Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Protein kinase Cζ (PKCζ) is highly expressed in the lung, where it plays several regulating roles in the pathogenesis of acute lung injury (ALI). Proliferation and differentiation of integrin β4⁺ distal lung epithelial progenitor cells seem to play a key role in proper lung regeneration. We investigated the effects of a myristoylated PKCζ inhibitor (PKCζi) in a murine model of bleomycin-induced ALI. After intratracheal injury, we treated mice three times a week with PKCζi or its vehicle, DMSO. We found that mice injured with bleomycin and then treated with PKCζi for one week showed decreased activation of PKCζ, improved lung compliance, and decreased lung protein permeability compared to injured mice treated with DMSO. Mice treated continuously with PKCζi for 6 weeks showed reduced evidence of lung fibrosis by computed tomographic images, decreased lung collagen deposition, and decreased active transforming growth factor-β in the bronchoalveolar lavage fluid. In addition, we found an increased number of lung β4⁺ cells compared to DMSO at Week 6. Therefore, we grew isolated integrin β4⁺ lung progenitor cells in the presence of PKCζi or DMSO and found that β4⁺ cells treated with PKCζi proliferated more in vitro compared to DMSO. We conclude that the use of a PKCζi promotes resolution of lung fibrosis in a bleomycin ALI model and increases the number of β4⁺ progenitor cells with regenerative potential in the lung.