Hydrogen sulfide protected gastric epithelial cell from ischemia/reperfusion injury by Keap1 s-sulfhydration, MAPK dependent anti-apoptosis and NF-κB dependent anti-inflammation pathway

Hydrogen sulfide (H₂S) has been proposed as a novel gas-transmittter, which plays multiple physiological and pathological functions in various body systems, including gastrointestinal tract. The present study was undertaken to investigate the effects and mechanisms of H₂S pharmacological preconditioning on gastric epithelial cells ischemia-reperfusion (I/R) injury. We report here that sodium hydrosulfide (NaHS), an H₂S donor, concentration-dependently suppressed I/R-induced cellular injury and apoptotic cell death. This protection effect was also confirmed by endogenous over-producing H₂S. Furthermore, NaHS also prevented I/R-induced oxidative stress and inflammatory responses, evidenced by increases in GSH level, decreases in MDA contents, reactive oxygen species generation and secretions of NO, IL-6 and TNF-α. NaHS also prevented I/R-induced p38- and c-Jun NH2-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB activation. H₂S also induced Keap1 s-sulfhydration, and further Keap1/Nrf2 disassociation and Nrf2 activation. H₂S exerted its protective effect through reactive oxygen species clearance, inhibition of p38 and JNK dependent cell apoptosis and NF-κB dependent inflammation pathway. Our results provide evidence that H₂S may have potential therapeutic value in acute gastric mucosal lesion, which is often caused by ischemia/reperfusion.