Critical Roles Of Kindlin-2 In The Progression Of Pulmonary Fibrosis

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 levels 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-?1 markedly increased the expression of kindlin-2 and PYCR1,resulting in increased formation of the kindlin-2-PYCR1 complex and proline synthesis.The levels of the kindlin-2-PYCR1 complex and proline synthesis were markedly reduced in response to pirfenidone,a clinically approved therapeutic drugs for pulmonary fibrosis.Furthermore,depletion of kindlin-2 alone was sufficient to suppress TGF-?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 levels 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.