The role of alveolar epithelial type I cells in bleomycin-induced lung injury: Characterization of fibrosis-relevant signal pathways

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At the beginning of this project, we studied signaling pathways associated with the purinergic receptor P2X7R in alveolar epithelial type I cells after bleomycin treatment of the human distal lung epithelial cell line, NCI-H441 and of mouse precision-cut lung slice cultures. We confirmed the evidence of the P2X7R-PKC-β-CaMKII axis during earliest stages after bleomycin exposure and we still investigate the importance of this pathway for the maintenance of the alveolar barrier function.Another important aspect of this project relates to the involvement of caveolin-1 in a proper maintaining alveolar barrier function. Here we could demonstrate that caveolin-1 is associated with the Src kinase Fyn. Fyn kinase was found to be selectively expressed in alveolar epithelial type I cells. Bleomycin reduces the transepithelial electrical resistance (TEER) in NCI-H441 cell monolayers and inhibition of Fyn attenuated the loss of TEER under these conditions. In addition, caveolin-1 knockout in mouse lungs presented with an altered cellular distribution of Fyn kinase.It is the main aim during the extension of this project to investigate the effect of pirfenidone, a recently approved anti-fibrosis agent, on anti-fibrotic pathways in alveolar epithelial cells. The planned experiments should clarify, whether p120 catenin, an important binding partner of the E-cadherin-catenin complex, is phosphorylated by Fyn and whether Fyn kinase is a target of pirfenidone. The pirfenidone-induced changes in caveolin-1 and E-cadherin expression, as already demonstrated in this project, emphasize the involvement of Fyn kinase and caveolin-1 in the regulation of intercellular communication in the alveolar epithelium.