Divergent role of heme oxygenase inhibition in the pathogenesis of sepsis (111.7)

Abstract

Abstract The reduction of neutrophil migration to an infectious focus is associated with high mortality in severe sepsis. The present study was designed to determine the role of heme oxygenase (HO) in sepsis induced by cecal ligation and puncture (CLP) model. We demonstrated that pre-treatment, but not the combination of pre- plus post-treatment with ZnPP IX, a HO inhibitor, prevented the reduction of CXCR2 on circulating neutrophils and the failure of intraperitoneal neutrophil migration to site of infection. Consequently, bacterial dissemination, systemic inflammatory response and organ injury were prevented. In addition, pre-treatment with the HO inhibitor avoided hypotension and consequently increased survival. Moreover, in mice subjected to Severe-CLP, the pre-treatment, but not the combination of pre- plus post-treatment with ZnPP IX, prevented the increase of plasmatic free heme observed in non-treated Severe-CLP. The administration of exogenous hemin to mice subjected to moderate sepsis consistently increased the mortality rate. Furthermore, hemin resulted in a reduction of neutrophil migration both in vivo and in vitro. Altogether, our results demonstrated that pre-treatment with the HO inhibitor prevents the pathological findings in Severe-CLP. However, the combination of pre- plus post-treatment with ZnPP IX enhances sepsis severity due to an increase in circulating levels of heme, which is deleterious to the host tissues and also inhibits neutrophil migration.