Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease

摘要

Background Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E2 (PGE2) and the cyclic AMP-dependent protein kinase A (PKA). Objective To determine if PGE2-dependent control of LT production by granulocytes is dysregulated in AERD. Methods Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses. Results Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP2 protein expression and PGE2-mediated cAMP accumulation, yet were resistant to PGE 2-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE2-mediated suppression of LTB4. The PKA inhibitor H89 potentiated LTB 4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls. Conclusions Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE2, whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.