Exposure to non-steroid anti-inflammatory drugs (NSAIDs) and suppressing hydrogen sulfide synthesis leads to altered structure and impaired function of the oesophagus and oesophagogastric junction.

INTRODUCTION: The non-steroid anti-inflammatory drugs (NSAIDs) are among the drugs that can commonly cause injury in the esophagus, such as non-reflux oesophagitis, with important clinical consequences. This injury may be 'silent' and therefore often overlooked. Recently, we established that hydrogen sulfide (H2S) is a critical mediator of esophageal mucosal protection and repair. The aim of the study was to determine the effect of naproxen, the most commonly used NSAIDs, on the oesophagus and oesophagogastric junction and its relation with suppression or stimulation of endogenous H2S synthesis during naproxen-induced oesophageal injury. METHODS: Rats were treated with vehicle (control) or naproxen, with or without being subjected to water immersion restricted stress (Takagi et al. Chem Pharm Bul 12:465-472, 1964). Subgroups of rats were pre-treated with an inhibitor of H2S synthesis cystathionine γ-lyase (CSE) or cystathionine ß-synthase (CBS), or with the Sodium sulphide (NaHS), which spontaneously generates H2S in solution. Damage of the oesophageal mucosa and oesophagogastric junction was estimated and scored using a histological damage index. RESULTS: Treatment with naproxen increased the thickness of the corneal and epithelial layers of the oesophagus, as well as producing disorganization of the muscle plate and irregular submucosal oedema. Both injury factors, stress and suppression of H2S synthesis resulted in the development of severe esophagitis and damage to the oesophagogastric junction. The damage was exacerbated by inhibitors of H2S biosynthesis, and attenuated by treatment with NaHS. CONCLUSIONS: Inhibition of endogenous H2S synthesis provides a novel experimental model that can be useful in preclinical studies NSAID-related non-reflux oesophagitis. H2S contributes significantly to mucosal defence in the oesophagus.

Cytoprotective effects of hydrogen sulfide in novel rat models of non-erosive esophagitis.

Non-erosive esophagitis is a chronic inflammatory condition of the esophagus and is a form of gastroesophageal reflux disease. There are limited treatment options for non-erosive esophagitis, and it often progresses to Barrett's esophagus and esophageal carcinoma. Hydrogen sulfide has been demonstrated to be a critical mediator of gastric and intestinal mucosal protection and repair. However, roles for H2S in esophageal mucosal defence, inflammation and responses to injury have not been reported. We therefore examined the effects of endogenous and exogenous H2S in rat models of non-erosive esophagitis. Mild- and moderate-severity non-erosive esophagitis was induced in rats through supplementation of drinking water with fructose, plus or minus exposure to water-immersion stress. The effects of inhibitors of H2S synthesis or of an H2S donor on severity of esophagitis was then examined, along with changes in serum levels of a pro- and an anti-inflammatory cytokine (IL-17 and IL-10, respectively). Exposure to water-immersion stress after consumption of the fructose-supplemented water for 28 days resulted in submucosal esophageal edema and neutrophil infiltration and the development of lesions in the muscular lamina and basal cell hyperplasia. Inhibition of H2S synthesis resulted in significant exacerbation of inflammation and injury. Serum levels of IL-17 were significantly elevated, while serum IL-10 levels were reduced. Treatment with an H2S donor significantly reduced the severity of esophageal injury and inflammation and normalized the serum cytokine levels. The rat models used in this study provide novel tools for studying non-erosive esophagitis with a range of severity. H2S contributes significantly to mucosal defence in the esophagus, and H2S donors may have therapeutic value in treating esophageal inflammation and injury.

Effect of CCl4 and blocking H2S biosynthesis on oesophageal mucosa rats: model of nonerosive oesophagitis.

Nonerosive esophagitis (NEO) - a chronic inflammatory condition with diagnostic and therapy unclear approaches. The aim of study was to develop the new models of NEO using the chemical ulcerogens: carbon tetrachloride (CCl(4)), hydrogen sulfide (H(2)S). We modified the method of NEO with cytoprotective prostaglandins (COX) and H(2)S biosynthesis carried out on rats, divided into groups: 1st - vehicle (1 ml 0.9% NaCl), CCl(4) (twice 0.3 ml/200g/body weight); the next day 2(nd) - vehicle; 3(rd) - nonselective blocker of COX (naproxen; 30 mg/kg); 4(th) - ATB-346 (H(2)S-releasing naproxen; 43.5 mg/kg, «Antibe Therapeutics¼, Canada) with per os administration. After H(2)S-biosythesis modification by intraperitoneal administration of cystathionine g-lyase (CSE) inhibitor, DL-propargylglycine (PAG, 25 mg/kg), cystathionine-b-synthetase (CBS) inhibitor, O-carboxymethyl-hydroxylamine hemihydrochloride (CHH, 50 mg/kg) or H(2)S donor NaHS (100 mlmol/kg), stress was inducted by Takagi, 1964. The lower third of EM and esophagogastric junction were estimated via histological score index, IL-17, IL-10 by ELISA. The obtained data indicated the strong cytotoxic influence of CCl(4) on EM, corneal and epithelial layers thickness increasing, muscle plate and submucosal edema disorganization vs control and ATB-346 treatment. Over-expression of IL-17 was achieved using PAG and BCA vs control. WIRS-associated EM injury with blocking CSE, CBS characterized by submucosal oedema, neutophilic infiltration, destructive lesions, HSI rising up to 6 vs control. Increased IL-17 to 65% and decreased IL-10 in 30% vs control. H(2)S plays key role in the integrity of oesophageal mucosa and modification of H(2)S synthesis and CCl(4)-related injury can be novel approach of animal model production NEO, similar to human NERD and will help in its pathogenesis identification and preventive drugs creation.