 1 week. At 3 weeks, the mucosa was almost intact. Colonic wet weight was maximal at 7 days. Myeloperoxidase activity and NO generation were increased in the first 72 hours, and NO synthase activity and prostaglandin E2 generation were increased up to 21 days. Leukotriene B4 and leukotriene C4 generation were increased up to 14 days. One week after iodoacetamide plus L-NAME treatment, lesion area was reduced by 85% and NO synthase activity by 52%.. Inflammatory mediators have an important contribution to the pathogenesis of colonic injury induced by a sulfhydryl alkylator. The protective effect of L-NAME indicates that NO contributes to tissue injury and that its modulation may be a novel approach to treat inflammatory bowel disease.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Colitis; Colon; Dinoprostone; Intestinal Mucosa; Iodoacetamide; Leukotriene B4; Leukotriene C4; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Peroxidase; Rats; Rats, Sprague-Dawley

TEMPOL, a cyclic nitroxide stable radical blocks biological damage by breaking chain reactions through termination reaction with free radicals, and by inhibiting the catalytic effect of transition metals. This study tested its protective effect on two models of experimental colitis as free radicals play an important part in their pathogenesis. TEMPOL was given intragastrically immediately after induction of colitis with acetic acid or trinitrobenzene sulphonic acid (TNB) and mucosal damage was assessed one, three, or seven days later. Cellular partition of TEMPOL was determined by electron paramagnetic resonance spectroscopy. In vitro experiments showed that TEMPOL immediately penetrates colonic mucosa and, following its intragastric administration, it persists in both gastric and colonic mucosa for several hours. Intragastric administration of TEMPOL, 0.5 g/kg/bw, immediately after intracaecal administration of 5% acetic acid significantly decreased mucosal lesion area, myeloperoxidase activity, and leukotriene B4 and C4 generation when assessed 24 hours after damage induction. Intragastric administration of TEMPOL, 0.5 g/kg/bw, immediately after intracolonic administration of 30 mg TNB in 0.25 ml 50% ethanol, and once daily thereafter, significantly decreased mucosal lesion area assessed after one, three, and seven days, having no effect on LTC4 generation and affecting colonic weight, myeloperoxidase activity, and LTB4 generation only sporadically. In conclusion, TNB and acetic acid induced colitis can be pharmacologically manipulated by TEMPOL. TEMPOL may be beneficial in the treatment or prevention of inflammatory bowel disease.

Topics: Acetates; Animals; Antioxidants; Colitis; Cyclic N-Oxides; Disease Models, Animal; Electron Spin Resonance Spectroscopy; Intestinal Mucosa; Leukotriene B4; Leukotriene C4; Lipoxygenase; Male; Peroxidase; Rats; Rats, Sprague-Dawley; Spin Labels; Time Factors; Trinitrobenzenesulfonic Acid