Impaired E Prostanoid₂ Expression and Resistance to Prostaglandin E₂ in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease

Abstract

Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E 2 (PGE 2 ), which elicits antiproliferative effects mediated through the E prostanoid (EP) 2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE 2 and a selective EP 2 agonist (P , 0.0001 at 1 mM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP 2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P , 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP 2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP 4 , and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP 2 promoter correlated strongly with baseline EP 2 mRNA (r = 0.80; P , 0.01). These studies suggest that the EP 2 promotor is under epigenetic control, and one explanation for PGE 2 resistance in AERD is an epigenetically mediated reduction of EP 2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.

Immune deficiency in chronic rhinosinusitis: screening and treatment

“…For instance, B-cell differentiation can be altered by specific DNA demethylation patterns of gene segments that have been associated with the binding sites of B-cell-specific transcription factors, such as early B-cell factor 1, paired box 5, and E2F [48]. A recent article by Cahill et al [49] highlights the importance of epigenetic modifications in the pathogenesis of a subphenotype of aspirin exacerbated respiratory disease (AERD). The authors show that nasal polyp fibroblasts from patients with AERD are resistant to the anti-proliferative effects of prostaglandin E 2 (PGE 2 ).…”

Genetic and Epigenetic Components of Aspirin-Exacerbated Respiratory Disease

“…The role of epigenetic targeting of PGE 2 pathway genes involved in the expansion of nasal polyps in AERD patients was recently investigated 80 . Fibroblasts, which are the major effector cells for airway remodeling, express the arachidonic acid pathway genes that are upregulated in AERD, and stimulation of the EP 2 receptor by PGE 2 represses the activation and growth of these cells.…”

“…In addition, fibroblasts from nasal polyps of patients with AERD have intrinsically lower expression of COX-2, PGE 2 and EP 2 receptor protein vs. aspirin-tolerant (AT) control subjects 81 . Cahill et al hypothesized that an intrinsic defect in EP 2 expression in nasal polyp fibroblasts, potentially a result of epigenetic modification at this locus, underlies the aggressive expansion and proliferation of nasal polyps in AERD patients 80 . To investigate this, the authors first isolated and cultured fibroblasts from nasal polyps of 18 patients with AERD and nine aspirin-tolerant patients with chronic rhinosinusitis and nasal polyposis, and nasal tissue from eight non-asthmatic controls undergoing surgery for concha bullosa 80 .…”

“…Cahill et al hypothesized that an intrinsic defect in EP 2 expression in nasal polyp fibroblasts, potentially a result of epigenetic modification at this locus, underlies the aggressive expansion and proliferation of nasal polyps in AERD patients 80 . To investigate this, the authors first isolated and cultured fibroblasts from nasal polyps of 18 patients with AERD and nine aspirin-tolerant patients with chronic rhinosinusitis and nasal polyposis, and nasal tissue from eight non-asthmatic controls undergoing surgery for concha bullosa 80 . In contrast to ATA, fibroblasts from AERD patients proliferated quickly and also demonstrated persistent growth in response to treatment with PGE 2 , as well as having reduced expression levels of the EP 2 receptor 80 .…”

Lipid regulation of group 2 innate lymphoid cell function: Moving beyond epithelial cytokines

“…15 A very recent report demonstrated that ILC2s are recruited to the nasal mucosa during COX-1 inhibitor reactions in patients with AERD, and multiple studies have shown that eosinophilic nasal polyps are enriched with ILC2s. 1,16 Interestingly, some patients with AERD have shown PGE 2 hyporesponsiveness in granulocytes and polyp fibroblasts, 17,18 and if ILC2s in patients with AERD are also resistant to PGE 2 , then perhaps this is one mechanism by which persistent ILC2 activation could contribute to disease. As with the entire ILC2 field, we are witnessing a rapidly emerging and exciting window into novel mechanisms of allergic diseases.…”