Role of Bcl-xL in hepatocyte growth factor-elicited epithelial protection in idiopathic pulmonary fibrosis

Hepatocyte growth factor (HGF) is a cytokine with pleiotropic functions during wound healing and repair. Its anti-fibrotic effects were shown in animal models of lung fibrosis and linked to improved cellular survival and proliferation and reduced myofibroblast accumulation. HGF-elicited, pro-survival pathways have yet not been investigated in detail in lung epithelial cells. Based on literature, our study is focused on Bcl-xL, pro-survival protein involved in mitochondrial control of apoptosis.

Analysis of IPF lung homogenates revealed significantly increased expression of Bcl-xL when compared to donor lungs. In human IPF, much less in donor lungs, Bcl-xL protein is highly expressed in hyperplastic alveolar epithelial type II cells, basal cells and bronchial epithelial cells. Furthermore, Bcl-xL expression co-localized with specific HGF receptor c-Met. In vitro data shows decreased expression of Bcl-xL in murine epithelial MLE12/15 cells in response to oxidative stress-induced apoptosis. Under these conditions, HGF treatment resulted in increased survival of cells that correlated with increased Bcl-xL expression. The same effect of HGF is seen after treatment of cells with the potent ER-stress inducer thapsigargin. Anti-apoptotic effect of HGF was abolished after pre-incubation with c-Met inhibitor. Knock-down of Bcl-xL protein made epithelial cells much more sensitive to injury caused by oxidative stress, as well as ER stress, however did not affect HGF pro survival activity.

In conclusion, our data shows that HGF has a strong pro-survival effect on alveolar epithelial cells. Its interdependency with Bcl-xL protein needs to be further investigated, however Bcl-xL seems to be an important factor in epithelial response to injury.