Acute pancreatitis is a debilitating disease that affects more than 280,000 people in the United States. A hallmark of acute pancreatitis is systemic injury and multi-organ failure leading to mortality in 3-20% of patients. There are currently no treatments for acute pancreatitis. Alcohol consumption is a major cause of human acute pancreatitis and despite intensive investigation the pathogenesis of alcohol-induced pancreatitis remains poorly understood. Evidence suggests that acinar cell injury is associated with mitochondrial dysfunction leading to ATP depletion and prevention of mitochondrial damage or restoration of mitochondrial function may limit pancreatitis. Phosphate availability is required for ATP synthesis. Clinical hypophosphatemia is common in alcoholic patients and alcohol itself impairs dietary phosphate absorption. In preliminary studies, we discovered that reduced serum phosphate levels in patients with acute pancreatitis are associated with increased pancreatitis severity. We proposed that reduced phosphate availability may predispose to alcohol-induced pancreatic injury and may be central to the development of alcoholic pancreatitis. Our preliminary data indicate that alcohol rapidly induces pancreatitis when mice are fed a low phosphate diet, consistent with the concept that hypophosphatemia sensitizes the pancreas to alcohol. The current study is designed to test the hypothesis that alcohol-induced pancreatitis can be ameliorated by phosphate administration. We will determine the contribution of hypophosphatemia to pancreatitis severity, the protective effects of phosphate treatment in mouse models of pancreatitis, and the mechanisms underlying the effects of hypophosphatemia on pancreatic injury. Successful completion of these studies will yield compelling pre-clinical data for a novel, simple and effective treatment for pancreatitis that will provide the basis for a clinical trial in humans.
The exocrine pancreas is a highly metabolic organ due to abundant protein synthesis. Energy in the form of adenosine triphosphate (ATP) is required to maintain proper intracellular processing of organelles which if compromised leads to premature enzyme activation, cell disruption and ultimately pancreatitis. Unfortunately, there currently is no specific treatment for pancreatitis. We discovered that loss of ATP and pancreatitis can be prevented by supplementing animals with inorganic phosphate. This project is designed to determine if phosphate can be used as a treatment for acute pancreatitis.
