title: Inhibition of BMP activity protects epithelial barrier function in lung injury.
abstract: Epithelial injury is a central finding in pulmonary disease and is accompanied by disruption of epithelial barrier function, leading to pulmonary oedema and inflammation. Injured epithelial cells lose their properties and gain mesenchymal characteristics, a phenotypic switch that contributes to lung remodelling after injury. Here we studied bone morphogenetic protein (BMP) signalling and, in particular, the role of BMP2 and the BMP modulator BMPER in injured lung epithelium. Increased BMP activity, reflected by up-regulation of the Smad1/5-Id1 axis, is detected after injury of lung epithelium in vitro and in vivo. Two members of the BMP family, BMP2 and BMPER, have opposing effects. BMP2 is up-regulated after epithelial injury and causes epithelial dysfunction and hyperpermeability, mediated by the Smad1/5-Id1-dependent down-regulation of E-cadherin. In contrast, BMPER expression is decreased following injury, which in turn impairs epithelial integrity, characterized by reduction of E-cadherin and epithelial leakage in vitro and in vivo. High levels of BMPER antagonized BMP2-Smad5-Id1 signalling and prevented BMP2-mediated decrease of E-cadherin and hyperpermeability, suggesting that BMPER restores epithelial homeostasis. Supporting this notion, pharmacological inhibition of BMP signalling by LDN193189 prevented reduction of E-cadherin and disruption of epithelial barrier function. Inhibition of excessive BMP activation could be a new approach to restore epithelial integrity and prevent disruption of epithelial barrier function after lung injury.
authors.affiliation: Cardiology and Angiology I, Heart Centre, Freiburg University, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helbing
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Herold
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hornstein
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wintrich
authors.forename: Jennifer
authors.initials: J
authors.lastname: Heinke
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grundmann
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D015824:Blood-Air Barrier; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D002463:Cell Membrane Permeability; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C525718:BMP2 protein, human; C476724:BMPER protein, human; D055396:Bone Morphogenetic Protein 2; D015820:Cadherins; D002352:Carrier Proteins; C554430:LDN 193189; D011720:Pyrazoles; D011743:Pyrimidines; D051896:Smad Proteins, Receptor-Regulated; D001761:Bleomycin
keywords: BMPER; bone morphogenetic protein; epithelial permeability; lung injury