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PAI-1 Regulation of TGF-β1-induced ATII Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages

PAI-1 Regulation of TGF-β1-induced ATII Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages

American Journal of Respiratory Cell and Molecular Biology 2019:

Senescence of alveolar type II (ATII) cells, progenitors of the alveolar epithelium, is a pathological feature and contributes importantly to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Despite recognition of the importance of ATII cell senescence in IPF pathogenesis, how ATII cell senescence is regulated and how senescent ATII cells contribute to lung fibrogenesis remain unclear. In this study, we show that TGF-β1, a most ubiquitous and potent profibrotic cytokine, induces plasminogen activator inhibitor 1 (PAI-1), a cell senescence and fibrosis mediator, and p16 as well as senescence, but not apoptosis, in primary mouse ATII cells. We also found that senescent ATII cells secretes various cytokines and chemokines, including interleukin 4 (IL-4) and 13 (IL-13), which stimulate the expression of genes associated with a pro-fibrotic phenotype in alveolar macrophages. Similar responses were also observed in TGF-β1-treated rat ATII (L2) and rat macrophage NR8383 cells. Deletion of PAI-1 or inhibition of PAI-1 activity with a small molecule PAI-1 inhibitor, on the other hand, blocks TGF-β1-induced senescence as well as senescence associated secretion phenotype (SASP) in ATII and L2 cells and, consequently, the stimulatory effects of the conditional medium from senescent ATII/L2 cells on macrophages. Moreover, we show that silencing p16 ameliorates PAI-1 protein-induced ATII cell senescence and secretion of pro-fibrotic mediators. Our data suggest that PAI-1 mediates TGF-β 1-induced ATII cell senescence and secretion of pro-fibrotic mediators through inducing p16 and that senescent ATII cells contribute to lung fibrogenesis in part by activating alveolar macrophages through secreting pro-fibrotic and pro-inflammatory mediators.

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Accession: 069332190

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PMID: 31513752

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