Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 65, Issue 1, Pages 54-69Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2020-0320OC
Keywords
pulmonary fibrosis; proline synthesis; kindlin-2; PYCR1; TGF-beta 1
Funding
- National Key R&D Program of China [2019YFA0906000]
- National Natural Science of Foundation of China [81430068]
- Natural Science Foundation of Guangdong Province [2017B030301018]
- Shenzhen Innovation Committee of Science and Technology [JCYJ20190809115017189, JCYJ20180302174228311, ZDSYS20140509142721429]
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The study highlights the crucial role of kindlin-2 in lung fibroblast activation, collagen matrix synthesis, and pulmonary fibrosis progression. Therapeutic interventions targeting the kindlin-2 signaling pathway show promise in controlling this deadly lung disease.
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-beta 1 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-beta 1-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.
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