Reduced expression of the prostaglandin E2 receptor E-prostanoid 2 on bronchial mucosal leukocytes in patients with aspirin-sensitive asthma

Background
Prostaglandin E2 (PGE2) is thought to play a role in the pathogenesis of aspirin-sensitive asthma (ASA).

Objective
We sought to extend our previous observations implicating impaired inflammatory cell responsiveness to PGE2 as a pathogenetic mechanism in patients with aspirin-sensitive rhinosinusitis to the bronchial mucosa in patients with ASA.

Methods
Immunohistochemistry was used to enumerate inflammatory cells and their expression of cysteinyl leukotriene receptors 1 and 2 (CysLT1 and CysLT2) and the PGE2 receptors E-prostanoid 1 to 4 (EP1-EP4) in bronchial biopsy specimens from patients with ASA, patients with aspirin-tolerant asthma, and control subjects (n = 15 in each group). Concentrations of PGE2 in bronchoalveolar lavage fluid were measured by using ELISA. The effects of PGE2 and EP receptor agonists on CD3/CD28-stimulated cytokine production by PBMCs were measured by using ELISA. Airways responsiveness to LTD4in vivo was measured in asthmatic patients by means of bronchial challenge.

Results
Compared with patients with aspirin-tolerant asthma, patients with ASA had increased bronchial mucosal neutrophil and eosinophil numbers but reduced percentages of T cells, macrophages, mast cells, and neutrophils expressing EP2. Both groups showed increased bronchial sensitivity to inhaled LTD4, but this did not correlate with mucosal expression of CysLT1 or CysLT2. Bronchoalveolar lavage fluid PGE2 concentrations were comparable in all groups. In vitro PGE2 inhibited cytokine production by PBMCs through EP2 but not other PGE2 receptors.

Conclusion
Our data are consistent with the hypothesis that impaired inhibition of inflammatory leukocytes by PGE2 acting through the EP2 receptor has a role in the pathogenesis of ASA.