PAI-1 regulation of TGF-β1-induced alveolar Type II cell senescence, SASP secretion, and SASP-mediated activation of alveolar macrophages

Academic Article

Abstract

  • © 2020 by the American Thoracic Society. 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. Despite recognition of the importance of ATII cell senescence in idiopathic pulmonary fibrosis 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 (transforming growth factor-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 secrete various cytokines and chemokines, including IL-4 and IL-13, which stimulate the expression of genes associated with a profibrotic 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 smallmolecule PAI-1 inhibitor, however, blocks TGF-β1-induced senescence as well as a senescence-associated secretory phenotype in ATII and L2 cells and, consequently, the stimulatory effects of the conditioned medium fromsenescentATII/L2 cells onmacrophages.Moreover,we showthat silencing p16 ameliorates PAI-1 protein-inducedATII cell senescence and secretion of profibrotic mediators. Our data suggest that PAI-1 mediates TGF-β1-induced ATII cell senescence and secretion of profibroticmediators through inducing p16, and they also suggest that senescent ATII cells contribute to lung fibrogenesis in part by activating alveolar macrophages through secreting profibrotic and proinflammatory mediators.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 2897310
  • Author List

  • Rana T; Jiang C; Liu G; Miyata T; Antony V; Thannickal VJ; Liu RM
  • Start Page

  • 319
  • End Page

  • 330
  • Volume

  • 62
  • Issue

  • 3