title: High tidal volume mechanical ventilation with hyperoxia alters alveolar type II cell adhesion.
abstract: Patients with acute respiratory distress syndrome undergoing mechanical ventilation may be exposed to both high levels of stretch and high levels of oxygen. We hypothesized that the combination of high stretch and hyperoxia promotes loss of epithelial adhesion and impairs epithelial repair mechanisms necessary for restoration of barrier function. We utilized a model of high tidal volume mechanical ventilation (25 ml/kg) with hyperoxia (50% O(2)) in rats to investigate alveolar type II (AT2) cell adhesion and focal adhesion signaling. AT2 cells isolated from rats exposed to hyperoxia and high tidal volume mechanical ventilation (MVHO) exhibited significantly decreased cell adhesion and reduction in phosphotyrosyl levels of focal adhesion kinase (FAK) and paxillin compared with control rats, rats exposed to hyperoxia without ventilation (HO), or rats ventilated with normoxia (MV). MV alone increased phosphorylation of p130(Cas). RhoA activation was increased by MV, HO, and the combination of MV and HO. Treatment of MVHO cells with keratinocyte growth factor (KGF) for 1 h upon isolation reduced RhoA activity and restored attachment to control levels. Attachment and migration of control AT2 cells was significantly decreased by constitutively active RhoA or a kinase inactive form of FAK (FRNK), whereas expression of dominant negative RhoA in cells from MVHO-treated rats restored cell adhesion. Mechanical ventilation with hyperoxia promotes changes in focal adhesion proteins and RhoA in AT2 cells that may be deleterious for cell adhesion and migration.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Leena P
authors.initials: LP
authors.lastname: Desai
authors.forename: Scott E
authors.initials: SE
authors.lastname: Sinclair
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Chapman
authors.forename: Aviv
authors.initials: A
authors.lastname: Hassid
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002469:Cell Separation; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D018496:Hyperoxia / Q000139:chemically induced / Q000473:pathology*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial; D013990:Tidal Volume / Q000187:drug effects; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D050719:Crk-Associated Substrate Protein; D051419:Paxillin; D051523:Fibroblast Growth Factor 7; D019000:Phosphotyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein