This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200907-1065OCv1 181/6/556    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dekkers, B. G. J. Articles by Meurs, H. PubMed PubMed Citation Articles by Dekkers, B. G. J. Articles by Meurs, H.

The Integrin-blocking Peptide RGDS Inhibits Airway Smooth Muscle Remodeling in a Guinea Pig Model of Allergic Asthma

¹ Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; and ² Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada

Correspondence and requests for reprints should be addressed to Bart G. J. Dekkers, M.Sc., Pharm.D., Department of Molecular Pharmacology, University Center for Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: B.G.J.Dekkers{at}rug.nl

Rationale: Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. The mechanisms driving these changes are, however, incompletely understood. Recently, an important role for extracellular matrix proteins in regulating ASM proliferation and contractility has been found, suggesting that matrix proteins and their integrins actively modulate airway remodeling.

Objectives: To investigate the role of RGD (Arg-Gly-Asp)–binding integrins in airway remodeling in an animal model of allergic asthma.

Methods: Using a guinea pig model of allergic asthma, the effects of topical application of the integrin-blocking peptide RGDS (Arg-Gly-Asp-Ser) and its negative control GRADSP (Gly-Arg-Ala-Asp-Ser-Pro) were assessed on markers of ASM remodeling, fibrosis, and inflammation induced by repeated allergen challenge. In addition, effects of these peptides on human ASM proliferation and maturation were investigated in vitro.

Measurements and Main Results: RGDS attenuated allergen-induced ASM hyperplasia and hypercontractility as well as increased pulmonary expression of smooth muscle myosin heavy chain and the proliferative marker proliferating cell nuclear antigen (PCNA). No effects were observed for GRADSP. The RGDS effects were ASM selective, as allergen-induced eosinophil and neutrophil infiltration as well as fibrosis were unaffected. In cultured human ASM cells, we demonstrated that proliferation induced by collagen I, fibronectin, serum, and platelet-derived growth factor requires signaling via RGD-binding integrins, particularly of the ₅β₁ subtype. In addition, RGDS inhibited smooth muscle -actin accumulation in serum-deprived ASM cells.

Conclusions: This is the first study indicating that integrins modulate ASM remodeling in an animal model of allergic asthma, which can be inhibited by a small peptide containing the RGD motif.

Key Words: airway remodeling • extracellular matrix • integrin • airway smooth muscle hyperplasia • airway smooth muscle contractility

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Integrins have been shown to modulate airway smooth muscle proliferation and contractile protein expression in vitro. However, the involvement of integrins in allergen-induced airway smooth muscle remodeling in vivo has not yet been explored. What This Study Adds to the Field Inhibition of RGD-binding integrins by the small peptide RGDS inhibits airway smooth muscle hyperplasia, contractile protein expression, and hypercontractility in a guinea pig model of allergic asthma.