Advanced Therapies in Severe Acute Pancreatitis: Pancreatic Cooling

Background: Acute pancreatitis (AP) is a painful, potentially life-threatening condition of the pancreas with a typically abrupt and unexpected onset. It is severe in 20%-30% of the cases, causing breathing difficulties (acute lung injury), failing kidneys, and sometimes death. There is no reliable way to predict who is going to have a severe attack and no specific treatment for AP. Annually, 274,000 Americans are hospitalized for pancreatitis, resulting in 3,510 deaths, costing the system $3.7 billion. In this proposal, we build on successes of the preceding grant (PR110417), i.e., pancreatic cooling via a cooling balloon in the stomach. This can treat pancreatitis in many ways. One parallel would be a refrigerator, which prevents the spoilage of many types of food – uncooked, cooked, vegetables, or meat. Cooling similarly was an effective treatment for pancreatitis in rats, both mild and severe and helped even when the causes of pancreatitis were different. In Aim 1 of the current proposal, we will study whether such a cooling device can cool the pancreas in an alert, large animal, i.e., a pig. In Aims 2 and 3, we will explore how cooling helped reduce lung and pancreas injury in the presence of bile, which is one of the most common causes of AP. Therefore, this project may help in treating AP as well as acute lung injury (ALI), which affect our Veterans and Soldiers on active duty. Relevance to Veterans: Whereas AP accounts for 0.1%-0.6% of the diagnoses in general hospitals, it is much more common (2%-3%) in the Veterans Administration system (i.e., among Veterans). Veterans, who had amputations of their proximal limbs due to Service-related trauma, when followed for 30 years, had a 3.8-fold increased risk of AP compared to distal amputees. These Veterans also had a higher chance of dying from AP. This project will aid Veterans by moving forward a device to treat AP (Aim 1) and will also help in understanding the mechanisms of how AP becomes severe and causes ALI (Aims 2 and 3). In Aim 1, we propose to advance the pancreatic cooling device towards human use by ensuring that it is safe, comfortable, and effective in cooling the pancreas in an awake, alert, large animal, i.e., a pig. If successful, based on the previous effectiveness of this technology in treating rats with pancreatitis (during PR110417), we propose to design a device to treat pancreatitis in humans, which will benefit our Veterans. During AP, large amounts of fat surrounding the pancreas are broken into toxic fatty acids (oily material). When a gallstone causing pancreatitis also blocks the flow of bile, it increases the amount of bile acids in the blood and in the pancreas. In PR110417 we discovered that cooling reduced bile acids in the blood and this could explain the reduced toxicity of fatty acids. We will thus explore this bile-fat interaction in Aims 2 and 3. In Aim 2, we will study the mechanisms of how bile makes fatty acids toxic using in-depth methods that study the physics of their interactions, water solubility and stability, along with employing novel tools like fluorescent fatty acids, and studying their uptake and behavior in cells in real time. In Aim 3, we will look for direct evidence of whether and how bile acids worsen pancreatitis and ALI in rats. For this we will compare the injury caused by fatty acids alone to that caused in the presence of bile. We will examine the pancreas and distant organs like the lungs looking for evidence of ALI. Relevance to Soldiers on Active Duty: This lies in the evidence mentioned above showing fatty acids cause ALI during severe pancreatitis. The lessons we learn may also be relevant to burns, trauma, hemorrhage, all of which can happen in active combat and can result in ALI. Our studies on how bile acids may worsen this fatty acid induced ALI are thus relevant to these conditions also. Patients with trauma, hemorrhage, or burns have elevated serum fatty acid