任天堂
特发性肺纤维化
血小板源性生长因子受体
医学
肺纤维化
纤维化
间质性肺病
肺
病理
癌症研究
内科学
受体
生长因子
作者
Audrey Joannes,Thierry Voisin,Claudie Morzadec,Alice Letellier,Francisco Llamas Gutierrez,Dan Cristian Chiforeanu,Cécile Le Naourès,Samuel Guillot,Bertrand Richard De Latour,Simon Rouzé,Madeleine Jaillet,Bruno Crestani,Lutz Wollin,S. Jouneau,Laurent Vernhet
标识
DOI:10.1016/j.pupt.2023.102267
摘要
The tyrosine kinase inhibitor nintedanib has been recently approved for the treatment of Interstitial Lung Diseases (ILDs) that manifest a progressive fibrosis phenotype other than Idiopathic pulmonary Fibrosis (IPF). Nintedanib reduces the development of lung fibrosis in various animal models resembling features of PF-ILD and in vitro, it inhibits the fibrosing phenotype of human lung fibroblasts (HLFs) isolated from patients with IPF. To get insight on the cellular and molecular mechanisms that drive the clinical efficiency of nintedanib in patients with non-IPF PF-ILD, we investigated its effects on the fibrosing functions of HLFs derived from patients with PF-hypersensitivity pneumonitis (PF-HP, n = 7), PF-sarcoidosis (n = 5) and pleuroparenchymal fibroelastosis (PPFE, n = 4). HLFs were treated with nintedanib (10 nM-1 μM) and then stimulated with PDGF-BB (25-50 ng/ml) or TGF-β1 (1 ng/ml) for 24-72 h to assess proliferation and migration or differentiation. At nanomolar concentrations, nintedanib reduced the levels of PDGF receptor and ERK1/2 phosphorylation, the proliferation and the migration of PF-HP, PF-sarcoidosis and PPFE HLFs stimulated with PDGF-BB. Moreover, nintedanib also attenuates the myofibroblastic differentiation driven by TGF-β1 but only when it is used at 1 μM. The drug reduced the phosphorylation of SMAD2/3 and decreased the induction of collagen, fibronectin and α-smooth muscle actin expression induced by TGF-β1. In conclusion, our results demonstrate that nintedanib counteracts fundamental fibrosing functions of lung fibroblasts derived from patients with PF-HP, PF-sarcoidosis and PPFE, at concentrations previously reported to inhibit control and IPF HLFs. Such effects may contribute to its clinical benefit in patients suffering from these irreversible ILDs.
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