Aberrant activation of alveolar epithelial cells (AECs) in lung fibrosis. (a) Recapitulation of the developmental pathway of AECs in lung fibrosis: (1) Wnt/β signaling: type II AEC (AEC II) and fibroblast isolated from idiopathic pulmonary fibrosis (IPF) patients overexpress the members of the Wnt/wingless pathway and exhibit excessive nuclear accumulations of β-catenin. Several Wnt ligands render fibroblasts more active. WNT1-inducible signaling protein-1 (WISP1) is upregulated in AEC II in both a murine bleomycin-induced lung fibrosis model and IPF lungs. WISP1 activates AEC II and fibroblasts. Depletion of WISP1 attenuates bleomycin-induced lung fibrosis in mice. Inhibition of Wnt/β-catenin/CREB binding protein (CBP) also ameliorates lung fibrosis of bleomycin-treated mice. (2) Sonic hedgehog (Shh) signaling: a high expression of Shh protein is seen in the epithelial cells lining honeycomb cysts in lungs affected by IPF. TGF-β induced Shh expression in cultured murine AECs, whereas Shh induced TGF-β and alpha-smooth muscle actin (α-SMA) expression in cultured murine lung fibroblasts. (b) Defect of molecules essential for epithelial integrity: (1) Shp2: AEC-specific deletion of Shp2 in mice induces deregulated surfactant homeostasis, increased AEC II apoptosis, and spontaneous inflammation-independent lung fibrosis. (2) CD151: tetraspanin CD151 is expressed at the basolateral surface of AECs and is important in maintaining AEC integrity via rigid adhesion to the basement membrane (BM). CD151-deleted cultured AECs show attenuated adhesion on the BM. CD151-KO mice exhibit spontaneous age-related lung fibrosis. (c) Acceleration of aging-related properties: (1) cell biological characteristics of aging in the IPF lungs and (2) PTEN-induced putative kinase 1 (PINK1). AEC II in IPF lungs exhibits marked accumulation of dysmorphic and dysfunctional mitochondria, defective autophagy, and decreased PINK1 expression. Lung epithelial cell-specific PINK1-deleted mice show dysmorphic and dysfunctional mitochondria and vulnerability to apoptosis. PINK1 KO mice also show increased susceptibility to lung fibrosis after both MHV68 (a murine gammaherpesvirus homologous to EBV) infection and bleomycin treatment. EMT: epithelial mesenchymal transition; ECM: extracellular matrix; TCF: T-cell factor.