Hydrogen Sulfide: A Rescue Molecule for Mucosal Defence and Repair

Abstract

In the past decade, hydrogen sulfide (H2S) has taken on something of a new identity. Long recognized as an industrial pollutant and environmental toxin, H2S is now known to be produced throughout the body and to regulate important functions in most organs and tissues [1–3]. In the digestive system, H2S exerts potent anti-inflammatory actions, regulates blood flow and smooth muscle tone, modulates epithelial secretion and promotes healing of ulcers [4, 5]. Indeed, many of the actions of H2S overlap with those of nitric oxide (NO), another gaseous mediator recognized mainly as a pollutant and toxin before its physiological importance was elucidated [1–4]. H2S also bears some similarity to NO with respect to its synthetic pathways in mammals. Like NO, H2S is synthesized from an amino acid (L-cysteine), and this can occur via three (at least) enzyme pathways. Inhibitors of these pathways are available for use in experimental settings, but they are imperfect, lacking specificity for the target enzymes. A number of H2S donors are available for assessing the effects of this mediator in experimental settings, including some derived from natural products, such as garlic [3, 5]. Like NO, H2S is an important mediator of gastric mucosal defence (Table 1) [5]. Inhibition of endogenous H2S synthesis increases the susceptibility of the mucosa to damage induced by nonsteroidal anti-inflammatory drugs (NSAIDs), for example [6, 7]. On the other hand, exogenous H2S donors can increase the resistance of the mucosa to injury [5–7]. Moreover, H2S synthesis is markedly up-regulated after mucosal injury occurs, and it contributes significantly to promoting the healing of the injured tissue [8, 9]. H2S donors can accelerate ulcer healing in experimental models [8, 9]. There is emerging evidence that H2S plays an important role in promoting resolution of inflammation, in part by up-regulating cyclooxygenase-2 expression [9]. In the current issue of this journal, Mard et al. [10] report that administration of H2S just prior to an episode of ischemia–reperfusion can dose-dependently protect the stomach of the rat from damage. Protection could similarly be afforded through administration of L-cysteine, the precursor for H2S synthesis. Further evidence that H2S played a pivotal role in the maintenance of mucosal integrity during ischemia–reperfusion was the observation that suppression of endogenous H2S synthesis, with propargylglycine, resulted in a significant exacerbation of gastric injury. The authors suggest that it is the suppression of mRNA expression and plasma levels of pro-inflammatory cytokines that accounts for the reduction of gastric damage when the rats were pre-treated with an H2S donor or L-cysteine. One cannot exclude the possibility that the reduced cytokine expression/production occurred, at least in part, as a consequence of the reduced gastric injury, though H2S has been shown to reduce pro-inflammatory cytokine expression/synthesis in other in vivo models, including colitis [9, 11, 12]. The reduced gastric injury observed in the study of Mard et al. [10] may have been attributable to effects of H2S on any of a number of components of mucosal defence, including bicarbonate secretion [13] and mucosal blood flow [6] (see summary in Table 1). A number of recent studies suggest that the ability of H2S to maintain mitochondrial function in the face of challenges such as ischemia may underlie some of the beneficial effects of this J. L. Wallace (&) Farncombe Family Digestive Health Research Institute, McMaster University, 1280 Main Street West, HSC-3N4, Hamilton, ON L8S 4K1, Canada e-mail: jwalla@mcmaster.ca