PGE 缺乏通过引起肥大细胞高反应性而导致过敏反应易感性。

PGE deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness.

机构信息

Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

出版信息

J Allergy Clin Immunol. 2020 Dec;146(6):1387-1396.e13. doi: 10.1016/j.jaci.2020.03.046. Epub 2020 May 11.

DOI:10.1016/j.jaci.2020.03.046

PMID:32407837

Abstract

BACKGROUND

Reduced levels of prostaglandin E (PGE) contribute to aspirin-induced hypersensitivity. COX inhibitors are also frequent cofactors in anaphylaxis. Whether alterations in the PGE system contribute to anaphylaxis independently of COX inhibitor intake is unclear.

OBJECTIVE

Our aim was to test the hypothesis that relative PGE deficiency predisposes to anaphylaxis.

METHODS

Sera from 48 patients with anaphylaxis and 27 healthy subjects were analyzed for PGE levels and correlated against severity; 9α,11β-PGF and PGI metabolites were measured for control purposes. PGE stabilization by 15-hydroxyprostaglandin dehydrogenase inhibitor or EP2 or EP4 receptor agonists were used in a murine model of passive systemic anaphylaxis. FcεRI-triggered mediator release was determined in bone marrow-derived cultured mast cells (MCs) and human skin-derived MCs. Signaling was studied by Western blot analysis.

RESULTS

Patients with anaphylaxis were characterized by markedly reduced PGE levels vis-à-vis healthy subjects, whereas prostacyclin metabolite levels were diminished only weakly, and 9α,11β-PGF levels conversely increased. PGE was negatively correlated with severity. Lower PGE levels and higher susceptibility to anaphylaxis were also found in C57BL/6 mice vis-à-vis in Balb/c mice. Stabilization of PGE level by 15-hydroxyprostaglandin dehydrogenase inhibitor protected mice against anaphylaxis. Exogenous PGE attenuated bone marrow-derived cultured MC activation through EP2 and EP4 receptors. EP2 and EP4 agonism also curbed FcεRI-mediated degranulation of human MCs. Mechanistically, PGE interfered with the phosphorylation of phospholipase C gamma-1 and extracellular signal-regulated kinase.

CONCLUSIONS

Homeostatic levels of PGE attenuate MC activation via EP2/EP4 and protect against anaphylaxis. Relative deficiency of PGE predisposes to anaphylaxis in humans and mice, whereas PGE stabilization protects against anaphylactic reactions.

摘要

背景

前列腺素 E (PGE) 水平降低会导致阿司匹林过敏。环氧化酶抑制剂也是过敏反应的常见诱因。PGE 系统的改变是否独立于环氧化酶抑制剂的摄入导致过敏反应尚不清楚。

目的

我们的目的是检验相对 PGE 缺乏易导致过敏反应的假说。

方法

分析 48 例过敏反应患者和 27 例健康对照者的血清 PGE 水平，并与严重程度相关；为了对照目的，还测量了 9α,11β-PGF 和 PGI 代谢产物。在被动全身过敏反应的小鼠模型中，使用 15-羟基前列腺素脱氢酶抑制剂或 EP2 或 EP4 受体激动剂稳定 PGE。在骨髓来源的培养肥大细胞（MCs）和人皮肤来源的 MCs 中测定 FcεRI 触发的介质释放。通过 Western blot 分析研究信号转导。

结果

与健康对照组相比，过敏反应患者的 PGE 水平明显降低，而前列腺素代谢产物水平仅略有降低，9α,11β-PGF 水平相反升高。PGE 与严重程度呈负相关。与 Balb/c 小鼠相比，C57BL/6 小鼠的 PGE 水平较低，对过敏反应的易感性也较高。15-羟基前列腺素脱氢酶抑制剂稳定 PGE 水平可保护小鼠免受过敏反应。外源性 PGE 通过 EP2 和 EP4 受体减弱骨髓来源的培养 MC 激活。EP2 和 EP4 激动剂也抑制了 FcεRI 介导的人 MCs 的脱颗粒作用。在机制上，PGE 干扰了磷脂酶 C γ-1 和细胞外信号调节激酶的磷酸化。