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

Pooja Shivshankar, Christopher Brampton, Shelley Miyasato, Michael Kasper, Victor J. Thannickal, Claude T Chapman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)28-36
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume47
Issue number1
DOIs
StatePublished - Jul 2012

Fingerprint

Caveolin 1
Pulmonary Fibrosis
Cell Aging
Epithelial Cells
Bleomycin
Lung Injury
Wounds and Injuries
Collagen
Chemical activation
Chemokine CXCL2
Apoptosis
Phenotype
Tenascin
Idiopathic Pulmonary Fibrosis
Messenger RNA
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Fibroblasts
Smooth Muscle
Muscle

Keywords

  • Apoptosis
  • Caveolin-1
  • Cellular senescence
  • Fibrosis
  • Lung injury

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. / Shivshankar, Pooja; Brampton, Christopher; Miyasato, Shelley; Kasper, Michael; Thannickal, Victor J.; Chapman, Claude T.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 47, No. 1, 07.2012, p. 28-36.

Research output: Contribution to journalArticle

Shivshankar, Pooja ; Brampton, Christopher ; Miyasato, Shelley ; Kasper, Michael ; Thannickal, Victor J. ; Chapman, Claude T. / Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. In: American Journal of Respiratory Cell and Molecular Biology. 2012 ; Vol. 47, No. 1. pp. 28-36.
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