Epithelial Pten Controls Acute Lung Injury and Fibrosis by Regulating Alveolar Epithelial Cell Integrity

Rationale: Injury to alveolar epithelial cells (AECs) and to their repair process is integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and their intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown. Objectives: To determine the role of epithelial Pten in ALI and lung fibrosis. Methods: Bronchioalveolar epithelium-specific Pten-deleted SP-C-rtTA/(tetO)(7)-Cre/Pten(Delta/Delta)(SOPten(Delta/Delta)) mice were studied by structural, biochemical, and physiologic analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF. Measurements and Main Results: SOPten(Delta/Delta) mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPten(Delta/Delta) mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-beta 1 expressions. Akt inactivation definitively saved SOPten(Delta/Delta) mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs. Conclusions: Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.