title: Neutrophilic oxidative stress mediates organic dust-induced pulmonary inflammation and airway hyperresponsiveness.
abstract: Airway exposure to organic dust (OD) from swine confinement facilities induces airway inflammation dominated by neutrophils and airway hyperresponsiveness (AHR). One important neutrophilic innate defense mechanism is the induction of oxidative stress. Therefore, we hypothesized that neutrophils exacerbate airway dysfunction following OD exposure by increasing oxidant burden. BALB/C mice were given intranasal challenges with OD or PBS (1/day for 3 days). Mice were untreated or treated with a neutrophil-depleting antibody, anti-Ly6G, or the antioxidant dimethylthiourea (DMTU) prior to OD exposure. Twenty-four hours after the final exposure, we measured airway responsiveness in response to methacholine (MCh) and collected bronchoalveolar lavage fluid to assess pulmonary inflammation and total antioxidant capacity. Lung tissue was harvested to examine the effect of OD-induced antioxidant gene expression and the effect of anti-Ly6G or DMTU. OD exposure induced a dose-dependent increase of airway responsiveness, a neutrophilic pulmonary inflammation, and secretion of keratinocyte cytokine. Depletion of neutrophils reduced OD-induced AHR. DMTU prevented pulmonary inflammation involving macrophages and neutrophils. Neutrophil depletion and DMTU were highly effective in preventing OD-induced AHR affecting large, conducting airways and tissue elastance. OD induced an increase in total antioxidant capacity and mRNA levels of NRF-2-dependent antioxidant genes, effects that are prevented by administration of DMTU and neutrophil depletion. We conclude that an increase in oxidative stress and neutrophilia is critical in the induction of OD-induced AHR. Prevention of oxidative stress diminishes neutrophil influx and AHR, suggesting that mechanisms driving OD-induced AHR may be dependent on neutrophil-mediated oxidant pathways.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Toby K
authors.initials: TK
authors.lastname: McGovern
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Allard
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and.
authors.forename: Kjell
authors.initials: K
authors.lastname: Larsson
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; and Mikael.Adner@ki.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018384:Oxidative Stress / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology*
chemical_list: D016207:Cytokines; D016210:Methacholine Chloride
keywords: anti-Ly6G; antioxidants; neutrophilia; organic dust; oxidative stress