Zymogen activation in pancreatitis

胰腺炎中的酶原激活

• 批准号: 8245549
• 负责人: Fred Sanford Gorelick
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245549
• 关键词: Acids; Acinar Cell; Acinus organ component; Acute; Acute Disease; Affect; Age; Alcohol abuse; Animal Model; Blood; Buffers; Calcium; Cause of Death; Cell model; Cells; Cholelithiasis; Coupled; Data; Development; Disease; Effectiveness; Enzyme Precursors; Fluid Therapy; Funding; G-Protein-Coupled Receptors; Gastroenterology; Goals; Hydrogen; Hyponatremia; IV Fluid; Immunoblot Analysis; In Vitro; Incidence; Individual; Inflammatory; Intravenous; Investigation; Ions; Laboratories; Lactated Ringer' s Solution; Lead; Ligands; Liquid substance; Magnesium; Mediating; Modeling; Modification; Molecular; Normal saline; Operative Surgical Procedures; Organ; Pancreas; Pancreatitis; Pathologic; Patients; Physiological; Population; Prevention; Probability; Protons; Reporting; Risk; Rodent; Rodent Model; Severities; Severity of illness; Signal Transduction; Sodium; Sodium Lactate; Sodium-Hydrogen Antiporter; Solutions; Time; Trauma; Treatment Protocols; Veterans; Work; acute pancreatitis; design; disorder risk; extracellular; in vivo; in vivo Model; insight; receptor; response

DESCRIPTION (provided by applicant): Acute pancreatitis has an incidence of up to 5/10,000 and can cause death in 30% of those with severe disease. Since pancreatitis is often caused by alcohol abuse and increases in incidence with age, the disease is frequently encountered in our Veteran population. Treatments for pancreatitis have changed little over the past 25 years; one of the mainstays of therapy is intravenous fluid. Optimization of such therapy may affect the course of disease and risk and/or severity of disease in susceptible individuals (ERCP/papillotomy/surgery/trauma). During our current funding period, we reported the effects of an acid load in pancreatitis (Gastroenterology 137: 1083-1092, 2009) . We found that an acute acid load is a potent sensitizer both in vivo and in vitro using rodent models of pancreatitis. While pursuing our studies, we found unexpected effects of standard intravenous fluids on pancreatitis. The two most commonly used intravenous fluids used in pancreatitis are normal saline (NL) and lactated Ringer's (LR). The composition of both of these fluids might have negative effects in this disease. Thus, NS is usually acidic (pH often <5.5) and when given in large amounts can present a large acid load. LR is usually less acidic (pH ~6.5), but contains high concentrations of calcium, magnesium, and lactate. Using in vivo and cellular models of acute pancreatitis, we have made the following preliminary observations. Short-term in vivo studies show that LR may have time-dependent effects on pancreatitis responses that differ from NS. Studies in isolated groups of acinar cells (acini) suggest lactate affects pancreatitis responses independent of extracellular pH. These responses are observed within the concentration range of lactate seen in physiologic and pathologic conditions (1-20 mM). These lactate responses may be mediated by GPR81, the only G-protein coupled receptor activated by lactate. Using PCR and immunoblot analysis, GPR81 was localized to the pancreatic acinar cell. GPR81 expression was maintained during experimental pancreatitis. Lactate may act through GPR81 to affect pancreatitis responses. The concentration of sodium also differs among intravenous solutions; administering fluids low in sodium can reduce its levels in the blood (hyponatremia). We find that pancreatitis responses can be modulated by the concentration of extracellular sodium; sodium-hydrogen exchangers may mediate this response. This affect of hyponatremia may be through an indirect of affect on cytosolic pH of the acinar cell. We propose to extend our preliminary data by pursuing the following specific objectives: 1) Examine the effects of standard intravenous buffers in in vivo models of mild and severe pancreatitis, 2) Investigate the effects of lactate and its receptor, GPR81, on physiologic and pancreatitis responses including cell signaling in acini and in vivo, 3) Study the effects extracellular sodium and sodium- hydrogen exchange on pancreatitis responses and acinar cell pH. The findings of these studies could lead to modifications in intravenous solutions that optimize their effectiveness for the prevention and treatment of acute pancreatitis and provide insights into disease mechanisms. ) PUBLIC HEALTH RELEVANCE: Acute pancreatitis is an inflammatory disease that begins in the pancreas and can involve multiple organs when severe. About 25% of patients with will have severe disease, and 30% of those will die. The most common causes of acute pancreatitis are alcohol abuse and gallstones. Because both conditions are common in our population, the incidence of acute pancreatitis is high in Veterans. Although the most important therapy for this disease is intravenous fluids, there are many types of fluids available and these differ in some of their basic components. Using animal and cellular model of pancreatitis, we have discovered that some standard fluids can affect pancreatitis responses. The goal of our work is to use this information to design the optimal intravenous fluid treating acute pancreatitis.

