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，我们建议测试是否去除PAF和相关 磷脂降低了与某些形式的败血症相关的死亡率。到 检验该假设，我们将研究给药的影响 重组PAF乙酰水合酶，使PAF和相关的酶 磷脂，致脓毒症的动物。我们将使用生存作为 端点，但也将通过 比较用安慰剂治疗的动物的细胞因子水平或 重组蛋白。我们将利用两个败血症的实验模型：盲肠 奈瑟氏菌注射引起的结扎，穿刺和败血症 脑膜炎。作为临床推论，我们将确定PAF的水平 患者血浆中乙酰水合酶活性和细胞因子水平 经历败血症和脑膜炎球菌。这些研究的重要目标， 除了测试PAF乙酰水合酶作为治疗的潜力 代理人是要确定可能受益最大的患者群体 PAF乙酰水合酶给药。最近的临床研究未能 证明抗炎或免疫调节剂具有有益的 败血症治疗的影响。这一观察结果的可能解释 是研究的患者人群包括各种受试者 不同的机制导致败血症。这可能排除了 经过测试的代理在有限的患者组中显示出有益作用 因为在整个患者组的分析中，这种影响会失去。 我们的假设是，具有相似的子人群的定义 病因将是我们对败血症的理解的关键因素。这种方法 将有助于识别标记以表征进化和 疾病的结果以及鉴定新疗法。例如， 患有脑膜炎药物相关败血症的患者可以识别为 化粪池患者的同质亚群。这里提出的研究可能 促进对种群的分子鉴定和处理 PAF乙酰水合酶给药可显着受益。这些研究 将主要在巴西进行，作为NIH SCOR Grant P50的扩展 HL50153（项目5）。它们构成了研究的理想补充 目前由Drs执行。 Prescott和Stafforini，他们是 急性SCOR项目5的首席研究员兼项目总监 肺损伤分别。