Suppression of cirrhossis-mediate immune suppression by prostaglandin receptor antagonism

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.

Liver cirrhosis is the 5th leading cause of death in the UK causing a seven-fold increased risk of infection with up to 90% mortality. While leukocyte dysfunction has been proposed, it is unclear why cirrhosis patients are hyper-susceptible to infection. Experiments on rodents and humans with decompensated liver cirrhosis compared with controls suggest that cyclooxygenase (COX)-derived PGE2 is the key immune suppression factor in cirrhotic liver disease exerting its effects through EP2 and/or EP4 receptors. However, the source of PGE2 in cirrhosis is unknown, specifically whether it is constitutive or inducible COX-derived. Indeed, the PGE2 receptor/s that transduce PGE2's immune suppressive effects in cirrhosis, of which there are four (EP1-4), require further investigation. Our aim, therefore, is to use rodent models of cirrhosis and samples from cirrhotic patients to determine the biochemical pathways that generate PGE2 and confirm the receptors that transduce its immune suppressive effects. NSAIDs represent one strategy to inhibit PGE2. However, NSAIDs have renal and gastrointestinal toxicity. Instead, we predict that antagonising EP2 and/or EP4 receptors expressed on cells of the innate immune system will restore immune competence without affecting PGE2's protective role in the kidney and gut, which is largely exerted through EP1/EP3 and EP1, respectively. This hypothesis will be tested in cirrhotic mice bearing bacterial infections. Finally, using a novel experimental medicines approach utilising EP receptor antagonists in cirrhotic patients we will determine whether blocking the action of elevated PGE2 in these individuals restores immune competence. In summary, data from this project will propose a new paradigm for management of cirrhosis-related infection based on inhibiting synthesis/mode of action of PGE2, a simple and effective strategy that will reinstate immune competence and increase survival without causing renal or gastrointestinal toxicity.

In "Academic Beneficiaries" we outlined the members of the immediate and wider academic community who will benefit directly/indirectly from the research proposed in this application. In this section, we will underline the direct health benefits arising from this application. To reiterate, we hypothesise that cyclooxygenase (COX)-derived prostaglandin (PG)E2 underlines immune suppression in liver cirrhosis. PGE2 is a lipid hormone with a role in acute inflammation synthesised by COX, the target for the mode of action of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin. The synthesis, measurement, and inhibition of PGE2 by NSAIDs, is well understood. This, therefore, provides us with a target with which to prevent immune suppression/infection in cirrhosis patients. In terms of prevention, inhibiting PGE2 synthesis by NSAIDs would appear to be an immediate and effective strategy. However, NSAIDs cause gastrointestinal bleeding in some individuals and in cirrhosis patients in particular, NSAID cause renal toxicity. However, targeting the specific receptor that PGE2 exerts its immune suppressive effects through may carry less renal and gastrointestinal side effects. Specifically, PGE2 has four receptors, namely EP1-4. From our data and that published by others we believe that EP2 and EP4 receptors expressed on cells of the immune system transduce PGE2's immune suppressive 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, but without their side effects. In terms of drug availability for this project and its objectives, 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. Thus, we may have a drug that is ready for a "first-in-man" study in a relatively short time period. 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 suggest a strategy that will reinstate immune competence and increase survival in patients with cirrhotic liver disease.