title: Divergent role of heme oxygenase inhibition in the pathogenesis of sepsis.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Andressa
authors.initials: A
authors.lastname: Freitas
authors.forename: José C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Silvia Cellone
authors.initials: SC
authors.lastname: Trevelin
authors.forename: Fernando
authors.initials: F
authors.lastname: Spiller
authors.forename: Marina Moreira
authors.initials: MM
authors.lastname: Suavinha
authors.forename: Daniele Carvalho
authors.initials: DC
authors.lastname: Nascimento
authors.forename: Cezar Rangel
authors.initials: CR
authors.lastname: Pestana
authors.forename: Daniela
authors.initials: D
authors.lastname: Dal-Secco
authors.forename: Fabiane
authors.initials: F
authors.lastname: Sônego
authors.forename: Paula Giselle
authors.initials: PG
authors.lastname: Czaikoski
authors.forename: Carlos
authors.initials: C
authors.lastname: Curti
authors.forename: Christina
authors.initials: C
authors.lastname: Barja-Fidalgo
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000097:blood; D002432:Cecum / Q000473:pathology; D006418:Heme / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D006427:Hemin / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000502:physiology; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology*; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis; D018805:Sepsis / Q000209:etiology / Q000401:mortality* / Q000473:pathology
chemical_list: D011524:Protoporphyrins; D023063:Receptors, Interleukin-8B; C017803:zinc protoporphyrin; D006418:Heme; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin