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目的 Caveolin-1 (Cav-1), a major structural protein of caveolae, is involved in many physiological and pathophysiological process such as energy homeostasis and lung fibrosis.Although it is well-recognized that Cav-1 deficiency promotes pulmonary fibrosis in mice, the relationship to lung energy metabolism remains unexplored. 方法 Cav-1 gene disrupted mice (Cav-1-/- mice) and the corresponding controls B6129 mice (male, 8-10 weeks old) were used. When applicable, mice received 12.5 mg of glucose metabolism inhibitor 2-deoxyglucose (2-DG) or vehicle in a total volume of 100 μl of sterile PBS by daily ip injection.AMPK activation and the unfolded protein response were assessed in whole lung tissue and isolated primary AECII cells by performing Western blot analysis.ATP levels were measured using commercially available kits. Lung fibrosis was assessed by measuring TGF-β1 levels in BAL fluid, by quantifying transcripts and protein levels for TGF-β1 and collagen1α1.Apoptotic cell death was assessed in whole tissue by evaluating caspase 3 cleavage.Alveolar epithelial A549 cells were transfected with Cav-1 shRNA lentivirus and used for evaluating Cav-1 depletion-induced metabolic and ER tress in culture. 结果 We found that Cav-1 deficiency induced severe metabolic stress in the lung, significantly suppressing ATP levels and enhancing the phosphorylation of AMPK.Further, we showed that alterations in metabolic homeostasis were associated with an increase in ER stress as evident by an upregulation in each of the major ER stress sensors (IRE-1, ATF6, PERK) in whole tissues and primary alveolar type Ⅱ cells from Cav-1 -/- mice.Moreover, we found that metabolic and ER stress was enhanced in the lungs of Cav-1 -/- mice undergoing further metabolic with 2-DG treatment.Also, this coincided with the increase in TGF-β1 and collagen levels and apoptotic death.Similarly, silencing Cav-1 with shRNA induced AMPK activation, ER stress and caspase-3 activation in A549 cells. 结论 Our data provide evidence that Cav-1 play a critical role in regulating energy metabolism in the lung epithelium and suggests that deficiency in Cav-1 might promote lung fibrosis by enhancing ER stress and activating apoptotic pathways.