We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E₂ and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked.

We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD.

Fibroblasts were obtained from nasal mucosa; samples of control subjects (NM-C, n = 8) and from nasal polyps from patients with aspirin-exacerbated respiratory disease (NP-AERD, n = 8). Expression of the autocrine loop components regulating PGE₂ production and signaling, namely IL-1 type I receptor (IL-1RI), COX-2, microsomal prostaglandin E synthase 1 (mPGES-1), and EP receptors, was assessed at baseline and after stimulation with IL-1β, PGE₂, and specific EP receptor agonists.

Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP₂ receptor were lower in NP-AERD fibroblasts. IL-1β–induced IL-1RI, COX-2, and mPGES-1 expression levels were also lower in these cells. Levels of IL-1RI positively correlated with COX-2 and mPGES-1 expression in both NM-C and NP-AERD fibroblasts. Incubation with either exogenous PGE₂ or selective EP₂ agonist significantly increased expression of IL-1RI in NM-C fibroblasts and had hardly any effect on NP-AERD fibroblasts. Alterations in IL-1RI, COX-2, and mPGES-1 expression that were found in NP-AERD fibroblasts were corrected when EP₂ receptor expression was normalized by transfection of NP-AERD fibroblasts.

Altered expression of EP₂ in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1β to increase COX-2 and mPGES-1 expression, which results in low PGE₂ production. This impairment in the generation of PGE₂ subsequently reduces its ability to induce IL-1RI.