Serpine 1 induces alveolar type II cell senescence through activating p53‐p21‐Rb pathway in fibrotic lung disease

Abstract

SummarySenescence 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.

Syndecan-1 promotes lung fibrosis by regulating epithelial reprogramming through extracellular vesicles

“…Furthermore, recent studies using scRNA-Seq approaches have reinforced the importance of aberrant Wnt activation in the ATII cells within the fibrotic lungs (48,50). Wnt/β-catenin signaling is dysregulated in the aged lung and promotes senescence, and a pathogenic feature of reprogrammed fibrotic lung epithelial cells is cellular senescence (8,9,48,60,61). Altogether, these findings suggest that aberrant signaling through this pathway can promote lung fibrosis via initiation of cellular senescence.…”

“…Although the abnormal fibroproliferation that occurs in IPF involves a complex interplay between parenchymal and immune cells, the epithelial barrier has a fundamental role, particularly in early events that lead to lung fibrosis (3). Recently, senescence or depletion of alveolar epithelial cells has been implicated in the pathogenesis of lung fibrosis (4)(5)(6)(7)(8)(9). In addition, several epithelial-expressed genes have been found to confer a risk for the development of pulmonary fibrosis (e.g., MUC5B, SFTPC, SFTPA2, ABCA), further supporting dysfunctional alveolar epithelium as a sentinel event in the development of fibrosis (10).…”

Lung cellular senescence is independent of aging in a mouse model of COPD/emphysema

“…Previously, Jiang et al . showed that Serpine1 promotes senescence of alveolar type II cells by inducing p53-p21-Rb cell cycle repression pathway in lung disease 66 . Increased expression of Serpine1 in older air vs. younger air-exposed mice suggests that Serpine1 upregulation could mediate cellular senescence of pulmonary cells as the mice age.…”

Erratum: Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

“…Activation of the p53 pathway in the AEC2s of IPF lungs is also associated with high levels of PAI1. Deletion of PAI1 in AEC2s in mice protected these cells from bleomycin-induced senescence 125 . Moreover, a small molecule PAI1 inhibitor (TM5275) blocked fibrosis in mice treated with bleomycin and protected AEC2s from senescence 126 .…”