title: The role of the extracellular matrix protein mindin in airway response to environmental airways injury.
abstract: BACKGROUND
  Our previous work demonstrated that the extracellular matrix protein mindin contributes to allergic airways disease. However, the role of mindin in nonallergic airways disease has not previously been explored.
  
  
  OBJECTIVE
  We hypothesized that mindin would contribute to airways disease after inhalation of either lipopolysaccharide (LPS) or ozone.
  
  
  METHODS
  We exposed C57BL/6J and mindin-deficient (-/-) mice to aerosolized LPS (0.9 μg/m3 for 2.5 hr), saline, ozone (1 ppm for 3 hr), or filtered air (FA). All mice were evaluated 4 hr after LPS/saline exposure or 24 hr after ozone/FA exposure. We characterized the physiological and biological responses by analysis of airway hyperresponsiveness (AHR) with a computer-controlled small-animal ventilator (FlexiVent), inflammatory cellular recruitment, total protein in bronchoalveolar lavage fluid (BALF), proinflammatory cytokine profiling, and ex vivo bronchial ring studies.
  
  
  RESULTS
  After inhalation of LPS, mindin-/- mice demonstrated significantly reduced total cell and neutrophil recruitment into the airspace compared with their wild-type counterparts. Mindin-/- mice also exhibited reduced proinflammatory cytokine production and lower AHR to methacholine challenge by FlexiVent. After inhalation of ozone, mice had no detectible differences in cellular inflammation or total BALF protein dependent on mindin. However, mindin-/- mice were protected from increased proinflammatory cytokine production and AHR compared with their C57BL/6J counterparts. After ozone exposure, bronchial rings derived from mindin-/- mice demonstrated reduced constriction in response to carbachol.
  
  
  CONCLUSIONS
  These data demonstrate that the extracellular matrix protein mindin modifies the airway response to both LPS and ozone. Our data support a conserved role of mindin in production of proinflammatory cytokines and the development of AHR in two divergent models of reactive airways disease, as well as a role of mindin in airway smooth muscle contractility after exposure to ozone.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, North Carolina, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Frush
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Li
authors.forename: Erin N
authors.initials: EN
authors.lastname: Potts
authors.forename: Wanglei
authors.initials: W
authors.lastname: Du
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Eu
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
authors.forename: John W
authors.initials: JW
authors.lastname: Hollingsworth
mesh_terms: D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000276:immunology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020556:Neutrophil Infiltration / Q000187:drug effects; D010126:Ozone / Q000633:toxicity; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C121491:mindin; D010126:Ozone