Metabolic regulation of pancreatitis

摘要 急性胰腺炎是一种使人虚弱的疾病，在美国有超过28万人受到影响。一个 急性胰腺炎的特点是全身损伤和多器官衰竭，导致3%-20%的人死亡 病人。目前还没有治疗急性胰腺炎的方法。饮酒是导致癌症的主要原因 人类急性胰腺炎与酒精性胰腺炎发病机制的深入研究 人们对此仍然知之甚少。有证据表明腺泡细胞损伤与线粒体有关 导致ATP耗竭的功能障碍和线粒体损伤或修复的预防 功能可能会限制胰腺炎。磷酸是合成三磷酸腺苷所必需的。临床 低磷血症在酗酒患者中很常见，酒精本身会损害饮食中的磷酸盐吸收。在……里面 初步研究发现，急性胰腺炎患者血磷水平降低 与胰腺炎严重程度增加有关。我们提出，磷酸盐有效性的降低可能会 易发生酒精性胰腺损伤，并可能是酒精性胰腺炎发生的中心环节 胰腺炎。我们的初步数据表明，当小鼠喂食低剂量酒精时，酒精会迅速诱发胰腺炎。 磷酸盐饮食，与低磷血症使胰腺对酒精敏感的概念一致。这个 目前的研究旨在验证酒精诱导的胰腺炎可以通过以下方法改善的假设 磷酸盐管理。我们将确定低磷血症对胰腺炎严重程度的影响， 磷酸盐治疗对小鼠胰腺炎模型的保护作用及其机制 低磷血症对胰腺损伤的影响。成功完成这些研究将产生令人信服的结果 一种新的、简单有效的胰腺炎治疗方法的临床前数据将为 在人体上进行临床试验。

Abstract 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.