Suppression of cirrhossis-mediate immune suppression by prostaglandin receptor antagonism

通过前列腺素受体拮抗作用抑制肝硬化介导的免疫抑制

• 批准号: MR/M005291/1
• 负责人: Derek Gilroy
• 金额: $ 58.73万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM005291%2F1
• 关键词: Suppression; cirrhossis; mediate; immune; suppression

While deaths from respiratory and cardiovascular disease as well as cancer are declining, mortality from liver cirrhosis is rising. Liver cirrhosis is currently the 5th leading cause of death in the UK with patients having an increased predisposition to and mortality from infection. In 50% of cirrhotic inpatients, infection is the precipitant for hospital admission and a further 15-35% will develop hospital-based infections compared to 5-7% of general patients. Of those cirrhotic patients who develop sepsis and organ dysfunction, 80-90% will die. Thus, in patients with liver cirrhosis, there is a profound immune suppression that predisposes to a substantial risk of infection, the nature of which is poorly understood. While various hypotheses have been proposed over the years, it is largely appreciated that defective immune cell functioning is the root cause. However, the nature of this defect remains elusive. Based on data obtained from rodent models of liver cirrhosis and from humans with decompensated liver cirrhosis compared to stable cirrhotic patients and healthy volunteers, we now propose that prostaglandin (PG)E2 is the principle factor underlining immune suppression in liver cirrhosis. PGE2 is a lipid hormone made my many cells in the body traditionally implicated in acute inflammatory responses and is synthesised by cyclooxygenase, the target of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin. In which case, NSAID reversal of immune suppression in cirrhotic patients would appear to be an immediate and effective strategy with which to reverse immune suppression and prevent infection in these individuals. However, NSAIDs cause gastrointestinal bleeding in some individuals and in cirrhosis patients in particular, NSAID cause renal toxicity. As an alternative, we propose targeting the specific receptor that PGE2 exerts its immune suppressive effects through. This approach would have all the PGE2-nulling effects of NSAIDs, but without their side effects. Specifically, PGE2 has four receptors namely EP1-4. From our data and that published by others we believe that EP2 and/or EP4 receptors are expressed on cells of the immune system that transduce PGE2's immune-dampening effects, particularly in cirrhotic patients. Given that the other two receptors, EP1 and EP3, are expressed in the kidney and gastrointestinal system mediating PGE2's protective effects there, we hypothesise that antagonising EP2 and EP4 will have all the immune restorative properties of NSAIDs without causing renal failure or gastrointestinal toxicity. In terms of drug availability for this project, EP2 receptor antagonists are available for testing in both rodents and in humans from two separate pharmaceutical companies (One Pharmaceuticals, Japan and Pfizer) who have agreed to collaborate with us, while Ono Pharmaceuticals are preparing EP4 antagonists for clinical trials in summer 2014. Therefore, we plan to characterise the biochemical pathways that generate PGE2 in rodent models of cirrhosis as well as in samples from patients with cirrhosis. Thereafter, we wish to investigate whether EP2 and/or EP4 receptor inhibition reverses immune suppression in rodents with bacterial infections similar to those contracted by cirrhosis patients. We will complete this project with a novel experimental medicines approach utilising EP2 and/or EP4 receptor antagonists in cirrhotic patients asking whether blocking the action of elevated PGE2 in these individuals restores their immune competence in order to kill bacteria and prevent widespread infection. In summary, data from this project will propose a new paradigm for management of cirrhosis-related infection based on inhibiting the mode of action of PGE2 and therefore suggest a strategy that will reinstate immune competence in chronic liver disease.

虽然呼吸道和心血管疾病以及癌症的死亡率正在下降，但肝硬化的死亡率正在上升。肝硬化目前是英国的第五大死亡原因，患者感染的易感性和死亡率增加。在50%的腹泻住院患者中，感染是入院的诱因，与普通患者的5-7%相比，另外15-35%将发展医院感染。在那些发生败血症和器官功能障碍的腹泻患者中，80-90%将死亡。因此，在肝硬化患者中，存在严重的免疫抑制，其易导致感染的实质性风险，其性质知之甚少。虽然多年来已经提出了各种假设，但人们普遍认为免疫细胞功能缺陷是根本原因。然而，这一缺陷的性质仍然难以捉摸。根据从肝硬化啮齿动物模型和失代偿性肝硬化患者与稳定性肝硬化患者和健康志愿者相比获得的数据，我们现在提出前列腺素（PG）E2是肝硬化免疫抑制的主要因素。PGE 2是一种脂质激素，使我体内的许多细胞传统上参与急性炎症反应，并由环氧合酶合成，非甾体抗炎药（NSAID），包括阿司匹林的目标。在这种情况下，非甾体类抗炎药逆转哮喘患者的免疫抑制似乎是一种立即有效的策略，可以逆转这些患者的免疫抑制并预防感染。然而，NSAID在一些个体中引起胃肠道出血，特别是在肝硬化患者中，NSAID引起肾毒性。作为替代方案，我们建议靶向PGE 2发挥其免疫抑制作用的特定受体。这种方法将具有NSAID的所有PGE 2无效效应，但没有副作用。具体来说，PGE 2有四种受体，即EP 1 -4。根据我们的数据和其他人发表的数据，我们相信EP 2和/或EP 4受体在免疫系统细胞上表达，这些细胞抑制PGE 2的免疫抑制作用，特别是在阿尔茨海默病患者中。考虑到另外两种受体EP 1和EP 3在肾脏和胃肠道系统中表达，介导PGE 2在那里的保护作用，我们假设拮抗EP 2和EP 4将具有NSAID的所有免疫恢复特性，而不会引起肾衰竭或胃肠道毒性。就该项目的药物可用性而言，EP 2受体拮抗剂可用于啮齿动物和人类的测试，来自两家同意与我们合作的独立制药公司（One Pharmaceuticals，日本和辉瑞），而Ono Pharmaceuticals正在为2014年夏季的临床试验准备EP 4拮抗剂。因此，我们计划在啮齿动物肝硬化模型以及肝硬化患者样本中检测产生PGE 2的生化途径。此后，我们希望研究是否EP 2和/或EP 4受体抑制逆转啮齿动物的免疫抑制与肝硬化患者的合同类似的细菌感染。我们将通过一种新的实验性药物方法来完成这个项目，该方法利用EP 2和/或EP 4受体拮抗剂治疗前列腺癌患者，询问阻断这些个体中升高的PGE 2的作用是否可以恢复他们的免疫能力，以杀死细菌并防止广泛感染。总之，来自该项目的数据将提出一种基于抑制PGE 2作用模式的新范式，用于管理与肝硬化相关的感染，因此提出了一种将恢复慢性肝病免疫能力的策略。

项目成果

Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway.

• DOI: 10.1016/j.jhepr.2021.100332
• 发表时间: 2021-12
• 期刊: JHEP reports : innovation in hepatology
• 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
• 通讯作者: O'Brien A

A Comparison of Human Neutrophils Acquired from Four Experimental Models of Inflammation.

• DOI: 10.1371/journal.pone.0165502
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Maini AA;George MJ;Motwani MP;Day RM;Gilroy DW;O'Brien AJ
• 通讯作者: O'Brien AJ