期刊
JOURNAL OF CELLULAR PHYSIOLOGY
卷 237, 期 1, 页码 566-579出版社
WILEY
DOI: 10.1002/jcp.30500
关键词
calpain; fibrosis; migration; pleural mesothelial cell
资金
- National Natural Science Foundation of China [81973991, 81873401, 82070066, 82070098, 81900068, 91643101]
- Canadian Institute of Health Research [FRN81189]
- United States Department of Veterans Affairs [BX002035]
Idiopathic pulmonary fibrosis (IPF) is characterized by fibrosis in the peripheral or sub-pleural area, with migration of pleural mesothelial cells (PMC) contributing to the fibrotic process. Calpain plays a key role in PMC migration and activation of calpain leads to cell migration, proliferation, and collagen synthesis. Inhibition of calpain attenuates pulmonary fibrosis and prevents PMC migration, indicating its potential as a therapeutic target for IPF.
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia. It is unknown why fibrosis in IPF distributes in the peripheral or named sub-pleural area. Migration of pleural mesothelial cells (PMC) should contribute to sub-pleural fibrosis. Calpain is known to be involved in cell migration, but the role of calpain in PMC migration has not been investigated. In this study, we found that PMCs migrated into lung parenchyma in patients with IPF. Then using Wt1(tm1(EGFP/Cre)Wtp)/J knock-in mice, we observed PMC migration into lung parenchyma in bleomycin-induced pleural fibrosis models, and calpain inhibitor attenuated pulmonary fibrosis with prevention of PMC migration. In vitro studies revealed that bleomycin and transforming growth factor-beta 1 increased calpain activity in PMCs, and activated calpain-mediated focal adhesion (FA) turnover as well as cell migration, cell proliferation, and collagen-I synthesis. Furthermore, we determined that calpain cleaved FA kinase in both C-terminal and N-terminal regions, which mediated FA turnover. Lastly, the data revealed that activated calpain was also involved in phosphorylation of cofilin-1, and p-cofilin-1 induced PMC migration. Taken together, this study provides evidence that calpain mediates PMC migration into lung parenchyma to promote sub-pleural fibrosis in IPF.
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