Mr Alastair Hayes (Pancreatitis)

Institution: University of Edinburgh

Title: Defining the mechanistic role of kynurenine 3-monooxygenase (KMO) inhibition in the resolution of organ dysfunction in severe acute pancreatitis

Project Start Date: 11 August 2014

Completion Date: 10 August 2017

Summary:

Acute inflammation of the pancreas, called ‘acute pancreatitis’, is a common reason to be admitted to hospital with abdominal pain. One in five patients experiences a particularly serious attack, which results in damage to vital organ systems. The current medical approach to severe acute pancreatitis consists of supportive treatment in a critical care unit, but there is no specific pancreatitis drug therapy or operation that can help in this condition. In fact, one in twenty people do not survive acute pancreatitis, with half of the deaths occurring within the first week of the attack. There is an urgent need to develop a treatment that targets the progression of pancreatitis.

The sickest pancreatitis patients have high blood levels of a potentially harmful molecule called ‘3-HK’, which stands for 3-hydroxykynurenine. This molecule is made by an enzyme called ‘KMO’ which stands for kynurenine-3-monooxygenase. The research group of Mr Hayes’ supervisor, Mr Damian Mole, had discovered previously that blocking the function of the KMO enzyme in a laboratory experimental model of acute pancreatitis reduced the severity of the disease. However this effect was only measured in the earliest stages of the disease, within 24 hours of the attack.

Mr Hayes Fellowship therefore focussed on the early disease recovery phase from 24 hours to 7 days. He wanted to know whether blocking the KMO enzyme or changing 3-HK levels would change the recovery of the disease and how this might be taking place. He was keen to explore whether the protection seen by his supervisor in the initial 24 hours continued into the critical first week.

Using a laboratory experimental model, Mr Hayes used a new drug chemical to block the KMO enzyme over a seven-day pancreatitis period. He found that this reduced and delayed critical illness from pancreatitis in the laboratory.

These are encouraging research findings. Mr Hayes work is part of a larger ongoing program of acute pancreatitis research lead by his supervisor, Mr Damian Mole, at The University of Edinburgh. The results of Mr Hayes’ project give further support to the concept of blocking the function of KMO to reduce severity in acute pancreatitis and improve the outcomes for patients. Mr Mole’s group have a research partnership with the pharmaceutical company, GlaxoSmithKline, and hope to use these promising laboratory findings to design experimental drug studies in patients using KMO inhibitors.

This work may make a significant difference to those people who suffer a severe attack of acute pancreatitis, not only in the short term but will also improve understanding of the longer-term effects, providing new insights into targeted treatments.