The role of monocytes and macrophages in the outcome of acute liver failure

Liver disease is the 5th commonest cause of death in the UK. The majority of it in Western communities is caused by the effects of excess alcohol consumption. Alcoholic liver disease is increasing in the UK and alcoholic hepatitis (AH) is it's most florid manifestation, affecting 5 in every 100,000 people. AH hospitalises relatively young people, the average age being 51, and so it impacts heavily on both quality and quantity of life in our communities. In the UK, acute liver failure (ALF) occurs in up to one thousand people per year. It is a devastating condition that carries a high mortality rate (>40%) despite the use of liver transplantation. ALF accounts for 10-20% of all liver transplants performed in the UK. At present only 6-7 hundred donor organs are available each year for liver transplantation. This fails to meet the current demand resulting in deaths on the waiting list, some 30-50% of patients listed not proceeding to transplantation. Acute liver failure cases are listed under an emergency category and given priority on the waiting list over elective cases, exacerbating the risk of death on waiting list for patients with end-stage chronic liver disease. Drug induced liver injury, particularly paracetamol toxicity is the commonest cause of ALF. Infection is very common in both AH and ALF and is associated with a rapid decline in liver function and premature death in over fifty percent of these patients. The cause for this marked susceptibility to infections is largely unknown, but our recent data indicate that monocytes, a subset of circulating white blood cells, are markedly defective and unable to combat infectious agents such as bacteria and viruses. A significant proportion of this research will study monocytes from the bloodstream of patients suffering from AH and ALF and we will assess their ability to fight infectious agents. I will consider whether patients with poorly functioning monocytes have an increased risk of infection by following their admission to hospital. In addition, I will look for factors in their blood which prevent these immune cells from working properly which, if removed, could restore immune function. This understanding will allow us to develop targeted, individualised treatments that restore the immune response to infection and save lives in patients with AH and ALF. Currently, treatment strategies for ALF are limited with no specific targeted therapies in current clinical care used to ameliorate the severity of liver damage. The second component of this research will focus on the role of macrophages in the damaged and inflamed livers of patients with ALF and AH. Macrophages, which reside in tissue, represent more mature immune cell population, derived from circulating monocytes and are major determinants of the body's response to tissue injury. They possess both tissue destructive capacity, required to clear damaged cells, and also tissue repair properties. Their role during ALF and AH is not fully understood. We have recently shown that, within the liver of patients undergoing emergency liver transplantation for ALF, there is an abundance of macrophages attempting to promote tissue repair. We would like to investigate the role played by hepatic macrophages in during experimental and human models of acute liver injury. In particular, we would like to focus our work towards understanding whether these immune cells resolve liver damage and promote tissue repair. Better understanding of the mechanisms that control the function of this pivotal immune cell should provide novel insight into the progression of acute liver injury and identify key therapeutic targets to promote recovery following acute liver injury. Recovery of patients with ALF without need for transplantation would impact greatly on health resource utilization and further improve availability of organs for patients with chronic liver disease.