Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis.

摘要: Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition TGF-β limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover little-known connection between signalling casein kinase (CK) activity. have examined the abundance CK1 delta epsilon (CK1δ/e) in lung tissue from IPF patients non-diseased controls, investigated whether CK1δ/e with PF670462 inhibits fibrosis. levels controls were assessed immunohistochemistry. Anti-fibrotic effects inhibitor pre-clinical models, acute chronic bleomycin mouse models vitro experiments on spheroids made primary human fibroblast cells control donors, A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression CK1δ e lungs compared was accompanied increased product, phospho-period 2. In vitro, prevented TGF-beta-induced epithelial-mesenchymal transition. The stiffness IPF-derived reduced TGF-beta induced fibrogenic gene inhibited. administered systemically or locally inhalation both bleomycin-induced mice. ‘therapeutic’ regimen (day 7 onwards) collagen accumulation. Elevated activity δ anti-fibrogenic dual CKTransforming