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

Bart G. J. Dekkers*, I. Sophie T. Bos, Reinoud Gosens, Andrew J. Halayko, Johan Zaagsma, Herman Meurs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Scopus)

Abstract

Rationale: Airway remodeling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyper-responsiveness 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 alpha(5)beta(1) subtype. In addition, RGDS inhibited smooth muscle alpha-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.

Original languageEnglish
Pages (from-to)556-565
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume181
Issue number6
DOIs
Publication statusPublished - 15-Mar-2010

Keywords

  • airway remodeling
  • extracellular matrix
  • integrin
  • airway smooth muscle hyperplasia
  • airway smooth muscle contractility
  • EXTRACELLULAR-MATRIX PROTEINS
  • OBSTRUCTIVE PULMONARY-DISEASE
  • MAP KINASE ACTIVATION
  • MEDIATE ENHANCEMENT
  • CELL PROLIFERATION
  • HYPERRESPONSIVENESS
  • EXPRESSION
  • FIBRONECTIN
  • PHENOTYPE
  • COLLAGEN

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