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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Laidlaw, Tanya M.^1,2  Cutler, Anya J.²  Kidder, Molly S.²  Liu, Tao²  Cardet, Juan Carlos^1,2  Chhay, Heng²  Feng, Chunli²  Boyce, Joshua A.^1,2,3 

[1] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[2] Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Jeff & Penny Vinik Ctr Allerg Dis Res, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA

关键词: Samter's triad;    aspirin-exacerbated respiratory disease;    AERD;    aspirin triad;    nonsteroidal anti-inflammatory drug;    asthma;    leukotriene;    protein kinase A;    prostaglandin E-2;    cyclic AMP;   

DOI  :  10.1016/j.jaci.2013.12.1034

来源: Elsevier

【 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 E-2 (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA). Objective: To determine if PGE(2)-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 PGE(2)-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 PGE(2)-mediated suppression of LTB4. The PKA inhibitor H89 potentiated LTB4 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 PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction.

【 授权许可】

Free