Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice

Academic Article

Abstract

  • Idiopathic pulmonary fibrosis is associated with a decreased expression of caveolin-1 (cav-1), yet its role remains unclear. To investigate the role of cav-1, we induced pulmonary fibrosis in wild-type (WT) andcav-1-deficient (cav-1-/-) miceusing intratracheal instillation of bleomycin. Contrary to expectations, significantly less collagen deposition was measured in tissue from cav-1-/- mice than in their WT counterparts, consistent with reduced mRNA expression of procollagen1a2 and procollagen3a1. Moreover, cav-1-/- mice demonstrated 77% less α-smooth muscle actin staining, suggesting reduced mesenchymal cell activation. Levels of pulmonary injury, assessed by tenascin-C mRNA expression and CD44v10 detection, were significantly increased at Day 21 after injury in WT mice, an effect significantly attenuated in cav-1-/- mice. The apparent protective effect against bleomycin-induced fibrosis in cav-1-/- mice was attributed to reduce cellular senescence and apoptosis in cav-1 -/-epithelial cells during the early phase of lung injury. Reduced matrix metalloproteinase (MMP)-2 and MMP-9 expressions indicated a low profile of senescence-associated secretory phenotype (SASP) in the bleomycin-injured cav-1-/- mice. However, IL-6 and macrophage inflammatory protein 2 were increased in WT and cav-1-/- mice after bleomycin challenge, suggesting that bleomycin-inducedinflammatory response substantiated the SASP pool. Thus, loss of cav-1 attenuates early injury response to bleomycin by limiting stress-induced cellular senescence/apoptosis in epithelial cells. In contrast, decreased cav-1 expression promotes fibroblast activation and collagen deposition, effects that may be relevant in later stages of reparative response. Hence, therapeutic strategies to modulate the expression of cav-1 should take into account cell-specific effects in the regenerative responses of the lung epithelium to injury. Copyright © 2012 by the American Thoracic Society.
  • Digital Object Identifier (doi)

    Author List

  • Shivshankar P; Brampton C; Miyasato S; Kasper M; Thannickal VJ; Le Saux CJ
  • Start Page

  • 28
  • End Page

  • 36
  • Volume

  • 47
  • Issue

  • 1