The Role of Stat2 in Acute Pancreatitis
Acute inflammation of the pancreas is generally a mild and self-limiting illness. However up to 25% of patients develop a severe form which results in multiple systems failing in the body, shock and death in up to 34% of cases.
Overall the mortality of pancreatitis is 11%. Pancreatitis is characterised by a huge inflammatory response in the body designed to protect against the damaging effects of injured gland but actually causing organ failure by a combination of inflammatory cell rises and release of toxic inflammatory proteins or cytokines.
At present there is no treatment available in the world which can reduce the severity of pancreatitis and prevent death. Treatment is directed entirely at supporting organs that are failing and hoping they recover once the acute injury has subsided.
The Stat2 protein appears to mediate the body’s inflammatory response via interferon receptors. By reducing Stat2 availability the powerful toxins that cause organ damage are reduced and more cells fighting inflammation are produced. This manipulation of inflammation is difficult to study in humans but can be produced and studied in mice, also allowing for tissue biopsies (universally unavailable in humans during severe pancreatitis) to understand exactly what is driving the pancreatitic process. If the main cause of severe pancreatitis is production of inflammatory toxins, this could be prevented by drugs that “knock out” Stat2. If it is a cellular inflammatory process, then drugs that reduce the availability and attraction of these cells to organs could be used to reduce the severity of attacks.
There is already significant data (from this laboratory) that shows Stat2 is involved in inflammatory conditions of the liver and inflammatory bowel disease. The hypothesis is that it is also involved in the severity of pancreatitis attacks. This experimental work is aimed at introducing the first treatment in the world to reduce severity and hence mortality from a condition that affects 6 000 people in the UK per year.
Summary of experimental work
Loss of Stat2 in models is associated with increased inflammatory cell production but notable absence of inflammatory (potentially toxic) proteins. An established model of severe acute pancreatitis exists. There have also been developed models with normal levels of Stat2 and those that genetically have no Stat2 gene and therefore cannot produce Stat2 protein (called Stat2-/-). The severity of pancreatitis can be recorded in these two genetically different populations and compared.
A clinical study in patients was undertaken at the Royal London Hospital liver and pancreatic unit. This is a tertiary referral unit for all patients who develop severe acute pancreatitis from a catchment population of 3.5 million. Blood samples from all patients (who consent) with mild or severe pancreatitis was collected and divided into their white cell or inflammatory cell subtype populations (there are many different white blood cells controlling infection and inflammation within the body with different tasks). Stat2 levels were measured in these cell types by flow cytometry – an established technique already in use in the laboratory.
Gene and protein expression have been directly analysed in samples of inflamed pancreatic tissue. The cells can be split into pancreatic cells and inflammatory cells that have been attracted to the area of damage. Gene and protein expression of a number of proteins within the inflammatory pathway including Stat2 (and those proteins that Stat2 activates or inhibits to produce inflammation) have been analysed directly from severe pancreatitis samples. One particular downstream target of Stat2 that already has a number of available inhibitors potentially of use in clinical practice is NFkB. One theory that has been tested is that Stat2’s effect on pancreatitis is caused by altered signals to this downstream protein thus opening the door for further therapeutic interventions.
The results of this study:
Stat2 is a mediator of acute pancreatitis and required for MAPK and NK-kB function. Stat2 or associated factors identified in this study ARE potential biomarkers for pancreatic inflammation and/or therapuetic targets.
- Reduced incidence of severe acute pancreatitis with reduced mortality from this disease
- Better understanding of all diseases where acute severe inflammation plays a role
- Creation of novel therapeutic agents for treating inflammatory conditions
- Creation of PhD thesis