Endogenous hydrogen sulfide regulates inflammatory response by activating the ERK pathway in polymicrobial sepsis

Hydrogen sulfide (H2S) up-regulates inflammatory response in several inflammatory diseases. However, to date, little is known about the molecular mechanism by which H2S provokes the inflammatory response in sepsis. Thus, the aim of this study was to investigate the signaling pathway underlying the proinflammatory role of H2S in cecal ligation and puncture (CLP)-induced sepsis. Male Swiss mice were subjected to CLP and treated with DL-propargylglycine (PAG; 50 mg/kg i.p., an inhibitor of H2S formation), NaHS (10 mg/kg, i.p., an H2S donor), or saline. PAG was administered 1 h before CLP, whereas NaHS was given at the time of CLP. CLP-induced sepsis resulted in a time-dependent increase in the synthesis of endogenous H2S. Maximum phosphorylation of ERK1/2 and degradation of I kappa B alpha in lung and liver were observed 4 h after CLP. Inhibition of H2S formation by PAG significantly reduced the phosphorylation of ERK1/2 in lung and liver 4 h after CLP, coupled with decreased degradation of I kappa B alpha and activation of NF-kappa B. In contrast, injection of NaHS significantly enhanced the activation of ERK1/2 in lung and liver, therefore leading to a further rise in tissue NF-kappa B activity. As a result, pretreatment with PAG significantly reduced the production of cytokines and chemokines in sepsis, whereas exogenous H2S greatly increased it. In addition, pretreatment with PD98059, an inhibitor of ERK kinase (MEK-1), significantly prevented NaHS from aggravating systemic inflammation in sepsis. In conclusion, the present study shows for the first time that H2S may regulate systemic inflammatory response in sepsis via ERK pathway.