title: Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice.
abstract: The myeloperoxidase (MPO)-hydrogen peroxide-halide system is an efficient oxygen-dependent antimicrobial component of polymorphonuclear leukocyte (PMN)-mediated host defense. However, MPO deficiency results in few clinical consequences indicating the activation of compensatory mechanisms. Here, we determined possible mechanisms protecting the host using MPO(-/-) mice challenged with live gram-negative bacterium Escherichia coli. We observed that MPO(-/-) mice unexpectedly had improved survival compared with wild-type (WT) mice within 5-12 h after intraperitoneal E. coli challenge. Lungs of MPO(-/-) mice also demonstrated lower bacterial colonization and markedly attenuated increases in microvascular permeability and edema formation after E. coli challenge compared with WT. However, PMN sequestration in lungs of both groups was similar. Basal inducible nitric oxide synthase (iNOS) expression was significantly elevated in lungs and PMNs of MPO(-/-) mice, and NO production was increased two- to sixfold compared with WT. Nitrotyrosine levels doubled in lungs of WT mice within 1 h after E. coli challenge but did not change in MPO(-/-) mice. Inhibition of iNOS in MPO(-/-) mice significantly increased lung edema and reduced their survival after E. coli challenge, but iNOS inhibitor had the opposite effect in WT mice. Thus augmented iNOS expression and NO production in MPO(-/-) mice compensate for the lack of HOCl-mediated bacterial killing, and the absence of MPO-derived oxidants mitigates E. coli sepsis-induced lung inflammation and injury.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, 835 S. Wolcott, Chicago, Illinois 60612, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brovkovych
authors.forename: Xiao-Pei
authors.initials: XP
authors.lastname: Gao
authors.forename: Evan
authors.initials: E
authors.lastname: Ong
authors.forename: Svitlana
authors.initials: S
authors.lastname: Brovkovych
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Brennan
authors.forename: Xiao
authors.initials: X
authors.lastname: Su
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
authors.forename: Randal A
authors.initials: RA
authors.lastname: Skidgel
mesh_terms: D000818:Animals; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D008168:Lung / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D016877:Oxidants / Q000378:metabolism; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism*; D011654:Pulmonary Edema / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D018805:Sepsis / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism
chemical_list: D016877:Oxidants; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse