Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma

J Clin Invest. 2017 Jan 3;127(1):365-374. doi: 10.1172/JCI88555. Epub 2016 Dec 5.


Treatment options are limited for severe asthma, and the need for additional therapies remains great. Previously, we demonstrated that integrin αvβ6-deficient mice are protected from airway hyperresponsiveness, due in part to increased expression of the murine ortholog of human chymase. Here, we determined that chymase protects against cytokine-enhanced bronchoconstriction by cleaving fibronectin to impair tension transmission in airway smooth muscle (ASM). Additionally, we identified a pathway that can be therapeutically targeted to mitigate the effects of airway hyperresponsiveness. Administration of chymase to human bronchial rings abrogated IL-13-enhanced contraction, and this effect was not due to alterations in calcium homeostasis or myosin light chain phosphorylation. Rather, chymase cleaved fibronectin, inhibited ASM adhesion, and attenuated focal adhesion phosphorylation. Disruption of integrin ligation with an RGD-containing peptide abrogated IL-13-enhanced contraction, with no further effect from chymase. We identified α5β1 as the primary fibronectin-binding integrin in ASM, and α5β1-specific blockade inhibited focal adhesion phosphorylation and IL-13-enhanced contraction, with no additional effect from chymase. Delivery of an α5β1 inhibitor into murine airways abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. Finally, α5β1 blockade enhanced the effect of the bronchodilator isoproterenol on airway relaxation. Our data identify the α5β1 integrin as a potential therapeutic target to mitigate the severity of airway contraction in asthma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Asthma / genetics
  • Asthma / metabolism*
  • Asthma / physiopathology*
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Line
  • Chymases / toxicity
  • Disease Models, Animal
  • Humans
  • Integrin alpha5beta1 / genetics
  • Integrin alpha5beta1 / metabolism*
  • Interleukin-13 / genetics
  • Interleukin-13 / metabolism
  • Isoproterenol / pharmacology*
  • Mice
  • Muscle Relaxation / drug effects*
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Oligopeptides / genetics
  • Oligopeptides / metabolism
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Rabbits


  • Integrin alpha5beta1
  • Interleukin-13
  • Oligopeptides
  • arginyl-glycyl-aspartic acid
  • Chymases
  • Isoproterenol