Gaseous transmitters are a growing family of regulatory\ud molecules involved in multilevel regulation of physiological\ud and pathological functions in mammalian tissues. Hydrogen\ud sulfide (H2S) is best known for its characteristic smell of\ud rotten eggs. It is now widely recognized that H2S, along with\ud nitric oxide (NO) and carbonmonoxide (CO), is involved in a\ud multitude of physiological functions. The generation of H2S\ud bymammalian tissues is likely to occur in a slow and constant\ud rate, and it appears to be involved in several processes including\ud neuromodulation, hypertension, inflammation, edema,\ud hemorrhagic shock, pain perception, gastric mucosal integrity,\ud and vascular tone.\ud This Perspective has been designed in order to give to the\ud reader an updated overview on the physiology and biochemistry\ud of H2S. In particular we have summarized the effects of\ud H2S inhibitors and H2S donors in animal models of disease\ud ordered for apparatus. Finally there is a section that addresses\ud the potential for therapeutic exploitation ofH2S and provides\ud an update on the patents so far filed

Background and purpose:Hydrogen sulphide is an important mediator of gastric mucosal defence. The use of non-steroidal anti-inflammatory drugs continues to be limited by their toxicity, particularly in the upper gastrointestinal tract. We evaluated the gastrointestinal safety and anti-inflammatory efficacy of a novel hydrogen sulphide-releasing derivative of naproxen, ATB-346 [2-(6-methoxy-napthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester]. Experimental approach: The ability of ATB-346 versus naproxen to cause gastric damage was evaluated in healthy rats and in rats with compromised gastric mucosal defence. Effects on the small intestine and on the healing of ulcers were also assessed. The ability of ATB-346 to inhibit cyclooxygenase-1 and 2 and to reduce inflammation in vivo was also evaluated. Key results: ATB-346 suppressed gastric prostaglandin E2 synthesis as effectively as naproxen, but produced negligible damage in the stomach and intestine. In situations in which the gastric mucosa was rendered significantly more susceptible to naproxen-induced damage (e.g. ablation of sensory afferent nerves, inhibition of endogenous nitric oxide or hydrogen sulphide synthesis, co-administration with aspirin, antagonism of KIR6.x channels), ATB-346 did not cause significant damage. Unlike naproxen and celecoxib, ATB-346 accelerated healing of pre-existing gastric ulcers. In a mouse airpouch model, ATB-346 suppressed cyclooxygenase-2 activity and inhibited leukocyte infiltration more effectively than naproxen. ATB-346 was as effective as naproxen in adjuvant-induced arthritis in rats, with a more rapid onset of activity. Unlike naproxen, ATB-346 did not elevate blood pressure in hypertensive rats. Conclusions and implications: ATB-346 exhibits anti-inflammatory properties similar to naproxen, but with substantially reduced gastrointestinal toxicity.

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In fibroblasts, thrombin induces collagen deposition through activation of a G-proteincoupled receptor, proteinase-activated receptor 1 (PAR 1 ). In the current study, we examined whether PAR 1 antagonism inhibits hepatic stellate cell (HSC) activation in vitro and whether it protects against fibrosis development in a rodent model of cirrhosis. A rat HSC line was used for in vitro studies whereas cirrhosis was induced by bile duct ligation (

Background and Purpose: Mesalamine is the first-line therapy for colitis, but it lacks potency and is only effective for mild-tomoderate forms of this disease. Hydrogen sulphide has been shown to be a potent, endogenous anti-inflammatory substance, modulating leukocyte-endothelial adhesion and leukocyte migration. The purpose of this study was to determine if an H 2 Sreleasing derivative of mesalamine (ATB-429) would exhibit increased potency and effectiveness in a mouse model of colitis. Experimental Approach: Colitis was induced in mice with trinitrobenzene sulphonic acid and the effects of ATB-429 and mesalamine were compared in several treatment regimens. The severity of colitis was determined using several indices, including a disease activity score (comprised of scores for diarrhea, weight loss and fecal blood), colonic myeloperoxidase activity and macroscopic/microscopic scoring of tissue injury. Key Results: Irrespective of the treatment regiment, ATB-429 was more effective than mesalamine in reducing the severity of colitis. ATB-429 was particularly effective in reducing granulocyte infiltration into the colonic tissue (by B70%), as well as reducing the expression of mRNA for several key proinflammatory cytokines/chemokines (e.g., TNFa, IFNg). Treatment with ADT-OH, the H 2 S-releasing moiety of ATB-429, did not affect severity of colitis. Conclusions and Implications: ATB-429 exhibits a marked increase in anti-inflammatory activity and potency in a murine model of colitis, as compared to mesalamine. These results are consistent with recently described anti-inflammatory effects of H 2 S. ATB-429 may represent an attractive alternative to mesalamine for the treatment of inflammatory bowel disease.