The integrin-blocking peptide RGDS inhibits airway smooth muscle remodeling in a guinea pig model of allergic asthma.
BACKGROUND
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.


OBJECTIVE
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.


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.
Dekkers
Bart G J
BG
Department of Molecular Pharmacology, University of Groningen, The Netherlands. B.G.J.Dekkers@rug.nl
Bos
I Sophie T
IS
Gosens
Reinoud
R
Halayko
Andrew J
AJ
Zaagsma
Johan
J
Meurs
Herman
H
D000287:Administration, Topical; D056151:Airway Remodeling / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001249:Asthma / Q000276:immunology / Q000503:physiopathology*; D015415:Biomarkers; D015153:Blotting, Western; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005355:Fibrosis / Q000276:immunology; D006168:Guinea Pigs; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000276:immunology; D009842:Oligopeptides / Q000276:immunology / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000276:immunology / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000187:drug effects / Q000276:immunology
D000906:Antibodies; D015415:Biomarkers; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D018809:Proliferating Cell Nuclear Antigen; C046617:arginyl-glycyl-aspartyl-serine