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.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive lung scarring, impaired oxygen diffusion, exertional dyspnea, and a mean life expectancyDecaris et al Respir Res (2021) 22:265 of < 4 years [1, 2]
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
An αvβ1-specific small-molecule inhibitor, Compound A, was determined to have an IC50 of 2.3 nM for αvβ1 with 22-fold selectivity over αvβ6 and > 50-fold selectivity over other αv integrins
Summary
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive lung scarring, impaired oxygen diffusion, exertional dyspnea, and a mean life expectancyDecaris et al Respir Res (2021) 22:265 of < 4 years [1, 2]. The pathobiology of IPF, incompletely understood, is thought to initiate from chronic injury to and/ or aging of the alveolar epithelium, resulting in an aberrant wound healing response and the sustained production of pro-inflammatory and profibrotic factors [1, 2]. This leads to the activation and differentiation of perivascular and interstitial mesenchymal cells into myofibroblasts, the primary cell population responsible for pulmonary fibrogenesis (e.g. collagen synthesis). Because TGF-β regulates many important homeostatic functions throughout the body, its systemic inhibition may result in toxicities and a targeted approach for TGF-β inhibition is desired [8,9,10,11,12]
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