DIVERGENT ROLE OF HEME OXYGENASE INHIBITION IN THE PATHOGENESIS OF SEPSIS


Autoria(s): FREITAS, Andressa; ALVES-FILHO, Jose C.; TREVELIN, Silvia Cellone; SPILLER, Fernando; SUAVINHA, Marina Moreira; NASCIMENTO, Daniele Carvalho; PESTANA, Cezar Rangel; DAL-SECCO, Daniela; SONEGO, Fabiane; CZAIKOSKI, Paula Giselle; CURTI, Carlos; BARJA-FIDALGO, Christina; CUNHA, Fernando Q.
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

19/10/2012

19/10/2012

2011

Resumo

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.

FAPESP Fundacao de Amparo a Pesquisa do Estado de Sao Paulo

CAPES Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

CNPq Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico

Identificador

SHOCK, v.35, n.6, p.550-559, 2011

1073-2322

http://producao.usp.br/handle/BDPI/24193

10.1080/13608746.2010.521637

http://dx.doi.org/10.1080/13608746.2010.521637

Idioma(s)

eng

Publicador

LIPPINCOTT WILLIAMS & WILKINS

Relação

Shock

Direitos

restrictedAccess

Copyright LIPPINCOTT WILLIAMS & WILKINS

Palavras-Chave #Cecal ligation and puncture #CXCR2 #heme #severe sepsis #neutrophil migration failure #CARBON-MONOXIDE #OXIDATIVE STRESS #CECAL LIGATION #DYSFUNCTION #INFLAMMATION #BILIVERDIN #EXPRESSION #PROTECTION #REGULATOR #MIGRATION #Critical Care Medicine #Hematology #Surgery #Peripheral Vascular Disease
Tipo

article

original article

publishedVersion