期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 184, 期 10, 页码 2730-2741出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2014.06.017
关键词
-
类别
资金
- Flight Attendant Medical Research Institute [82384]
- NIH National Heart, Lung, and Blood Institute [R01 HL090660, R01 HL071595]
- American Heart Association [09FTF2090019]
- Yale Claude D. Pepper Older Americans Independence Center [P30 AG021342]
- NIH National Institute on Aging [R03 AG042358-02]
Emphysema is characterized by Loss of Lung elasticity and irreversible air space enlargement, usually in the later decades of Life. The molecular mechanisms of emphysema remain poorly defined. We identified a rote for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined Lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the Lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin Ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of Lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据