Divergent Regulation of Alveolar Type 2 Cell and Fibroblast Apoptosis by Plasminogen Activator Inhibitor 1 in Lung Fibrosis

Increased apoptosis sensitivity of alveolar type 2 (ATII) cells and increased apoptosis resistance of (myo)fibroblasts, the apoptosis paradox, contributes to the pathogenesis of idiopathic pulmonary fibrosis (IPF). The mechanism underlying the apoptosis paradox in IPF lungs, however, is unclear. Aging is the greatest risk factor for IPF. In this study, we show, for the first time, that ATII cells from old mice are more sensitive, whereas fibroblasts from old mice are more resistant, to apoptotic challenges, compared with the corresponding cells from young mice. The expression of plasminogen activator inhibitor 1 (PAI-1), an important profibrogenic mediator, was significantly increased in both ATII cells and lung fibroblasts from aged mice. In vitro studies using PAI-1 siRNA and active PAI-1 protein indicated that PAI-1 promoted ATII cell apoptosis but protected fibroblasts from apoptosis, likely through dichotomous regulation of p53 expression. Deletion of PAI-1 in adult mice led to a reduction in p53, p21, and Bax protein expression, as well as apoptosis sensitivity in ATII cells, and their increase in the lung fibroblasts, as indicated by in vivo studies. This increase was associated with an attenuation of lung fibrosis after bleomycin challenge. Since PAI-1 is up-regulated in both ATII cells and fibroblasts in IPF, the results suggest that increased PAI-1 may underlie the apoptosis paradox of ATII cells and fibroblasts in IPF lungs.

Automated summary

The increased sensitivity to apoptosis of alveolar type 2 cells (ATII) and the increased resistance to apoptosis of (myo)fibroblasts, known as the apoptosis paradox, could be attributed to the regulation of plasminogen activator inhibitor 1 (PAI-1), which is up-regulated in both cell types in idiopathic pulmonary fibrosis (IPF). The findings suggest that the age-related changes in PAI-1 levels may underlie the apoptosis sensitivity and resistance in ATII and fibroblast cells in IPF lungs. The genetic deletion of PAI-1 in mice led to alterations in p53, p21, and Bax protein expression, impacting the apoptosis response in these cells and ultimately affecting lung fibrosis development.