| First Author | Zhang P | Year | 2021 |
| Journal | Am J Respir Cell Mol Biol | Volume | 65 |
| Issue | 1 | Pages | 54-69 |
| PubMed ID | 33761308 | Mgi Jnum | J:326797 |
| Mgi Id | MGI:7314533 | Doi | 10.1165/rcmb.2020-0320OC |
| Citation | Zhang P, et al. (2021) Kindlin-2 Acts as a Key Mediator of Lung Fibroblast Activation and Pulmonary Fibrosis Progression. Am J Respir Cell Mol Biol 65(1):54-69 |
| abstractText | Pulmonary fibrosis is a progressive and fatal lung disease characterized by activation of lung fibroblasts and excessive deposition of collagen matrix. We show here that the concentrations of kindlin-2 and its binding partner PYCR1, a key enzyme for proline synthesis, are significantly increased in the lung tissues of human patients with pulmonary fibrosis. Treatment of human lung fibroblasts with TGF-beta1 markedly increased the expression of kindlin-2 and PYCR1, resulting in increased kindlin-2 mitochondrial translocation, formation of the kindlin-2-PYCR1 complex, and proline synthesis. The concentrations of the kindlin-2-PYCR1 complex and proline synthesis were markedly reduced in response to pirfenidone or nintedanib, two clinically approved therapeutic drugs for pulmonary fibrosis. Furthermore, depletion of kindlin-2 alone was sufficient to suppress TGF-beta1-induced increases of PYCR1 expression, proline synthesis, and fibroblast activation. Finally, using a bleomycin mouse model of pulmonary fibrosis, we show that ablation of kindlin-2 effectively reduced the concentrations of PYCR1, proline, and collagen matrix and alleviate the progression of pulmonary fibrosis in vivo. Our results suggest that kindlin-2 is a key promoter of lung fibroblast activation, collagen matrix synthesis, and pulmonary fibrosis, underscoring the therapeutic potential of targeting the kindlin-2 signaling pathway for control of this deadly lung disease. |
