title: Dual oxidase regulates neutrophil recruitment in allergic airways.
abstract: Enhanced reactive oxygen species production in allergic airways is well described and correlates with increased airway contractions, inflammatory cell infiltration, goblet cell metaplasia, and mucus hypersecretion. There is also an abundance of interleukin-4/interleukin-13 (IL-4/IL-13)- or interleukin-5-secreting cells that are thought to be central to the pathogenesis of allergic asthma. We postulated that the dual oxidases (DUOX1 and DUOX2), members of the nicotinamide adenine dinucleotide phosphate oxidase family that release hydrogen peroxide (H2O2) in the respiratory tract, are critical proteins in the pathogenesis of allergic airways. DUOX activity is regulated by cytokines, including IL-4 and IL-13, and DUOX-mediated H2O2 influences several important features of allergic asthma: mucin production, IL-8 secretion, and wound healing. The objective of this study was to establish the contribution of DUOXs to the development of allergic asthma in a murine model. To accomplish this goal, we utilized a DUOXA-deficient mouse model (Duoxa(-/-)) that lacked maturation factors for both DUOX1 and DUOX2. Our results are the first to demonstrate evidence of DUOX protein and DUOX functional activity in murine airway epithelium. We also demonstrate that DUOXA maturation factors are required for airway-specific H2O2 production and localization of DUOX to cilia of fully differentiated airway epithelial cells. We compared wild-type and Duoxa(-/-) mice in an ovalbumin exposure model to determine the role of DUOX in allergic asthma. In comparison to DUOX-intact mice, Duoxa(-/-) mice had reduced mucous cell metaplasia and lower levels of TH2 cytokine levels in bronchoalveolar fluid. In addition, increased airway resistance in response to methacholine was observed in Duoxa(+/+) mice, as expected, but was absent in Duoxa(-/-) mice. Surprisingly, Duoxa(-/-) mice had decreased influx of neutrophils in bronchoalveolar fluid and lung tissue sections associated with a lower level of the chemotactic cytokine IL-6. These findings suggest that DUOX-derived H2O2 has an important role in signaling neutrophils into allergic airways.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Linderholm
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Franzi
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kenyon
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at Davis, Davis, CA 95616, USA. Electronic address: rwharper@ucdavis.edu.
authors.forename: Richart
authors.initials: R
authors.lastname: Harper
mesh_terms: D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000276:immunology; D015153:Blotting, Western; D004195:Disease Models, Animal; D000074623:Dual Oxidases; D004797:Enzyme-Linked Immunosorbent Assay; D006861:Hydrogen Peroxide / Q000276:immunology / Q000378:metabolism; D006967:Hypersensitivity / Q000201:enzymology / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000502:physiology*; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000276:immunology
chemical_list: D006861:Hydrogen Peroxide; D000074623:Dual Oxidases; D019255:NADPH Oxidases; C519130:Duox1 protein, mouse
keywords: Asthma; BALF; DPI; DUOX; Dual oxidase; Free radicals; IL; L-T(4); Lung; Murine; Neutrophil; ROS; T(H); T-helper cell; TLR; Toll-like receptor; bronchoalveolar lavage fluid; diphenyleneiodonium; dual oxidase; interleukin; levothyroxine; reactive oxygen species