Treating sepsis with PAF Acetylhydrolase

用 PAF 乙酰水解酶治疗败血症

• 批准号: 6335496
• 负责人: Stephen M Prescott
• 金额: $ 4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6335496
• 关键词: Brazil; Neisseria meningitidis; acute disease /disorder; adult respiratory distress syndrome; bacterial disease; bacterial meningitis; carboxylic ester hydrolases; clinical research; clinical trials; cooperative study; cytokine; disease /disorder model; enzyme activity; enzyme mechanism; gene targeting; genetically modified animals; human subject; human therapy evaluation; laboratory mouse; lung injury; microorganism disease chemotherapy; nonhuman therapy evaluation; phospholipids; placebos; recombinant proteins

In this application we propose to test if removal of PAF and related phospholipids reduces the mortality associated with certain forms of sepsis. To test this hypothesis, we will examine the effect of administration of recombinant PAF acetylhydrolase, the enzyme that inactivates PAF and related phospholipids, to animals undergoing sepsis. We will use survival as the endpoint but will also characterize the response to enzyme administration by comparing cytokine levels in animals treated with placebo or with the recombinant protein. We will utilize two experimental models of sepsis: cecal ligation and puncture and sepsis induced by injection of Neisseria meningitidis. As a clinical corollary, we will determine the levels of PAF acetylhydrolase activity and cytokine levels in the plasma of patients undergoing sepsis and meningococcemia. An important goal of these studies, in addition to testing the potential of PAF acetylhydrolase as a therapeutic agent, is to identify patient groups that are likely to benefit the most from PAF acetylhydrolase administration. Recent clinical studies have failed to demonstrate that anti-inflammatory or immunomodulatory agents have beneficial effects in the treatment of sepsis. A possible explanation for this observation is that the patient population studied included subjects in whom a variety of different mechanisms resulted in sepsis. This may have precluded the ability of the agent(s) tested to show a beneficial effect in a limited group of patients because such effects would be lost in the analysis of the entire patient group. Our hypothesis is that the definition of sub-populations with similar etiologies will be a key factor in our understanding of sepsis. This approach will facilitate identification of markers to characterize the evolution and outcome of the disease as well as identify novel therapies. For example, patients suffering from meningococcemia-related sepsis can be identified as a homogeneous sub-population of septic patients. The studies proposed here may facilitate the molecular identification and treatment of populations that can significantly benefit from PAF acetylhydrolase administration. These studies will be carried out primarily in Brazil, as an extension of NIH SCOR grant P50 HL50153 (Project 5). They constitute an ideal complement to the studies currently being performed by Drs. Prescott and Stafforini, who are the Principal Investigator and Project Director of Project 5 of the SCOR in Acute Lung Injury, respectively.

在此应用程序中，我们建议测试是否移除PAF和相关 磷脂可降低某些形式的脓毒症的死亡率。至 检验这一假设，我们将检验给药的效果 重组PAF乙酰水解酶，使PAF及其相关酶失活 磷脂，对正在经历败血症的动物。我们将把生存作为 终点，但也将表征对酶注射的反应，通过 比较服用安慰剂和安慰剂的动物的细胞因子水平 重组蛋白。我们将利用两种脓毒症的实验模型：盲肠 注射奈瑟氏菌所致的结扎穿刺术和脓毒症 脑膜炎。作为临床推论，我们将测定PAF水平 患者血浆中乙酰水解酶活性和细胞因子水平的变化 正在经历败血症和脑膜炎双球菌血症。这些研究的一个重要目标是 除了测试PAF乙酰水解酶作为治疗药物的潜力 代理，是确定可能受益最大的患者群体 PAF乙酰水解酶给药。最近的临床研究未能达到 证明抗炎或免疫调节剂有好处 在脓毒症治疗中的作用。对这一观察结果有一种可能的解释 被研究的患者群体包括各种不同类型的 不同的机制导致败血症。这可能已经排除了 该制剂(S)经测试在有限的一组患者中显示出有益的效果 因为在对整个患者群体的分析中，这种影响将会消失。 我们的假设是，具有相似特征的亚种群的定义 病因将是我们了解脓毒症的关键因素。这种方法 将有助于识别标记以表征进化和 评估疾病的转归，以及确定新的治疗方法。例如, 患有脑膜炎球菌血症相关败血症的患者可被确定为 脓毒症患者的同质性亚群。这里提出的研究可能 促进分子鉴定和治疗能够 显著受益于PAF乙酰水解酶的应用。这些研究 将主要在巴西进行，作为NIH SCOR赠款的延期P50 HL50153(项目5)。它们构成了对研究的理想补充 目前由普雷斯科特博士和斯塔福里尼博士表演，他们是 SCOR项目5的首席调查员兼项目主任 肺损伤。