Activation of calpain by renin-angiotensin system in pleural mesothelial cells mediates tuberculous pleural fibrosis.

Jie Yang,Peter A Greer,Feng-Zhi Li,Yunchao Su,Peng-Cheng Cai,Hong Ye,Wan-Li Ma,Jian-Bao Xin,Fei Xiang,Fan Yu,Xiao-Xiao Xu,Qiong Zhou,Huan-Zhong Shi,Yu-Zhi Lu

doi:10.1152/ajplung.00348.2015

Abstract

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.

Highlights

PLEURAL FIBROSIS IS DEFINED as an excessive deposition of extracellular matrix that results in destruction of the normal pleural tissue architecture and compromised function
Calpain activity in Pleural mesothelial cells (PMCs) incubated with pleural fluid from patients with tuberculous pleural effusions (TPE) was significantly higher than that in PMCs incubated with pleural fluid from patients with malignant pleural effusion (MPE) or with serum from the same patient with TPE (STB) (Fig. 1C)
We show here for the first time that calpain plays an important role in tuberculous pleural fibrosis

Summary

Introduction

PLEURAL FIBROSIS IS DEFINED as an excessive deposition of extracellular matrix that results in destruction of the normal pleural tissue architecture and compromised function. Pleural fibrosis typically occurs following severe pleural inflammation, which is associated with exudative pleural effusion. Both TPE and malignant pleural effusion (MPE) are exudative pleural effusion. Reactive PMCs take part in pleural inflammation by upregulating vasoactive substances and enzymes in the oxidative pathway [19, 32]. PMCs proliferate and excrete plasminogen activator inhibitor-1 (PAI-1) [8] and extracellular matrix to repair the pleural injury. CALPAIN IN PLEURAL MESOTHELIAL CELL MEDIATES FIBROSIS tion of PMCs and overdeposition of extracellular matrix in response to injury result in pleural fibrosis. The phosphatidylinositol 3-kinase (PI3K)/Akt/NF-␬B pathway has been reported to be involved in cell proliferation and extracellular matrix regulation of PMCs [31]

Methods

Results

Conclusion