Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway.
Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway.
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DOI：
10.1016/j.jhepr.2021.100332
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
O'Brien A
中科院分区：
文献类型：
--
作者：
Maini AA;Becares N;China L;Tittanegro TH;Patel A;De Maeyer RPH;Zakeri N;Long TV;Ly L;Gilroy DW;O'Brien A
感染是继发于单核细胞功能障碍的晚期肝病的主要问题。前列腺素(PG)E2升高是肝硬变患者单核细胞功能障碍的介质；因此，我们研究了门诊腹水患者和急性失代偿住院患者的PGE2信号，以确定旨在改善单核细胞功能障碍的潜在治疗靶点。采用11例门诊腹水患者和28例失代偿期肝硬变住院患者的标本，检测血浆前列腺素E_2(PGE_2)和脂多糖(LPS)水平，对单核细胞进行实时定量聚合酶链式反应(RT-PCR)，并检测外周血单核细胞功能。采用免疫印迹和免疫组织化学方法检测PG生物合成机制在肝组织中的表达。最后，我们利用多色流式细胞术和细胞因子的产生来研究PGE2拮抗剂在全血中的作用。我们的研究表明，失代偿期肝硬变患者，肝脏通过环氧合酶1-微粒体PGE合成酶1途径产生PGE2，循环单核细胞导致血浆PGE2升高。经颈静脉肝内采样未发现肝细胞或单核细胞产量较大。根据人类白细胞抗原(HL A)-DR亚型表达和肿瘤坏死因子α和IL 6的产生来评估，随着患者从门诊腹水患者发展到急性失代偿住院患者，血单核细胞数量增加，而个人单核细胞功能下降。PGE2通过其EP4受体介导这种功能障碍。PGE2通过其EP4受体介导失代偿期肝硬变患者的单核细胞功能障碍，住院患者的功能障碍比门诊腹水患者更严重。我们的研究确定了这些门诊腹水患者的潜在药物靶点和治疗机会，以逆转这一过程，以防止感染和住院。失代偿性肝硬变患者(黄疸、积液、神志不清和呕血)感染率高，导致高死亡率。在这些患者中，白细胞亚群单核细胞功能不佳，这是他们对感染敏感的一个关键因素。我们发现失代偿性肝硬变患者的单核细胞功能障碍是由血液中的一种脂质激素--前列腺素E_2介导的，前列腺素E_2水平升高是通过其EP4途径实现的。与门诊患者相比，当患者因肝硬变并发症住院时，这种功能障碍会恶化，这支持EP4途径作为患者预防感染和住院的潜在治疗目标。我们证明失代偿性肝硬变和顽固性腹水患者的单核细胞功能障碍是由PGE2通过其EP4受体介导的。失代偿期肝硬变患者的单核细胞HLA-DR表达也降低，至少部分是由于循环PGE2升高所致。高达55%的ACLF患者有感染性沉淀物。改善院前肝硬变腹水患者单核细胞功能可预防ACLF的发生。PGE2-EP4受体拮抗剂可能是改善门诊腹水患者单核细胞功能障碍的一种治疗方法。
Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction. Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production. We show that hepatic production of PGE2 via the cyclo-oxygenase 1–microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)–DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor. PGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission. Patients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation. We demonstrate that monocyte dysfunction in patients with decompensated cirrhosis and refractory ascites is mediated by PGE2 through its EP4 receptor. Monocyte HLA-DR expression was also reduced in both cohorts of patients with decompensated cirrhosis, at least in part, by elevated circulating PGE2. Up to 55% of patients with ACLF have an infective precipitant. Improving monocyte function in patients with pre-hospital cirrhosis and ascites could prevent development of ACLF. PGE2-EP4 receptor antagonists might represent a treatment to improve monocyte dysfunction in outpatients with ascites.
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影响因子：
24.5
作者：
Bajaj JS;O'Leary JG;Wong F;Reddy KR;Kamath PS
通讯作者：
Kamath PS
影响因子：
4.6
作者：
Henkel J;Coleman CD;Schraplau A;Jöhrens K;Weiss TS;Jonas W;Schürmann A;Püschel GP
通讯作者：
Püschel GP
影响因子：
24.5
作者：
Bernsmeier C;Triantafyllou E;Brenig R;Lebosse FJ;Singanayagam A;Patel VC;Pop OT;Khamri W;Nathwani R;Tidswell R;Weston CJ;Adams DH;Thursz MR;Wendon JA;Antoniades CG
通讯作者：
Antoniades CG
影响因子：
25.7
作者：
Asrani, Sumeet K.;Devarbhavi, Harshad;Kamath, Patrick S.
通讯作者：
Kamath, Patrick S.
DOI：
10.1186/cc11922
发表时间：
2013-01-25
期刊：
Critical care (London, England)
影响因子：
--
作者：
Almansa R;Wain J;Tamayo E;Andaluz-Ojeda D;Martin-Loeches I;Ramirez P;Bermejo-Martin JF
通讯作者：
Bermejo-Martin JF