Exacerbated alveolar flooding, failure of reconstitution of alveolar epithelial cell (AEC) integrity, and subsequent augmented fibrotic scarring in epithelial cell-specific Pten-deficient lungs compared to the normal repair and resolution of acute lung injury in wild-type lungs. (a) Normal condition of the alveolus: type I AEC (AEC I) and type II AEC (AEC II) establish close contacts with neighbors through laterally located intercellular junctional complexes (i.e., tight junctions and adherens junctions) and reside on basement membrane (BM). Paracellular permeability depends on claudin-family tight junction proteins. Though AEC I and AEC II have distinct patterns of claudin expression, claudin-4 expression is comparable between the two types of AECs. AECs barrier integrity is primarily regulated by claudin-4. (b) Acute injury phase in wild-type lungs: injury to the lung parenchyma and loss of AECs lead to a deposition of provisional extracellular matrix (ECM), which is conducive to the ingrowth of fibroblasts. To establish the normal reconstitution of AEC integrity, AEC II spreads and migrates on a denuded BM. (c) Resolution of acute lung injury: if the BM is intact and the loss of AECs integrity is limited, the provisional ECM is reabsorbed and the reepithelialization of AEC integrity occurs. (d) Acute injury phase in epithelial cell-specific Pten-deficient lungs: the intensified disruption of tight junctions leads to a greater deposition of intra-alveolar provisional ECM and a subsequent induction of greater numbers of fibroblast ingrowths. Epithelial cell-specific Pten-deficient lungs also show considerable degradation of the BM after injury. Loss of the BM leads to a failure of the normal reconstitution of AEC integrity through deprivation of the stable scaffolding from AECs which is necessary for normal spatial orientation in cell spreading and migration. (e) Fibrotic scarring in epithelial cell-specific Pten-deficient lungs: failure of the reconstitution of AEC integrity and persistent alveolar flooding cause the expansion and activation of fibroblasts and myofibroblasts, which results in excessive collagen-rich matrix and fibrotic scarring.