Excessive collagen type VII mediates pleural fibrosis via increasing extracellular matrix stiffness
Qian Li, Xin-Liang He, Shuai-Jun Chen, Qian Niu, Tan-Ze Cao, Xiao-Lin Cui, Zi-Heng Jia, He-De Zhang, Xiao Feng, Ye-Han Jiang, Li-Mei Liang, Pei-Pei Cheng, Shi-He Hu, Liang Xiong, Meng Wang, Hong Ye, Wan-Li Ma
Qian Li, Xin-Liang He, Shuai-Jun Chen, Qian Niu, Tan-Ze Cao, Xiao-Lin Cui, Zi-Heng Jia, He-De Zhang, Xiao Feng, Ye-Han Jiang, Li-Mei Liang, Pei-Pei Cheng, Shi-He Hu, Liang Xiong, Meng Wang, Hong Ye, Wan-Li Ma
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Research Article Cell biology Inflammation Pulmonology

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.

Authors

Qian Li, Xin-Liang He, Shuai-Jun Chen, Qian Niu, Tan-Ze Cao, Xiao-Lin Cui, Zi-Heng Jia, He-De Zhang, Xiao Feng, Ye-Han Jiang, Li-Mei Liang, Pei-Pei Cheng, Shi-He Hu, Liang Xiong, Meng Wang, Hong Ye, Wan-Li Ma

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Figure 6

ITGAV siRNA and cilengitide prevented increases of collagen I and α-SMA in vivo and in vitro.

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ITGAV siRNA and cilengitide prevented increases of collagen I and α-SMA ...
(A) Protein-protein interaction network analysis based on differentially expressed proteins identified by tandem mass tag analysis in Figure 1A. Key molecular interaction proteins with collagen VII are shown. (B) Flowchart of protocol. Mice with pleural fibrosis induced by BLM plus carbon particles were treated with the integrin inhibitor cilengitide. Cilengitide (20 μg/g) was administered intraperitoneally daily from day 7 to day 21 after BLM plus carbon injection. n = 5. (C) Representative images of Masson’s trichrome staining of visceral, parietal, and diaphragmatic pleura from model mice and cilengitide-treated model mice. Scale bars: 50 μm. (D–I) PMCs were treated with BLM (0.2 μg/mL), TBPE (5%), and recombinant collagen VII (1 μg/mL) with or without cilengitide (10 μg/mL) for 24 hours, after which collagen I and α-SMA proteins were detected by Western blotting. (D, F, and H) Representative images of Western blots of collagen I and α-SMA protein. (E, G, and I) Bar graphs showing changes of protein according to D, F, and H, respectively. Data are expressed as mean ± SD. Statistical significance was determined using 1-way ANOVA. n = 3. *P < 0.05, **P < 0.01. re-Collagen VII, recombinant collagen VII protein.