Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease
Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease
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DOI：
10.1016/j.jaci.2013.12.1034
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发表时间：
2014-06-01
影响因子：
14.2
通讯作者：
Boyce, Joshua A.
中科院分区：
文献类型：
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作者：
Laidlaw, Tanya M.;Cutler, Anya J.;Boyce, Joshua A.
背景：阿司匹林加重的呼吸系统疾病(AERD)是一种呼吸道炎症状态，以白三烯(LT)过度产生和大量循环中的粒细胞-血小板复合体为特征。前列腺素E-2(PGE(2))和环磷酸腺苷依赖的蛋白激酶A(PKA)可抑制LT的产生。目的：确定AERD患者粒细胞产生LT的PGE(2)依赖调控是否失调。方法：体外激活AERD患者和非AERD患者的粒细胞，并进行一系列的功能和生化分析。结果：AERD患者的粒细胞产生的LTB4和半胱氨酸LTs高于阿司匹林耐受性哮喘和非哮喘对照组的粒细胞。与对照组相比，AERD患者的粒细胞具有相似的EP2蛋白表达和PGE(2)介导的cAMP积聚，但对PGE(2)介导的LT生成抑制具有抵抗力。血小板黏附中性粒细胞的百分比与LTB4的生成呈正相关，与对PGE(2)介导的LTB4抑制的反应性呈负相关。PKA抑制剂H89可促进对照粒细胞产生LTB4，但对AERD患者的粒细胞无作用，对血小板P-选择素的诱导也无影响。AERD患者粒细胞紧张性PKA活性和PKA催化γ亚基蛋白水平均显著低于对照组。结论：AERD患者粒细胞PKA功能受损可能导致PGE(2)对5-脂氧合酶活性的调控失调，而黏附的血小板则导致LTS生成增加，从而导致持续性呼吸道炎症和LT过度生成的特征。
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.