Suppression of cirrhossis-mediate immune suppression by prostaglandin receptor antagonism

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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.