We and others have reported that PKD family kinases are critical for cell proliferation, the production and secretion of cytokines and growth factors in numerous types of cells in response to various stimuli. It is possible that activated PKD may contribute to the abnormal behavior of hyperplastic or regenerative AECs and the subsequent progressive course of IPF. Our studies support the hypothesis. We have recently shown that PKD overexpression or activation in lung epithelial cells markedly increased the cell barrier permeability by disrupting tight junctions. Moreover, we found that lung fibroblasts and endothelial cells can protect epithelial barrier integrity; however they can not reverse the defect in epithelial barrier function caused by PKD overexpression. These findings suggest that the increased expression and activation of PKD in regenerative AECs may result in an impaired barrier integrity, which could facilitate the transit of Monensin sodium salt profibrotic factors in IPF alveoli to reach mesenchymal cells that could proliferate with Hypotaurine distortion of the alveolar compartment. Indeed, the epithelial barrier dysfunction or disruption is a critical factor in the pathogenesis of IPF and bleomycin-induced lung injury and fibrosis. We found that PKD family kinases were increased and activated in alveolar macrophages in almost all IPF subjects examined. It has been recently shown that PKD1 is essential for TLR ligandinduced macrophage activation and cytokine production and that PKD inhibition suppresses microbial Ag-induced hypersensitivity pneumonitis in mice. There is a current belief that chronic inflammation influences the pathogenesis of IPF. Recent studies have suggested that macrophage polarization from an M1 to M2 phenotype may promote fibrogenesis. It is likely that PKD family kinases play roles in regulating alveolar macrophage activation and function in IPF, which merits future investigation. Increasing evidence indicates that the disorders of small airways are involved in the pathogenesis of IPF. Occlusion of the upstream airways may cause or promote the injury-induced damage to the downstream lung parenchyma. Fulmer et al reported that 94% of the IPF patients had peribronchiolar fibrosis, peribronchiolar inflammation or bronchiolitis, and suggested that IPF is a disease of small airway and alveoli. Bronchiolar hyperplasia with extension to the pleural surface was also identified in 88% of IPF cases in a later study. It has been recently reported that the expression of mucin 5B is increased in IPF distal airways and honeycomb cysts.