Rationale: Recovering the neutrophil migration to the infectious focus improves survival in severe sepsis. Recently, we demonstrated that the cystathionine -lyase (CSE)/hydrogen sulfide (H2S) pathway increased neutrophil recruitment to inflammatory focus during sterile inflammation.
Objectives: To evaluate if H2S administration increases neutrophil migration to infectious focus and survival of mice.
Methods: Sepsis was induced by cecal ligation and puncture (CLP).
Measurements and Main Results: The pretreatments of mice with H2S donors (NaHS or Lawesson's reagent) improved leukocyte rolling/adhesion in the mesenteric microcirculation as well as neutrophil migration. Consequently, bacteremia levels were reduced, hypotension and lung lesions were prevented, and the survival rate increased from approximately 13% to approximately 80%. Even when treatment was delayed (6 h after CLP), a highly significant reduction in mortality compared with untreated mice was observed. Moreover, H2S pretreatment prevented the down-regulation of CXCR2 and L-selectin and the up-regulation of CD11b and G protein–coupled receptor kinase 2 in neutrophils during sepsis. H2S also prevented the reduction of intercellular adhesion molecule–1 expression in the endothelium of the mesenteric microcirculation in severe sepsis. Confirming the critical role of H2S on sepsis outcome, pretreatment with dl-propargylglycine (a CSE inhibitor) inhibited neutrophil migration to the infectious focus, enhanced lung lesions, and induced high mortality in mice subjected to nonsevere sepsis (from 0 to 80%). The beneficial effects of H2S were blocked by glibenclamide (a ATP-dependent K+ channel blocker).
Conclusions: These results showed that H2S restores neutrophil migration to the infectious focus and improves survival outcome in severe sepsis by an ATP-dependent K+ channel–dependent mechanism.