S3-3 H2S in sepsis and shock – A story of mice and men

Abstract

Role of H 2 S in systemic inflammation and shock is incompletely understood. To date, numerous conflicting data regarding the pro- and anti-inflammatory effects of exogenous and endogenous sulfide have been reported. Although the reasons for these conflicting results are likely multifactorial, purity and/or specificity of chemical H 2 S donors and inhibitors have been questioned. Furthermore, congenital deficiency of cystathionine γ -lyase (CSE) that produces H 2 S endogenously alters levels of other enzymes that affect production and metabolism of H 2 S, making interpretation of experimental results difficult. To elucidate the role of H 2 S in sepsis and shock, we measured levels of H 2 S and its metabolites in mice and human patients with varying degrees of sepsis using the monobromobimane (MBB)-based HPLC method. We observed that endotoxemia decreased plasma sulfide levels in mice. Levels of sulfide metabolites are markedly altered in septic patients. Breathing H 2 S attenuates endotoxin-induced systemic inflammation and improves survival in mice by restoring sulfide and markedly increasing thiosulfate levels. We further demonstrate that administration of sodium thiosulfate (STS) per se dose-dependently improves survival rate of mice after endotoxin challenge. These results are corroborated by our recent findings that congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents acute liver failure at least in part by augmentation of antioxidant and anti-apoptotic defense mechanisms. Taken together, evidence suggests a complex role of H 2 S in systemic inflammation and shock, that warrant further studies.