Excessive collagen type VII mediates pleural fibrosis via increasing extracellular matrix stiffness.

Abstract

The interaction between cells and extracellular matrix (ECM) has been recognized in the mechanism of fibrotic diseases. Collagen type VII (collagen VII) is an ECM component that plays an important role in cell-ECM interaction, particularly in cell anchoring and maintenance of ECM integrity. Pleural mesothelial cells (PMCs) drive inflammatory reactions and ECM production in pleura. However, the role of collagen VII and PMCs in pleural fibrosis was poorly understood. In this study, collagen VII protein was found to be increased in pleura of patients with tuberculous pleural fibrosis. Investigation of cellular and animal models revealed that collagen VII began to increase at an early stage in the pleural fibrotic process. Increase of collagen VII occurred ahead of collagen I and α-SMA in PMCs and pleura of animal models. Inhibition of collagen VII by mesothelial cell-specific deletion of collagen VII gene (Wt1-Cre+ Col7a1fl/fl) attenuated mouse experimental pleural fibrosis. Finally, it was found that excessive collagen VII changed collagen conformation, which resulted in elevation of ECM stiffness. Elevation of ECM stiffness activated integrin/PI3K-AKT/JUN signaling and promoted more ECM deposition, as well as mediated pleural fibrosis. In conclusion, excessive collagen VII mediated pleural fibrosis via increasing ECM stiffness.