NDLI: Augmented inducible nitric oxide synthase expression and increased NO production reduce sepsis-induced lung injury and mortality in myeloperoxidase-null mice.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Brovkovych, Viktor Gao, Xiao-Pei Ong, Evan Brovkovych, Svitlana Brennan, Marie-Luise Su, Xiao Hazen, Stanley L. Malik, Asrar B. Skidgel, Randal A.
Description	Country affiliation: United States Author Affiliation: Brovkovych V ( Department of Pharmacology, University of Illinois College of Medicine, 835 S. Wolcott, Chicago, Illinois 60612, USA.)
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.
File Format	HTM / HTML
ISSN	10400605
e-ISSN	15221504
DOI	10.1152/ajplung.00450.2007
Journal	AJP: Lung Cellular and Molecular Physiology
Issue Number	1
Volume Number	295
Language	English
Publisher	American Physiological Society
Publisher Date	2008-07-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Cell Biology Discipline Physiology Discipline Molecular Biology Discipline Pulmonary Medicine Escherichia Coli Infections Enzymology Escherichia Coli Neutrophils Nitric Oxide Synthase Type Ii Biosynthesis Nitric Oxide Peroxidase Metabolism Pulmonary Edema Sepsis Animals Genetics Pathology Gene Expression Regulation, Enzymologic Lung Microbiology Lung Injury Mice Mice, Knockout Oxidants Tyrosine Analogs & Derivatives Research Support, N.i.h., Extramural
Content Type	Text
Resource Type	Article
Subject	Pulmonary and Respiratory Medicine Cell Biology Physiology Physiology (medical)

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