1. Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF
- Author
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Decaris, Martin L, Schaub, Johanna R, Chen, Chun, Cha, Jacob, Lee, Gail G, Rexhepaj, Megi, Ho, Steve S, Rao, Vikram, Marlow, Megan M, Kotak, Prerna, Budi, Erine H, Hooi, Lisa, Wu, Jianfeng, Fridlib, Marina, Martin, Shamra P, Huang, Shaoyi, Chen, Ming, Muñoz, Manuel, Hom, Timothy F, Wolters, Paul J, Desai, Tushar J, Rock, Fernando, Leftheris, Katerina, Morgans, David J, Lepist, Eve-Irene, Andre, Patrick, Lefebvre, Eric A, and Turner, Scott M
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Clinical Sciences ,Lung ,Rare Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Respiratory ,Animals ,Antifibrotic Agents ,Bleomycin ,Cell Line ,Coculture Techniques ,Collagen Type I ,alpha 1 Chain ,Disease Models ,Animal ,Epithelial Cells ,Fibroblasts ,Humans ,Idiopathic Pulmonary Fibrosis ,Integrin alpha6beta1 ,Mice ,Inbred C57BL ,Phosphorylation ,Receptors ,Vitronectin ,Signal Transduction ,Smad3 Protein ,Transforming growth factor-beta ,Precision-cut lung slice ,Antifibrotic ,alpha(v) integrin ,PLN-74809 ,Transforming growth factor-β ,αv integrin ,Cardiorespiratory Medicine and Haematology ,Respiratory System ,Cardiovascular medicine and haematology ,Clinical sciences - Abstract
Rationaleαv 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.ObjectivesWe evaluated multiple αv integrin inhibition strategies to assess which most effectively reduced fibrogenesis in explanted lung tissue from patients with idiopathic pulmonary fibrosis.MethodsSelective 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 resultsInhibition 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.ConclusionsIn 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.
- Published
- 2021