title: Deficiency of gp91phox inhibits allergic airway inflammation.
abstract: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multienzyme complex, is the major source for production of reactive oxygen species (ROS). ROS are increased in allergic diseases, such as asthma, but the role of ROS in disease pathogenesis remains uncertain. We hypothesized that mice unable to generate ROS via the NADPH oxidase pathway would have decreased allergic airway inflammation. To test this hypothesis, we studied gp91phox(-/-) mice in a model of allergic airway inflammation after sensitization and challenge with ovalbumin. Serum, bronchoalveolar lavage fluid, and lungs were then examined for evidence of allergic inflammation. We found that mice lacking a functional NADPH oxidase complex had significantly decreased ROS production and allergic airway inflammation, compared with wild-type (WT) control animals. To determine the mechanism by which allergic inflammation was inhibited by gp91phox deficiency, we cultured bone marrow-derived dendritic cells from WT and gp91phox(-/-) mice and activated them with LPS. IL-12 expression was significantly increased in the gp91phox(-/-) bone marrow-derived dendritic cells, suggesting that the cytokine profile produced in the absence of gp91phox enhanced the conditions leading to T helper (Th) type 1 differentiation, while inhibiting Th2 polarization. Splenocytes from sensitized gp91phox(-/-) animals produced significantly less IL-13 in response to ovalbumin challenge in vitro compared with splenocytes from sensitized WT mice, suggesting that NADPH oxidase promotes allergic sensitization. In contrast, inflammatory cytokines produced by T cells cultured from WT and gp91phox(-/-) mice under Th0, Th1, Th2, and Th17 conditions were not significantly different. This study demonstrates the importance of NADPH oxidase activity and ROS production in a murine model of asthma.
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232-2650, USA. carla.sevin@vanderbilt.edu
authors.forename: Carla M
authors.initials: CM
authors.lastname: Sevin
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.forename: Shinji
authors.initials: S
authors.lastname: Toki
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Sherrill
authors.forename: Madison G
authors.initials: MG
authors.lastname: Boswell
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Huckabee
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D018793:Interleukin-13 / Q000096:biosynthesis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058408:Th1-Th2 Balance; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D018793:Interleukin-13; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D018664:Interleukin-12; D010047:Ovalbumin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases