Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2.
Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2.
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DOI：
10.1038/nm.3516
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发表时间：
2014-05
期刊：
影响因子：
82.9
通讯作者：
Gilroy DW
中科院分区：
文献类型：
--
作者：
O'Brien AJ;Fullerton JN;Massey KA;Auld G;Sewell G;James S;Newson J;Karra E;Winstanley A;Alazawi W;Garcia-Martinez R;Cordoba J;Nicolaou A;Gilroy DW
晚期肝硬化患者经常发生感染，导致败血症，死亡率很高。虽然先天免疫功能障碍是这种脆弱性的基础，但确切的原因仍然难以捉摸。我们发现前列腺素（PGE 2）升高急性失代偿（AD）患者在免疫抑制水平。AD和终末期肝脏疾病（ESLD）患者的血浆以PGE 2受体依赖性方式抑制巨噬细胞细胞因子分泌和细菌杀伤，但在稳定型肝硬化中未观察到这种作用。小鼠模型（胆管结扎和CCL 4-肝损伤）也表现出升高的PGE 2，当被抑制时完全恢复免疫能力和感染后的存活。重要的是，白蛋白结合/灭活PGE 2，导致更大的PGE 2生物利用度。这导致AD血浆在低白蛋白水平患者中的免疫抑制作用增强。向AD患者给予白蛋白逆转了其血浆的免疫抑制特性;啮齿动物生存研究中重现了保护作用。因此，PGE 2升高与低白蛋白血症介导了AD和ESLD患者的免疫抑制，而白蛋白可以逆转这种抑制。
Patients with advanced cirrhosis experience frequent infections leading to sepsis, which carries high mortality. While innate immune dysfunction underlies this vulnerability, the precise cause remains elusive. We found prostaglandin (PGE2) elevated in acutely decompensated (AD) patients at immunosuppressive levels. Plasma from AD and end-stage liver disease (ESLD) patients suppressed macrophage cytokine secretion and bacteria killing in a PGE2 receptor-dependent manner, effects not seen in stable cirrhosis. Mouse models (bile duct ligation and CCL4-liver injury) also demonstrated elevated PGE2, which when inhibited completely restored immune competence and survival following infection. Importantly, albumin binds/inactivates PGE2 resulting in greater PGE2 bioavailability. This results in enhanced immunosuppressive effects of AD plasma in patients with low albumin levels. Administering albumin to AD patients reversed immunosuppressive properties of their plasma; protective effects recapitulated in rodent survival studies. Thus, elevated PGE2 combined with hypoalbuminemia mediates immunosuppression in AD and ESLD patients, which can be reversed with albumin.