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Dual inhibition of αvβ6 and αvβ1 reduces fibrogenesis in lung tissue explants from patients with IPF

Authors :
Patrick Andre
Martin Decaris
Chun Chen
Munoz Manuel
Hom Timothy
Scott M. Turner
Ming Chen
Tushar J. Desai
Megan M. Marlow
Cha Jacob
Eric Lefebvre
Steve S. Ho
Paul J. Wolters
Shaoyi Huang
Eve-Irene Lepist
Katerina Leftheris
David J Morgans
Lisa Hooi
Johanna R. Schaub
Vikram R. Rao
Jianfeng Wu
Marina Fridlib
Fernando Rock
Megi Rexhepaj
Erine H. Budi
Prerna Kotak
Gail Lee
Shamra Martin
Source :
Respiratory research, vol 22, iss 1, Respiratory Research, Vol 22, Iss 1, Pp 1-14 (2021)
Publication Year :
2021
Publisher :
eScholarship, University of California, 2021.

Abstract

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.

Details

Database :
OpenAIRE
Journal :
Respiratory research, vol 22, iss 1, Respiratory Research, Vol 22, Iss 1, Pp 1-14 (2021)
Accession number :
edsair.doi.dedup.....d8943da51a8a3553a1e3711bc9a9ed07