Calcitonin gene-related peptide– and vascular endothelial growth factor–positive inflammatory cells in late-phase allergic skin reactions in atopic subjects

Abstract

Allergen-induced late-phase skin reactions are characterized by erythema and edema, but the vasoactive mediators involved remain unclear. Limited evidence from human studies suggests that calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF), potent vasodilator and permeability factors, respectively, are expressed by infiltrating inflammatory cells in certain allergic tissue reactions. We sought to determine whether tissue swelling in allergen-challenged skin sites in atopic subjects is associated with the infiltration of CGRP(+) and VEGF(+) inflammatory cells. Skin biopsy specimens were obtained from atopic subjects at various times after cutaneous allergen challenge and studied by means of single and double immunohistochemistry and in situ hybridization. CGRP-immunoreactive and CGRP mRNA-positive cell numbers were increased in biopsy specimens from sites of late-phase skin reactions compared with those at the control site (P = .03 and P = .03, respectively). Their numbers paralleled the development and resolution of the edematous late-phase skin reaction, both peaking at 6 hours after allergen challenge. The majority of CGRP-immunoreactive cells were neutrophils and CD3(+) cells, whereas eosinophils were CGRP negative. VEGF-immunopositive cell numbers were also increased in 6-hour biopsy specimens from late-phase skin reactions compared with those seen at control sites (P = .001) with a lesser but significant response (P = .008) at 24 hours. VEGF(+) cells were largely eosinophils, neutrophils, and CD68(+) macrophages. Late-phase skin reactions in atopic subjects were associated with the infiltration of inflammatory cells expressing CGRP and VEGF, suggesting that these vasoactive factors might play a role in the erythema and edema characteristic of allergic inflammation. They could also be considered targets in attempts to control allergic inflammation.