Treating sepsis with PAF Acetylhydrolase

在本申请中，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脓毒症相关的死亡率。到 为了验证这一假设，我们将研究 重组PAF乙酰水解酶，使PAF失活的酶， 磷脂，对经历败血症的动物。我们将以生存作为 终点，但也将表征对酶给药的反应， 比较用安慰剂或用本发明的药物治疗的动物中的细胞因子水平。 重组蛋白我们将利用两种脓毒症的实验模型：盲肠 注射奈瑟氏菌致结扎穿孔和脓毒症 脑膜炎作为临床推论，我们将测定PAF水平， 患者血浆中的乙酰水解酶活性和细胞因子水平 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剂的潜力外， 代理人，是确定可能受益最多的患者群体， PAF乙酰水解酶给药。最近的临床研究未能 证明抗炎剂或免疫调节剂具有有益的 治疗败血症的效果。对这一观察结果的一种可能解释是 研究的患者人群包括受试者， 不同的机制导致败血症。这可能已经排除了 在有限的患者组中测试显示有益效果的药剂 因为在对整个患者组的分析中，这种效应会丢失。 我们的假设是，具有相似性的子群体的定义 病因学将是我们理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， 疾病的结果，并确定新的治疗方法。例如，在一个示例中， 患有脑膜炎球菌病相关脓毒症的患者可被鉴定为 脓毒症患者的同质亚群。这里提出的研究可能 促进对人群的分子鉴定和治疗， 显著受益于PAF乙酰水解酶给药。这些研究 将主要在巴西进行，作为NIH SCOR资助P50的扩展 HL50153（项目5）。它们是对研究的理想补充 目前由普雷斯科特和斯塔福里尼博士执行，他们是 急性呼吸道疾病研究中心第五项目首席研究员兼项目主任 肺损伤，分别。

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.