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* Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612;
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109;
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Department of Pediatrics, University of Indiana School of Medicine, Indianapolis, IN 46202
We addressed the role of O
2 generated by the NADPH oxidase
complex in the mechanism of polymorphonuclear leukocyte (PMN)
accumulation and transalveolar migration and lung microvascular injury.
Studies were made in mice lacking the p47phox
and gp91phox subunits of NADPH oxidase
(p47phox-/- and
gp91phox-/-) in which PMN are incapable
of the respiratory burst. The mice were challenged i.p. with live
Escherichia coli to induce sepsis. We observed
time-dependent increases in PMN sequestration and migration from 1 to
6 h after challenge with 2 x 108 E.
coli. The responses in knockout mice were greater
post-E. coli challenge compared with control mice; i.e.,
transalveolar PMN migration post-E. coli challenge
increased by 
50% in the null mice above values in wild type. The
increased PMN infiltration was associated with decreased lung bacterial
clearance. The generation of the chemoattractant
macrophage-inflammatory protein-2 in lung tissue was greater in NADPH
oxidase-defective mice after E. coli challenge than
control mice; moreover, macrophage-inflammatory protein-2 Ab
pretreatment prevented the PMN infiltration. We also observed that
E. coli failed to increase lung microvascular
permeability in p47phox-/- and
gp91phox-/- mice despite the greater
lung PMN sequestration. Thus, O2 production is required for
the induction of sepsis-induced lung microvascular injury. We conclude
that NADPH oxidase-derived O2 generation has an important
bactericidal role, such that an impairment in bacterial clearance in
NADPH oxidase-defective mice results in increased chemokine generation
and lung tissue PMN infiltration.
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