Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis.
Cathepsin B (CB) is involved in the turnover of proteins and has various roles in maintaining the normal metabolism of cells. In our recent study, CB is increased in the muscles of polymyositis/dermatomyositis (PM/DM). However, the role of CB in interstitial lung disease (ILD) has not been reported. ILD is a frequent complication of PM/DM, which is the leading cause of death in PM/DM. It carries high morbidity and mortality in connective tissue diseases, characterized by an overproduction of inflammatory cytokines and induced fibrosis, resulting in respiratory failure. The etiology and pathogenesis of ILD remain incompletely understood. This study investigated whether treatment with CA-074Me, a specific inhibitor of CB, attenuates ILD in PM. CB expression, inflammation, and fibrosis were analyzed in the lung tissues from patients with PM/DM. The animal model of PM was induced in guinea pigs with Coxsackie virus B1 (CVB1). CA-074Me was given 24 h after CVB1 injection for 7 consecutive days. At the end of the experiment, the animals were killed and lung tissues were collected for the following analysis. Inflammation, fibrosis and apoptosis cells, and cytokines were assessed by histological examinations and immunohistochemical analyses, western blot analysis and transferase-mediated dUTP nick-end labeling assay. In patients with PM/DM, the protein levels of CB were significantly elevated in lung tissues compared with healthy controls, which correlated with increases in inflammation and fibrosis. Similarly, the expression of CB, inflammation and fibrosis, CD8(+) T cell, CD68(+) cell, tumor necrosis factor-alpha, transforming growth factor-beta1 infiltrations, and apoptotic cell death were significantly increased in lung tissues of the guinea-pig model of CVB1-induced PM. These changes were attenuated by the administration of CA-074Me. In conclusion, this study demonstrates that PM/DM increases CB expression in lung tissues and inhibition of CB reduces ILD in a guinea-pig model of CVB1-induced PM. This finding suggests that CB may be a potential therapeutic target for ILD.
Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Li
L
Zhang
Department of Ultrasound, Shanghai Pudong Gongli Hospital, Shanghai, PR China.
Xiao-Hong
XH
Fu
Key Laboratory of Viral Heart Diseases, Ministry of Public Health, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Yong
Y
Yu
Department of Pathology, Tumor Hospital, Fudan University, Shanghai, PR China.
Ruo-Hong
RH
Shui
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Chun
C
Li
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Hai-Ying
HY
Zeng
Department of thoracic surgery, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Yu-Lei
YL
Qiao
Department of Dermatology, Shanghai Skin Diseases Hospital, Shanghai, PR China.
Li-Yan
LY
Ni
Department of Dermatology, Zhongshan Hospital, Fudan University, Shanghai, PR China.
Qiang
Q
Wang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003882:Dermatomyositis / Q000150:complications; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D017563:Lung Diseases, Interstitial / Q000150:complications / Q000517:prevention & control*; D011658:Pulmonary Fibrosis / Q000150:complications / Q000517:prevention & control*; D051381:Rats; D015854:Up-Regulation
C400541:CA 074 methyl ester; D004151:Dipeptides; D002401:Cathepsin B