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.

Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage whose better known member is the thrombin receptor. The pathophysiological role of PAR-2 remains poorly understood. Because PAR-2 is involved in inflammatory and injury response events, we investigated the role of PAR-2 in experimental myocardial ischemia-reperfusion injury. We show for the first time that PAR-2 activation protects against reperfusion-injury. After PAR-2-activating peptide (2AP) infusion, we found a significant recovery of myocardial function and decrease in oxidation at reflow. Indeed, the glutathione cycle (glutathione and oxidized glutathione) and lipid peroxidation analysis showed a reduced oxidative reperfusion-injury. Moreover, ischemic risk zone and creatine kinase release were decreased after PAR-2AP treatment. These events were coupled to elevation of PAR-2 and tumor necrosis factor ␣ (TNF␣) expression in both nuclear extracts and whole heart homogenates. The recovery of coronary flow was not reverted by L-nitroarginine methylester, indicating a NO-independent pathway for this effect. Genistein, a tyrosine kinase inhibitor, did not revert the PAR-2AP effect. During early reperfusion injury in vivo not only oxygen radicals are produced but also numerous proinflammatory mediators promoting neutrophil and monocyte targeting. In this context, we show that TNF␣ and PAR-2 are involved in signaling in pathophysiological conditions, such as myocardial ischemia-reperfusion. At the same time, because TNF␣ may exert pro-inflammatory actions and PAR-2 may constitute one of the first protective mechanisms that signals a primary inflammatory response, our data support the concept that this network may regulate body responses to tissue injury.

H 2 S functions as a neuromodulator and exerts anti-inflammatory activities. Recent data indicate that irritable bowel syndrome (IBS) is linked to inflammation of the gastrointestinal tract. In this study, we have investigated the role of a novel H 2 S-releasing derivative of mesalamine (5-amino-2-hydroxybenzoic acid 4-(5-thioxo-5H-[1,2]dithiol-3yl)-phenyl ester, ATB-429) in modulating nociception to colorectal distension (CRD), a model that mimics some features of IBS, in healthy and postcolitic rats. Four graded (0.4 -1.6 ml of water) CRDs were produced in conscious rats, and colorectal sensitivity and pain were assessed by measuring the abdominal withdrawal response and spinal c-Fos expression. In healthy rats, ATB-429 dose dependently (25, 50, or 100 mg/kg) attenuated CRD-induced hypersensitivity and significantly inhibited CRD-induced overexpression of spinal c-FOS mRNA, whereas mesalamine had no effect. ATB-429-induced antinociception was reversed by glibenclamide, a ATP-sensitive K ϩ (K ATP ) channel inhibitor. The antinociceptive effect of ATB-429 was maintained in a rodent model of postinflammatory hypersensitivity (4 weeks after colitis induction). At a dose of 100 mg/kg, ATB-429 reversed the allodynic response caused by CRD in postcolitic rats. Colonic cyclooxygenase-2 and interkeukin-1␤ mRNA and spinal c-FOS mRNA expression were significantly down-regulated by ATB-429, but not by mesalamine. ATB-429, but not mesalamine, increased blood concentrations of H 2 S in both healthy and postcolitic rats. Taken together, these data suggest that ATB-429 inhibits hypersensitivity induced by CRD in both healthy and postcolitic, allodynic rats by a K ATP channel-mediated mechanism. This study provides evidence that H 2 S-releasing drugs might have beneficial effects in the treatment of painful intestinal disorders.

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