title: NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury.
abstract: Recruitment of neutrophils and release of reactive oxygen species are considered to be major pathogenic components driving acute lung injury (ALI). However, NADPH oxidase, the major source of reactive oxygen species in activated phagocytes, can paradoxically limit inflammation and injury. We hypothesized that NADPH oxidase protects against ALI by limiting neutrophilic inflammation and activating Nrf2, a transcriptional factor that induces antioxidative and cytoprotective pathways. Our objective was to delineate the roles of NADPH oxidase and Nrf2 in modulating acute lung inflammation and injury in clinically relevant models of acute gastric aspiration injury, a major cause of ALI. Acid aspiration caused increased ALI (as assessed by bronchoalveolar lavage fluid albumin concentration) in both NADPH oxidase-deficient mice and Nrf2(-/-) mice compared with wild-type mice. NADPH oxidase reduced airway neutrophil accumulation, but Nrf2 decreased ALI without affecting neutrophil recovery. Acid injury resulted in a 120-fold increase in mitochondrial DNA, a proinflammatory and injurious product of cellular necrosis, in cell-free bronchoalveolar lavage fluid. Pharmacologic activation of Nrf2 by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9 (11)-dien-28-oyl]imidazole limited aspiration-induced ALI in wild-type mice and reduced endothelial cell injury caused by mitochondrial extract-primed human neutrophils, leading to the conclusion that NADPH oxidase and Nrf2 have coordinated, but distinct, functions in modulating inflammation and injury. These results also point to Nrf2 as a therapeutic target to limit ALI by attenuating neutrophil-induced cellular injury.
authors.affiliation: Department of Anesthesiology, University at Buffalo School of Medicine, Buffalo, NY 14214, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Davidson
authors.forename: R Robert
authors.initials: RR
authors.lastname: Vethanayagam
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Grimm
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Mullan
authors.forename: Krishnan
authors.initials: K
authors.lastname: Raghavendran
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Michael L
authors.initials: ML
authors.lastname: Freeman
authors.forename: Vanniarajan
authors.initials: V
authors.lastname: Ayyasamy
authors.forename: Keshav K
authors.initials: KK
authors.lastname: Singh
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sporn
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itagaki
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Hauser
authors.forename: Paul R
authors.initials: PR
authors.lastname: Knight
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
mesh_terms: D055371:Acute Lung Injury / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007442:Intubation, Intratracheal; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D051267:NF-E2-Related Factor 2; D019255:NADPH Oxidases