Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis.
Pleural fibrosis is defined as an excessive deposition of extracellular matrix (ECM) components that results in destruction of the normal pleural tissue architecture. It can result from diverse inflammatory conditions, especially tuberculous pleurisy. Pleural mesothelial cells (PMCs) play a pivotal role in pleural fibrosis. Calpain is a family of calcium-dependent endopeptidases, which plays an important role in ECM remodeling. However, the role of calpain in pleural fibrosis remains unknown. In the present study, we found that tuberculous pleural effusion (TPE) induced calpain activation in PMCs and that inhibition of calpain prevented TPE-induced collagen-I synthesis and cell proliferation of PMCs. Moreover, our data revealed that the levels of angiotensin (ANG)-converting enzyme (ACE) were significantly higher in pleural fluid of patients with TPE than those with malignant pleural effusion, and ACE-ANG II in TPE resulted in activation of calpain and subsequent triggering of the phosphatidylinositol 3-kinase (PI3K)/Akt/NF-κB signaling pathway in PMCs. Finally, calpain activation in PMCs and collagen depositions were confirmed in pleural biopsy specimens from patients with tuberculous pleurisy. Together, these studies demonstrated that calpain is activated by renin-angiotensin system in pleural fibrosis and mediates TPE-induced collagen-I synthesis and proliferation of PMCs via the PI3K/Akt/NF-κB signaling pathway. Calpain in PMCs might be a novel target for intervention in tuberculous pleural fibrosis.
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China;
Jie
J
Yang
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Respiratory Diseases, Ministry of Health of China, Wuhan, Hubei, China;
Fei
F
Xiang
Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China;
Peng-Cheng
PC
Cai
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China;
Yu-Zhi
YZ
Lu
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China;
Xiao-Xiao
XX
Xu
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Respiratory Diseases, Ministry of Health of China, Wuhan, Hubei, China;
Fan
F
Yu
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China;
Feng-Zhi
FZ
Li
Queen's University Cancer Research Institute, Kingston, Ontario, Canada;
Peter A
PA
Greer
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China;
Huan-Zhong
HZ
Shi
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Respiratory Diseases, Ministry of Health of China, Wuhan, Hubei, China;
Qiong
Q
Zhou
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Respiratory Diseases, Ministry of Health of China, Wuhan, Hubei, China;
Jian-Bao
JB
Xin
Key Laboratory of Respiratory Diseases, Ministry of Health of China, Wuhan, Hubei, China; Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and.
Hong
H
Ye
Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
Yunchao
Y
Su
Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Key Laboratory of Respiratory Diseases, Ministry of Health of China, Wuhan, Hubei, China; whmawl@aliyun.com.
Wan-Li
WL
Ma
D000293:Adolescent; D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000502:physiology; D002154:Calpain / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis; D004789:Enzyme Activation; D004848:Epithelium / Q000473:pathology; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010994:Pleura / Q000382:microbiology / Q000473:pathology; D016066:Pleural Effusion, Malignant / Q000201:enzymology; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D014396:Tuberculosis, Pleural / Q000201:enzymology* / Q000473:pathology; D055815:Young Adult
D024042:Collagen Type I; D000804:Angiotensin II; D002154:Calpain
calpain; fibrosis; pleural effusion; pleural mesothelial cell; tuberculosis