Journal
JOURNAL OF IMMUNOLOGY
Volume 168, Issue 8, Pages 3974-3982Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.168.8.3974
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Funding
- NHLBI NIH HHS [HL45638, HL27601, HL57243, HL60678, P50HL60289] Funding Source: Medline
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We addressed the role of O-2 generated by the NADPH oxidase complex in the mechanism of polymorphonuclear leukocyte (PMN) 2 accumulation and transalveolar migration and lung microvascular injury. Studies were made in mice lacking the p47(phox) and gp91(phox) subunits of NADPH oxidase (p47(phox-/-) and gp91(phox-/-)) 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 10(8) 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 similar to50% 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 p47(phox-/-) and gp91(phox-/-) mice despite the greater lung PMN sequestration. Thus, O-2(radical anion) production is required for the induction of sepsis-induced lung inicrovascular injury. We conclude that NADPH oxidase-derived O-2(radical anion) 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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