title: Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine.
abstract: Inhalation of ozone (O₃), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O₃-induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O₃ (2 parts/million). In wild-type mice, O₃ exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O₃-exposed wild-type mice. O₃ exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O₃ exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-β-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O₃ exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN-deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O₃ and functionally contributes to the development of O₃-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine.
authors.affiliation: Division of Pediatric Critical Care Medicine, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Ramon X
authors.initials: RX
authors.lastname: Barreno
authors.forename: Jeremy B
authors.initials: JB
authors.lastname: Richards
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schneider
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Cromar
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Nadas
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Hernandez
authors.forename: Lance M
authors.initials: LM
authors.lastname: Hallberg
authors.forename: Roger E
authors.initials: RE
authors.lastname: Price
authors.forename: Syed S
authors.initials: SS
authors.lastname: Hashmi
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Ikram U
authors.initials: IU
authors.lastname: Haque
authors.forename: Richard A
authors.initials: RA
authors.lastname: Johnston
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018893:Bronchoalveolar Lavage; D016085:Bronchoconstrictor Agents / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D016210:Methacholine Chloride / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D010083:Oxidants, Photochemical / Q000009:adverse effects* / Q000494:pharmacology; D010126:Ozone / Q000009:adverse effects* / Q000494:pharmacology; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D016085:Bronchoconstrictor Agents; D010083:Oxidants, Photochemical; C506896:Spp1 protein, mouse; D016210:Methacholine Chloride; D053495:Osteopontin; D010126:Ozone
keywords: bronchoalveolar lavage fluid; forced oscillation technique; inflammation; interleukin-6; macrophage