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

Respir Res. 2021 Oct 19;22(1):265. doi: 10.1186/s12931-021-01863-0.


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 αvβ6vβ1, 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 αvβ6vβ1 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 αvβ6vβ1 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.

Keywords: Antifibrotic; PLN-74809; Precision-cut lung slice; Transforming growth factor-β; αv integrin.

MeSH terms

  • Animals
  • Antifibrotic Agents / pharmacology*
  • Bleomycin
  • Cell Line
  • Coculture Techniques
  • Collagen Type I, alpha 1 Chain / genetics
  • Collagen Type I, alpha 1 Chain / metabolism
  • Disease Models, Animal
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Idiopathic Pulmonary Fibrosis / drug therapy*
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology
  • Integrin alpha6beta1 / antagonists & inhibitors*
  • Integrin alpha6beta1 / metabolism
  • Lung / drug effects*
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Receptors, Vitronectin / antagonists & inhibitors*
  • Receptors, Vitronectin / metabolism
  • Signal Transduction
  • Smad3 Protein / metabolism


  • Antifibrotic Agents
  • COL1A1 protein, human
  • Col1a1 protein, mouse
  • Collagen Type I, alpha 1 Chain
  • Integrin alpha6beta1
  • Receptors, Vitronectin
  • Smad3 Protein
  • Smad3 protein, mouse
  • integrin alphavbeta1
  • Bleomycin