title: The Rho pathway mediates transition to an alveolar type I cell phenotype during static stretch of alveolar type II cells.
abstract: Stretch is an essential mechanism for lung growth and development. Animal models in which fetal lungs have been chronically over or underdistended demonstrate a disrupted mix of type II and type I cells, with static overdistention typically promoting a type I cell phenotype. The Rho GTPase family, key regulators of cytoskeletal signaling, are known to mediate cellular differentiation in response to stretch in other organs. Using a well-described model of alveolar epithelial cell differentiation and a validated stretch device, we investigated the effects of supraphysiologic stretch on human fetal lung alveolar epithelial cell phenotype. Static stretch applied to epithelial cells suppressed type II cell markers (SP-B and Pepsinogen C, PGC), and induced type I cell markers (Caveolin-1, Claudin 7 and Plasminogen Activator Inhibitor-1, PAI-1) as predicted. Static stretch was also associated with Rho A activation. Furthermore, the Rho kinase inhibitor Y27632 decreased Rho A activation and blunted the stretch-induced changes in alveolar epithelial cell marker expression. Together these data provide further evidence that mechanical stimulation of the cytoskeleton and Rho activation are key upstream events in mechanotransduction-associated alveolar epithelial cell differentiation.
authors.affiliation: Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Cherie D
authors.initials: CD
authors.lastname: Foster
authors.forename: Linda S
authors.initials: LS
authors.lastname: Varghese
authors.forename: Linda W
authors.initials: LW
authors.lastname: Gonzales
authors.forename: Susan S
authors.initials: SS
authors.lastname: Margulies
authors.forename: Susan H
authors.initials: SH
authors.lastname: Guttentag
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000201:enzymology*; D000577:Amides / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D057167:Claudins; D005865:Gestational Age; D006801:Humans; D008168:Lung / Q000196:embryology / Q000201:enzymology; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D020115:Pepsinogen C / Q000378:metabolism; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D022502:Stress Fibers / Q000378:metabolism; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000577:Amides; D015415:Biomarkers; C495540:CAV1 protein, human; C473255:CLDN7 protein, human; D051242:Caveolin 1; D057167:Claudins; D008565:Membrane Proteins; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D037701:Pulmonary Surfactant-Associated Protein B; D011725:Pyridines; C051321:SERPINE1 protein, human; C066737:RHOA protein, human; C108830:Y 27632; D020115:Pepsinogen C; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein