title: Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice.
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) and cav-1-deficient (cav-1(-/-)) mice using 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-induced inflammatory 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.
authors.affiliation: Department of Medicine, Division of Cardiology/Pulmonary diseases, University of Texas Health Science Center at San Antonio, 78229, USA.
authors.forename: Pooja
authors.initials: P
authors.lastname: Shivshankar
authors.forename: Christopher
authors.initials: C
authors.lastname: Brampton
authors.forename: Shelley
authors.initials: S
authors.lastname: Miyasato
authors.forename: Michael
authors.initials: M
authors.lastname: Kasper
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.forename: Claude Jourdan
authors.initials: CJ
authors.lastname: Le Saux
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D054426:Chemokine CXCL2 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology*; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D008170:Lung Compliance; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011347:Procollagen / Q000378:metabolism
chemical_list: D000199:Actins; D051242:Caveolin 1; D054426:Chemokine CXCL2; D015850:Interleukin-6; D011347:Procollagen; D001761:Bleomycin; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9