Date Published: July 19, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Chunsun Jiang, Gang Liu, Tracy Luckhardt, Veena Antony, Yong Zhou, A. Brent Carter, Victor J. Thannickal, Rui‐Ming Liu.
Senescence of alveolar type 2 (ATII) cells, progenitors of the alveolar epithelium, is implicated in the pathogeneses of idiopathic pulmonary fibrosis (IPF), an aging‐related progressive fatal lung disorder with unknown etiology. The mechanism underlying ATII cell senescence in fibrotic lung diseases, however, remains poorly understood. In this study, we report that ATII cells in IPF lungs express higher levels of serpine 1, also known as plasminogen activator inhibitor 1 (PAI‐1), and cell senescence markers p21 and p16, compared to ATII cells in control lungs. Silencing PAI‐1 or inhibition of PAI‐1 activity in cultured rat ATII (L2) cells leads to decreases in p53 serine 18 phosphorylation (p53S18P), p53 and p21 protein expressions; an increase in retinoblastoma protein phosphorylation (ppRb); and a reduction in the sensitivity to bleomycin‐ and doxorubicin‐induced senescence. Silencing p53, on the other hand, abrogates PAI‐1 protein‐stimulated p21 expression and cell senescence. In vivo studies, using ATII cell‐specific PAI‐1 conditional knockout mouse model generated recently in this laboratory, further support the role of PAI‐1 in the activation of p53‐p21‐Rb cell cycle repression pathway, ATII cell senescence, and lung fibrosis induced by bleomycin. This study reveals a novel function of PAI‐1 in regulation of cell cycle and suggests that elevation of PAI‐1 contributes importantly to ATII cell senescence in fibrotic lung diseases.
Cellular senescence, a state of permanent inhibition of cell growth, has been linked to aging and aging‐related diseases (Akram et al., 2014). The mechanisms underlying cellular senescence under either physiological or pathological conditions, however, remain poorly understood. Alveolar type II (ATII) cells can self‐renew and also differentiate into type I alveolar epithelial cells and therefore are considered as alveolar progenitor cells (Aoshiba et al., 2003, 2013). ATII cell senescence is evident in fibrotic lung diseases, including IPF (Buckbinder et al., 1995; Chang et al., 2010; Bhandary et al., 2013; Barkauskas & Noble, 2014), and in experimental fibrosis models (Chao, 2015; Childs et al., 2015). A current disease paradigm is that lung fibrosis develops as a result of unremitting insults plus genetic and aging‐related risk factors, leading to alveolar epithelial cell injuries, which is followed by activation of myofibroblasts and replacement of injured alveolar epithelium with fibrotic tissue, due to a decreased reparative capacity of alveolar epithelium. Elucidation of the mechanisms underlying ATII cell senescence, therefore, may be a key to our understanding of the disease pathogenesis and thus development of effective therapeutics.
Fibrosis is a common pathological feature of many lung diseases, including IPF, an aging‐related progressive fatal lung disorder with unknown etiology (Maclaine & Hupp, 2011; Mark & Thurlimann, 2012). There is no cure for these fibrotic diseases due to incomplete understanding of the pathogenesis. ATII cells are progenitor cells of the alveolar epithelium; ATII cell senescence is evident in IPF and in experimental lung fibrosis models (Buckbinder et al., 1995; Chang et al., 2010; Bhandary et al., 2013; Barkauskas & Noble, 2014; Chao, 2015; Childs et al., 2015). The mechanism underlying ATII cell senescence in fibrotic lung diseases, however, is unknown. Using IPF lung tissues, cultured ATII (L2) cells, and a PAI‐1 conditional knockout mouse model, we show, for the first time in this study, that PAI‐1 induces and mediates bleomycin‐ and doxorubicin‐induced ATII cell senescence in vitro and in vivo. Our data also show that suppression of bleomycin‐induced ATII cell senescence in mice by specifically knocking out the PAI‐1 gene in these cells is associated with attenuation of lung fibrosis. These results suggest that elevation of PAI‐1 contributes importantly to ATII cell senescence in fibrotic lung diseases.
This work is supported by National Heart, Lung, and Blood Institute to Rui‐Ming Liu (5R01HL088141; R56HL131054) and to Victor J. Thannickal (P01 HL114470).
CJ conducted the experiments and analyzed and wrote the manuscript; TL helped with alveolar type II cell isolation; GL, VA, YZ, and ABC contributed intellectually to the experimental design and edited the manuscript; VJT contributed data interpretation and manuscript writing; RML conceived the project, designed the experiments, and wrote the manuscript.
The authors have no conflict of interest to declare.