title: The cardiac protein αT-catenin contributes to chemical-induced asthma.
abstract: Ten to 25% of adult asthma is occupational induced, a subtype caused by exposure to workplace chemicals. A recent genomewide association study identified single-nucleotide polymorphisms in the cardiac protein αT-catenin (αT-cat) that correlated with the incidence and severity of toluene diisocyanate (TDI) occupational asthma. αT-cat is a critical mediator of cell-cell adhesion and is predominantly expressed in cardiomyocytes, but its connection to asthma remains unknown. Therefore, we sought to determine the primary αT-cat-expressing cell type in the lung and its contribution to lung physiology in a murine model of TDI asthma. We show that αT-cat is expressed in lung within the cardiac sheath of pulmonary veins. Mechanically ventilated αT-cat knockout (KO) mice exhibit a significantly increased pressure-volume curve area compared with wild-type (WT) mice, suggesting that αT-cat loss affects lung hysteresis. Using a murine model of TDI asthma, we find that αT-cat KO mice show increased airway hyperresponsiveness to methacholine compared with WT mice. Bronchoalveolar lavage reveals only a mild macrophage-dominant inflammation that is not significantly different between WT and KO mice. These data suggest that αT-cat may contribute to asthma through a mechanism independent of inflammation and related to heart and pulmonary vein dysfunction.
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; The Driskill Graduate Training Program in Life Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Stephen Sai
authors.initials: SS
authors.lastname: Folmsbee
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.affiliation: Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent, Belgium; Department of Biomedical Molecular Biology, Molecular Cell Biology Unit, Ghent University, Ghent, Belgium; and Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Van Hengel
authors.affiliation: Department of Biomedical Molecular Biology, Molecular Cell Biology Unit, Ghent University, Ghent, Belgium; and Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Tyberghein
authors.affiliation: Department of Biomedical Molecular Biology, Molecular Cell Biology Unit, Ghent University, Ghent, Belgium; and Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Van Roy
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.affiliation: Department of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Bryce
authors.affiliation: Department of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Department of Cellular and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois; c-gottardi@northwestern.edu.
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Gottardi
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D059366:Asthma, Occupational / Q000139:chemically induced / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D011667:Pulmonary Veins / Q000378:metabolism / Q000473:pathology; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity*; D051178:alpha Catenin / Q000378:metabolism*
chemical_list: D000393:Air Pollutants; C575065:CTNNA3 protein, mouse; D051178:alpha Catenin; D014051:Toluene 2,4-Diisocyanate
keywords: cell-cell adhesion; lung hysteresis; occupational asthma; αT-catenin