描述（由申请人提供）： 急性胰腺炎的发病率高达 5/10,000，可导致 30% 的重症患者死亡。由于胰腺炎通常是由酗酒引起的，并且发病率随着年龄的增长而增加，因此这种疾病在我们的退伍军人群体中很常见。过去 25 年里，胰腺炎的治疗方法几乎没有变化；主要治疗方法之一是静脉输液。此类治疗的优化可能会影响易感个体的病程以及疾病的风险和/或严重程度（ERCP/乳头切开术/手术/创伤）。在我们当前的资助期间，我们报告了胰腺炎中酸负荷的影响（Gastroenterology 137：1083-1092，2009）。我们使用胰腺炎的啮齿动物模型发现，急性酸负荷在体内和体外都是一种有效的敏化剂。在进行研究时，我们发现标准静脉输液对胰腺炎有意想不到的作用。胰腺炎最常用的两种静脉输液是生理盐水 (NL) 和乳酸林格氏液 (LR)。这两种液体的成分可能会对这种疾病产生负面影响。因此，NS 通常是酸性的（pH 通常<5.5），并且当大量给予时会产生大量的酸负荷。 LR 通常酸性较低（pH ~6.5），但含有高浓度的钙、镁和乳酸。利用急性胰腺炎的体内和细胞模型，我们进行了以下初步观察。短期体内研究表明，LR 对胰腺炎反应可能具有与 NS 不同的时间依赖性影响。对孤立的腺泡细胞 (acini) 群体的研究表明，乳酸影响胰腺炎反应，与细胞外 pH 值无关。这些反应是在生理和病理条件下的乳酸浓度范围内 (1-20 mM) 观察到的。这些乳酸反应可能是由 GPR81 介导的，GPR81 是唯一由乳酸激活的 G 蛋白偶联受体。通过 PCR 和免疫印迹分析，GPR81 定位于胰腺腺泡细胞。 GPR81 表达在实验性胰腺炎期间得以维持。乳酸可能通过 GPR81 影响胰腺炎反应。不同静脉注射液中钠的浓度也不同；摄入低钠液体可以降低血液中的钠含量（低钠血症）。我们发现胰腺炎反应可以通过细胞外钠的浓度来调节；钠-氢交换器可能介导这种反应。低钠血症的这种影响可能是通过对腺泡细胞的胞质 pH 值的间接影响来实现的。我们建议通过追求以下具体目标来扩展我们的初步数据：1）检查标准静脉缓冲液在轻度和重度胰腺炎体内模型中的影响，2）研究乳酸及其受体 GPR81 对生理和胰腺炎的影响反应，包括腺泡和体内的细胞信号传导，3) 研究细胞外钠和钠-氢交换对胰腺炎反应和腺泡细胞 pH 的影响。这些研究的结果可能会导致静脉注射液的改进，从而优化其预防和治疗急性胰腺炎的有效性，并提供对疾病机制的见解。 ） 公共卫生相关性： 急性胰腺炎是一种始于胰腺的炎症性疾病，严重时可累及多个器官。大约25%的患者会病情严重，其中30%会死亡。急性胰腺炎最常见的原因是酗酒和胆结石。由于这两种情况在我们的人群中很常见，因此退伍军人中急性胰腺炎的发病率很高。虽然这种疾病最重要的治疗方法是静脉输液，但有多种类型 可用的液体有多种，它们的一些基本成分有所不同。使用胰腺炎的动物和细胞模型，我们发现一些标准液体可以影响胰腺炎反应。我们工作的目标是利用这些信息来设计治疗急性胰腺炎的最佳静脉输液。