title: Targeting integrin α5β1 ameliorates severe airway hyperresponsiveness in experimental asthma.
abstract: 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.
authors.forename: Aparna
authors.initials: A
authors.lastname: Sundaram
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.forename: Amin
authors.initials: A
authors.lastname: Khalifeh-Soltani
authors.forename: Amha
authors.initials: A
authors.lastname: Atakilit
authors.forename: Xin
authors.initials: X
authors.lastname: Ren
authors.forename: Wenli
authors.initials: W
authors.lastname: Qiu
authors.forename: Hyunil
authors.initials: H
authors.lastname: Jo
authors.forename: William
authors.initials: W
authors.lastname: DeGrado
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D053818:Chymases / Q000633:toxicity; D004195:Disease Models, Animal; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011817:Rabbits
chemical_list: D039081:Integrin alpha5beta1; D018793:Interleukin-13; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D053818:Chymases; D007545:Isoproterenol