Suppression of cirrhossis-mediate immune suppression by prostaglandin receptor antagonism

虽然呼吸系统疾病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。肝硬化目前是英国第五大死因，患者感染的易感性和死亡率都在增加。在50%的肝硬化住院患者中，感染是入院的诱因，另有15-35%的患者将发展为医院感染，而普通患者的这一比例为5-7%。并发败血症和器官功能障碍的肝硬化患者中，80-90%会死亡。因此，在肝硬化患者中，存在一种深刻的免疫抑制，易导致感染的重大风险，其性质尚不清楚。虽然多年来提出了各种各样的假设，但人们普遍认为免疫细胞功能缺陷是根本原因。然而，这种缺陷的性质仍然难以捉摸。基于肝硬化啮齿类动物模型和失代偿肝硬化患者与稳定型肝硬化患者和健康志愿者的数据，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。PGE2是一种脂质激素，使体内的许多细胞传统上与急性炎症反应有关，由环氧化酶合成，是包括阿司匹林在内的非甾体抗炎药的靶标。在这种情况下，非甾体抗炎药逆转肝硬化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，非甾体抗炎药在某些个体中引起胃肠道出血，特别是在肝硬化患者中，非甾体抗炎药引起肾毒性。作为一种替代方案，我们建议靶向PGE2发挥其免疫抑制作用的特定受体。这种方法具有非甾体抗炎药消除pge2的所有效果，但没有副作用。具体来说，PGE2有四个受体，即EP1-4。根据我们的数据和其他人发表的数据，我们认为EP2和/或EP4受体在免疫系统细胞上表达，介导PGE2的免疫抑制作用，特别是在肝硬化患者中。鉴于另外两个受体EP1和EP3在肾脏和胃肠道系统中表达，介导PGE2在那里的保护作用，我们假设拮抗EP2和EP4将具有非甾体抗炎药的所有免疫恢复特性，而不会引起肾功能衰竭或胃肠道毒性。就该项目的药物可用性而言，EP2受体拮抗剂可用于啮齿动物和人类的测试，两家独立的制药公司（日本One Pharmaceuticals和辉瑞）已同意与我们合作，而小野制药正在准备EP4拮抗剂用于2014年夏季的临床试验。因此，我们计划在肝硬化啮齿动物模型以及肝硬化患者样本中表征产生PGE2的生化途径。此后，我们希望研究EP2和/或EP4受体抑制是否能逆转与肝硬化患者相似的细菌感染啮齿动物的免疫抑制。我们将在肝硬化患者中使用EP2和/或EP4受体拮抗剂，通过一种新的实验药物方法来完成这个项目，研究阻断这些患者中升高的PGE2的作用是否能恢复他们的免疫能力，从而杀死细菌并防止广泛感染。总之，该项目的数据将提出一种基于抑制PGE2作用模式的肝硬化相关感染管理新模式，从而提出一种恢复慢性肝病免疫能力的策略。

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.