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Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■感染是单核细胞功能障碍继发的晚期肝病的主要问题。升高的前列腺素（PG）E2是肝硬化单核细胞功能障碍的介质；因此，我们检测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.
■使用11例腹水门诊患者和28例失代偿期肝硬化住院患者的样本，我们测定了血浆PGE2和脂多糖（LPS）的水平；对单核细胞进行了定量实时PCR；并检查了外周血单核细胞的功能。我们对肝脏组织中的PG生物合成机制表达进行了蛋白质印迹和免疫组织化学。最后,我们使用多色流式细胞术和细胞因子的产生研究了PGE2拮抗剂在全血中的作用.
■我们显示通过环加氧酶1-微粒体PGE合酶1途径肝脏产生PGE2，和循环单核细胞有助于失代偿期肝硬化中血浆PGE2的增加。经颈静脉肝内采样未显示肝或单核细胞的产生是否较大。血单核细胞数量增加,而随着患者从腹水门诊患者发展为急性失代偿住院患者，个体单核细胞功能下降，如通过人白细胞抗原（HLA）-DR同种型表达和肿瘤坏死因子α和IL6产生评估。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化中的单核细胞功能障碍，与腹水门诊患者相比，住院患者的功能障碍更为严重。我们的研究确定了这些腹水门诊患者的潜在药物靶标和治疗机会，以逆转这一过程，以防止感染和住院。
■失代偿期肝硬化患者（黄疸，流体积聚，混乱,和呕吐血）的感染率很高，导致死亡率很高。白细胞亚群,单核细胞,这些患者的功能很差，这是他们对感染敏感的关键因素。我们表明，失代偿期肝硬化的单核细胞功能障碍是由血液中的脂质激素介导的，前列腺素E2水平升高，通过其EP4途径。当患者因肝硬化并发症住院时，这种功能障碍会恶化，与门诊患者相比，它支持EP4通路作为患者预防感染和住院的潜在治疗靶点。
■使用11例腹水门诊患者和28例失代偿期肝硬化住院患者的样本，我们测定了血浆PGE2和脂多糖（LPS）的水平；对单核细胞进行了定量实时PCR；并检查了外周血单核细胞的功能。我们对肝脏组织中的PG生物合成机制表达进行了蛋白质印迹和免疫组织化学。最后,我们使用多色流式细胞术和细胞因子的产生研究了PGE2拮抗剂在全血中的作用.
■我们显示通过环加氧酶1-微粒体PGE合酶1途径肝脏产生PGE2，和循环单核细胞有助于失代偿期肝硬化中血浆PGE2的增加。经颈静脉肝内采样未显示肝或单核细胞的产生是否较大。血单核细胞数量增加,而随着患者从腹水门诊患者发展为急性失代偿住院患者，个体单核细胞功能下降，如通过人白细胞抗原（HLA）-DR同种型表达和肿瘤坏死因子α和IL6产生评估。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化中的单核细胞功能障碍，与腹水门诊患者相比，住院患者的功能障碍更为严重。我们的研究确定了这些腹水门诊患者的潜在药物靶标和治疗机会，以逆转这一过程，以防止感染和住院。
■失代偿期肝硬化患者（黄疸，流体积聚，混乱,和呕吐血）的感染率很高，导致死亡率很高。白细胞亚群,单核细胞,这些患者的功能很差，这是他们对感染敏感的关键因素。我们表明，失代偿期肝硬化的单核细胞功能障碍是由血液中的脂质激素介导的，前列腺素E2水平升高，通过其EP4途径。当患者因肝硬化并发症住院时，这种功能障碍会恶化，与门诊患者相比，它支持EP4通路作为患者预防感染和住院的潜在治疗靶点。
