Cholesterol-lowering drugs for treatment of pancreatitis: validation of a clinically significant novel therapeutic target and approach

胰腺炎是一种常见的、潜在的致命性胰腺外分泌疾病。有两种主要形式的 胰腺炎：急性（AP），通常产生暂时性疾病发作，和慢性（CP），相关 伴随着剧烈的疼痛，生活质量差，以及患上最致命的胰腺癌的风险增加。胰腺炎是 这是胃肠道疾病患者住院的第三大常见原因，也是美国的沉重负担。 保健系统主要AP反应包括消化酶的不适当/腺泡内激活， 血清淀粉酶水平升高、嗜中性粒细胞驱动的炎症和腺泡细胞死亡。关键病理特征 CP的主要原因是腺泡组织的丧失、慢性炎症和纤维化，最终导致外分泌的丧失， 胰腺内分泌功能据认为，CP是由重复的亚临床或临床明显发作引起的 的AP。过量饮酒是两种形式胰腺炎的主要风险因素;其他关键风险因素 吸烟与年龄这些因素的流行也导致退伍军人胰腺炎的高发病率 就像军人一样 胰腺炎的发病机制仍然不清楚，没有有效的治疗方法，主要是因为 我们不了解潜在的分子和细胞机制。最近的研究表明， 溶酶体/自噬途径-细胞消除受损或缺陷的关键分解代谢机制 细胞质细胞器和回收其成分的能量和生物合成的需要-被破坏， 胰腺炎我们最近的研究表明，这些途径是维持胆固醇稳态的关键 它们的紊乱导致腺泡细胞胆固醇超载。我们进一步表明， 降胆固醇药物辛伐他汀减轻实验性胰腺炎。总的来说，这些发现 提示胆固醇代谢是胰腺炎严重程度临床相关调节剂。验证角色 胆固醇失调在驱动胰腺炎和建立胆固醇合成途径作为一种治疗 目标服从药物干预胰腺炎，我们建议检查胆固醇的影响， 降低不同作用机制的药物辛伐他汀和苯哌多酸（BemA）对疾病严重程度的影响， 几种不同的小鼠和离体（细胞）胰腺炎模型。这些临床前AP和CP模型反映了 疾病严重程度和病因的谱，例如过度饮酒、胆结石和ERCP。 他汀类药物在30年前开始用于医疗用途; BemA的副作用比他汀类药物少， 被FDA批准用于降低胆固醇。 拟议的研究将检查这些药物对胰腺胆固醇水平和疾病的影响 在预防和治疗模式中使用各种药物给药方案来评估严重程度。具体 目的是确定辛伐他汀和BemA对AP临床前模型中胰腺炎参数的影响 (Aim 1）和CP（目的2）和这些模型中胆固醇水平的变化（目的3A）;并比较辛伐他汀的 在小鼠与人腺泡细胞中对离体胰腺炎反应的影响（Aim 3B）。 如果成功，该研究将提供必要的信息，以降低未来临床试验的风险， 将辛伐他汀和/或BemA重新用于胰腺炎治疗，从而解决以下未满足的临床需求： 老兵比较分析药物在几种临床前胰腺炎模型中的作用将使我们能够选择 通过排除对胰腺有毒性作用的治疗方案， 降低胆固醇能力不足，和/或对胰腺炎反应几乎没有有益影响。再利用 FDA批准的药物可以显著加快这些试验的速度并降低其成本。因此，建议的详细 临床前模型研究是临床试验的必要先决条件，以评估我们的风险和益处。 新方法来满足退伍军人的医疗保健需求。

Pancreatitis is a common, potentially fatal, disease of the exocrine pancreas. There are 2 major forms of pancreatitis: acute (AP), which usually produces an episode of temporary illness, and chronic (CP), associated with severe pain, poor quality of life, and increased risk for the deadliest pancreatic cancer. Pancreatitis is the third most common reason for hospital admissions in those with GI disease and a heavy burden on the U.S. healthcare system Major AP responses include inappropriate/intra-acinar activation of digestive enzymes, increased serum level of amylase, neutrophil-driven inflammation, and acinar cell death. Key pathologic features of CP are loss of acinar tissue, chronic inflammation and fibrosis, ultimately leading to the loss of exocrine and endocrine pancreatic function. It is believed that CP results from repetitive subclinical or clinically evident bouts of AP. Excessive alcohol consumption is a major risk factor for both forms of pancreatitis; other key risk factors are smoking and age. The prevalence of these factors results in high pancreatitis incidence in Veterans as well as in military personnel. The pathogenesis of pancreatitis remains obscure and no effective treatment is available, primarily because we do not understand the underlying molecular and cellular mechanisms. Recent studies indicate that the lysosomal/autophagy pathways – a key catabolic mechanism by which cells eliminate damaged or defective cytoplasmic organelles and recycle their constituents for energy and biogenesis needs – are disrupted in pancreatitis. Our recent study revealed that these pathways are critical for maintaining cholesterol homeostasis in pancreas and their disordering results in acinar cell cholesterol overload. We further showed that the cholesterol-lowering drug simvastatin alleviated experimental pancreatitis. Taken together, these findings suggest that cholesterol metabolism is a clinically relevant modulator of pancreatitis severity. To validate the role of cholesterol dysregulation in driving pancreatitis and establish cholesterol synthesis pathway as a therapeutic target amenable to pharmacologic intervention in pancreatitis, we propose to examine the effects of cholesterol- lowering drugs with different action mechanism, simvastatin and bempedoic acid (BemA), on disease severity in several dissimilar mouse and ex-vivo (cellular) pancreatitis models. These preclinical AP and CP models reflect the spectrum of disease severity and etiologies, such as excessive alcohol consumption, gallstones, and ERCP. Statins came to medical use 30 years ago; BemA, which elicits fewer adverse effects than statins, was recently approved by FDA for lowering cholesterol. The proposed studies will examine the effects of these drugs on pancreatic cholesterol levels and disease severity using various regimens of drug administration in both preventive and therapeutic modes. The Specific Aims will determine the effects of simvastatin and BemA on pancreatitis parameters in preclinical models of AP (Aim 1) and CP (Aim 2) and changes in cholesterol levels in these models (Aim 3A); and compare simvastatin’s effects on ex-vivo pancreatitis responses in mouse versus human acinar cells (Aim 3B). If successful the study will provide information necessary to de-risk future clinical trials to validate the repurposing of simvastatin and/or BemA for pancreatitis treatment, and thus address the unmet clinical needs of Veterans. Comparative analysis of drugs’ effects in several preclinical pancreatitis models will allow us to select the best candidate(s) for clinical trials by excluding treatment regimens with toxic effects in the pancreas, insufficient cholesterol-lowering capacity, and/or little beneficial impact on pancreatitis responses. Repurposing FDA-approved drugs can significantly speed up and lower the cost of these trials. Thus, the proposed detailed study in preclinical models is a necessary prerequisite for clinical trials to assess the risks and benefits of our novel approach to address Veteran healthcare needs.