Dual inhibition of α
| Autor: | Martin L, Decaris, Johanna R, Schaub, Chun, Chen, Jacob, Cha, Gail G, Lee, Megi, Rexhepaj, Steve S, Ho, Vikram, Rao, Megan M, Marlow, Prerna, Kotak, Erine H, Budi, Lisa, Hooi, Jianfeng, Wu, Marina, Fridlib, Shamra P, Martin, Shaoyi, Huang, Ming, Chen, Manuel, Muñoz, Timothy F, Hom, Paul J, Wolters, Tushar J, Desai, Fernando, Rock, Katerina, Leftheris, David J, Morgans, Eve-Irene, Lepist, Patrick, Andre, Eric A, Lefebvre, Scott M, Turner |
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| Rok vydání: | 2021 |
| Předmět: |
Precision-cut lung slice
Integrin alpha6beta1 Research Transforming growth factor-β αv integrin Epithelial Cells Fibroblasts Coculture Techniques Idiopathic Pulmonary Fibrosis Cell Line Collagen Type I alpha 1 Chain Mice Inbred C57BL Bleomycin Disease Models Animal Animals Humans Receptors Vitronectin Smad3 Protein Antifibrotic Agents Phosphorylation Antifibrotic Lung Signal Transduction PLN-74809 |
| Zdroj: | Respiratory Research |
| ISSN: | 1465-993X |
| Popis: | Rationale αv integrins, key regulators of transforming growth factor-β activation and fibrogenesis in in vivo models of pulmonary fibrosis, are expressed on abnormal epithelial cells (αvβ6) and fibroblasts (αvβ1) in fibrotic lungs. Objectives We evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis. Methods Selective αvβ6 and αvβ1, dual αvβ6/αvβ1, and multi-αv integrin inhibitors were characterized for potency, selectivity, and functional activity by ligand binding, cell adhesion, and transforming growth factor-β cell activation assays. Precision-cut lung slices generated from lung explants from patients with idiopathic pulmonary fibrosis or bleomycin-challenged mouse lungs were treated with integrin inhibitors or standard-of-care drugs (nintedanib or pirfenidone) and analyzed for changes in fibrotic gene expression or TGF-β signaling. Bleomycin-challenged mice treated with dual αvβ6/αvβ1 integrin inhibitor, PLN-74809, were assessed for changes in pulmonary collagen deposition and Smad3 phosphorylation. Measurements and main results Inhibition of integrins αvβ6 and αvβ1 was additive in reducing type I collagen gene expression in explanted lung tissue slices from patients with idiopathic pulmonary fibrosis. These data were replicated in fibrotic mouse lung tissue, with no added benefit observed from inhibition of additional αv integrins. Antifibrotic efficacy of dual αvβ6/αvβ1 integrin inhibitor PLN-74809 was confirmed in vivo, where dose-dependent inhibition of pulmonary Smad3 phosphorylation and collagen deposition was observed. PLN-74809 also, more potently, reduced collagen gene expression in fibrotic human and mouse lung slices than clinically relevant concentrations of nintedanib or pirfenidone. Conclusions In the fibrotic lung, dual inhibition of integrins αvβ6 and αvβ1 offers the optimal approach for blocking fibrogenesis resulting from integrin-mediated activation of transforming growth factor-β. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01863-0. |
| Databáze: | OpenAIRE |
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