title: Role of NADPH oxidase in the mechanism of lung neutrophil sequestration and microvessel injury induced by Gram-negative sepsis: studies in p47phox-/- and gp91phox-/- mice.
abstract: 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 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 approximately 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 p47(phox-/-) and gp91(phox-/-) mice despite the greater lung PMN sequestration. Thus, O(2) production is required for the induction of sepsis-induced lung microvascular injury. We conclude that NADPH oxidase-derived O(2) 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.
authors.affiliation: Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors.forename: Xiao-pei
authors.initials: XP
authors.lastname: Gao
authors.forename: Thedodore J
authors.initials: TJ
authors.lastname: Standiford
authors.forename: Arshad
authors.initials: A
authors.lastname: Rahman
authors.forename: Michael
authors.initials: M
authors.lastname: Newstead
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
authors.forename: Qing-hui
authors.initials: QH
authors.lastname: Liu
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC; D015169:Colony Count, Microbial; D016207:Cytokines / Q000096:biosynthesis; D004926:Escherichia coli / Q000254:growth & development; D004927:Escherichia coli Infections / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008168:Lung / Q000098:blood supply* / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D009929:Organ Size / Q000235:genetics / Q000276:immunology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D018805:Sepsis / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010750:Phosphoproteins; D018799:Intercellular Adhesion Molecule-1; C074302:keratinocyte-derived chemokines; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1