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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/L96    most recent 00450.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (1) Google Scholar Articles by Brovkovych, V. Articles by Skidgel, R. A. PubMed PubMed Citation Articles by Brovkovych, V. Articles by Skidgel, R. A.

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

¹Department of Pharmacology and ²Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois; and ³Departments of Cell Biology and Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio

Submitted 29 October 2007 ; accepted in final form 15 April 2008

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.

inflammation; endotoxin shock; rodent; host defense

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