title: Heme oxygenase inhibition enhances neutrophil migration into the bronchoalveolar spaces and improves the outcome of murine pneumonia-induced sepsis.
abstract: A reduction of the neutrophil migration into the site of infection during cecal ligation and puncture-induced sepsis increases host mortality. Inhibition of heme oxygenase (HO) prevents this neutrophil paralysis and improves host survival in the cecal ligation and puncture model. Taking into account that almost 50% of all sepsis cases are a consequence of pneumonia, we designed the present study to determine the role of HO in an experimental model of pneumonia-induced sepsis. The objective of this study was to evaluate whether the inhibition of HO improves the outcome and pathophysiologic changes of sepsis induced by an intratracheal instillation of Klebsiella pneumoniae. The pretreatment of mice subjected to pneumonia-induced sepsis with ZnDPBG (zinc deuteroporphyrin 2,4-bis glycol), a nonspecific HO inhibitor, increased the number of neutrophils in the bronchoalveolar spaces, reduced the bacterial load at the site of infection, and prevented the upregulation of CD11b and the downregulation of CXCR2 on blood neutrophils. Moreover, the pretreatment with ZnDPBG decreased alveolar collapse, attenuating the deleterious changes in pulmonary mechanics and gas exchanges and, as a consequence, improved the survival rate of mice from 0% to ∼20%. These results show that heme oxygenase is involved in the pathophysiology of pneumonia-induced sepsis and suggest that HO inhibitors could be helpful for the management of this disease.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Paula Giselle
authors.initials: PG
authors.lastname: Czaikoski
authors.forename: Daniele Carvalho
authors.initials: DC
authors.lastname: Nascimento
authors.forename: Fabiane
authors.initials: F
authors.lastname: Sônego
authors.forename: Andressa
authors.initials: A
authors.lastname: de Freitas
authors.forename: Walter Miguel
authors.initials: WM
authors.lastname: Turato
authors.forename: Michel A
authors.initials: MA
authors.lastname: de Carvalho
authors.forename: Raquel Souza
authors.initials: RS
authors.lastname: Santos
authors.forename: Gisele Pena
authors.initials: GP
authors.lastname: de Oliveira
authors.forename: Cynthia
authors.initials: C
authors.lastname: dos Santos Samary
authors.forename: Cristiane
authors.initials: C
authors.lastname: Tefe-Silva
authors.forename: José C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Sérgio Henrique
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Marcos Antonio
authors.initials: MA
authors.lastname: Rossi
authors.forename: Patricia Rieken Macedo
authors.initials: PR
authors.lastname: Rocco
authors.forename: Fernando
authors.initials: F
authors.lastname: Spiller
authors.forename: Fernando Queiroz
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control; D000818:Animals; D016470:Bacteremia / Q000201:enzymology* / Q000382:microbiology; D001980:Bronchi / Q000201:enzymology; D018925:Chemokines / Q000378:metabolism; D052279:Creatine Kinase, MB Form / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003905:Deuteroporphyrins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors*; D007154:Immune System Diseases / Q000201:enzymology*; D007710:Klebsiella Infections / Q000201:enzymology* / Q000382:microbiology; D007711:Klebsiella pneumoniae; D007960:Leukocyte Disorders / Q000201:enzymology*; D051379:Mice; D018410:Pneumonia, Bacterial / Q000201:enzymology* / Q000382:microbiology; D011650:Pulmonary Alveoli / Q000201:enzymology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D003905:Deuteroporphyrins; D004791:Enzyme Inhibitors; D023063:Receptors, Interleukin-8B; C060750:zinc deuteroporphyrin IX 2,4-bis(glycol); D006419:Heme Oxygenase (Decyclizing); D052279:Creatine Kinase, MB Form