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Am J Respir Crit Care Med. 2010 Aug 1;182(3):360-8. doi: 10.1164/rccm.200907-1145OC. Epub 2010 Mar 25.

Hydrogen sulfide improves neutrophil migration and survival in sepsis via K+ATP channel activation.

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1
Department of Pharmacology, University of Sao Paulo, Avenida Bandeirantes, Ribeirao Preto, Sao Paulo, Brazil.

Abstract

RATIONALE:

Recovering the neutrophil migration to the infectious focus improves survival in severe sepsis. Recently, we demonstrated that the cystathionine gamma-lyase (CSE)/hydrogen sulfide (H(2)S) pathway increased neutrophil recruitment to inflammatory focus during sterile inflammation.

OBJECTIVES:

To evaluate if H(2)S 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 H(2)S 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, H(2)S 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. H(2)S 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 H(2)S 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 approximately 80%). The beneficial effects of H(2)S were blocked by glibenclamide (a ATP-dependent K(+) channel blocker).

CONCLUSIONS:

These results showed that H(2)S restores neutrophil migration to the infectious focus and improves survival outcome in severe sepsis by an ATP-dependent K(+) channel-dependent mechanism.

PMID:
20339148
DOI:
10.1164/rccm.200907-1145OC
[Indexed for MEDLINE]
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