The reduction of neutrophil migration to an infectious focus is associated with a high mortality in
severe sepsis. Previously, we showed that
heme oxygenase (HO) products downregulate neutrophil recruitment in a noninfectious inflammatory model. The present study was designed to determine the role of HO in
sepsis induced by cecal
ligation and
puncture (CLP) model. We demonstrated that pretreatment, but not the combination of pretreatment plus posttreatment with
zinc protoporphyrin IX (
ZnPP IX), an HO inhibitor, prevented the reduction of CXCR2 on circulating neutrophils and the failure of intraperitoneal neutrophil migration to the site of
infection. Consequently, bacterial dissemination, systemic inflammatory response, and organ injury were prevented. In addition, pretreatment with the HO inhibitor avoided
hypotension and consequently increased survival. Moreover, in mice subjected to severe CLP, the pretreatment, but not the combination of pretreatment plus posttreatment with
ZnPP IX, prevented the increase of plasmatic free
heme observed in nontreated 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 pretreatment with the HO inhibitor prevents the pathological findings in severe CLP. However, the combination of pretreatment plus posttreatment with
ZnPP IX enhances
sepsis severity because of an increase in circulating levels of
heme, which is deleterious to the host tissues and also inhibits neutrophil migration.