Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 1, Pages 365-374Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI88555
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Funding
- National Heart, Lung, and Blood Institute (NHLBI), NIH [F32 HL 11258801, K08 HL 124049-01]
- National Institute of Allergy and Infectious Diseases (NIAID), NIH [U19, AI 070412-09]
- NHLBI, NIH [HL 102292]
- NIAID, NIH [U19 AI 077439]
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Treatment options are limited for severe asthma, and the need for additional therapies remains great. Previously, we demonstrated that integrin alpha(5)beta(6)-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 alpha(5)beta(1) as the primary fibronectin-binding integrin in ASM, and alpha(5)beta(1) -specific blockade inhibited focal adhesion phosphorylation and IL-13-enhanced contraction, with no additional effect from chymase. Delivery of an alpha(5)beta(1) inhibitor into murine airways abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. Finally, alpha(5)beta(1) blockade enhanced the effect of the bronchodilator isoproterenol on airway relaxation. Our data identify the alpha(5)beta(1) integrin as a potential therapeutic target to mitigate the severity of airway contraction in asthma.
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