Treating sepsis with PAF Acetylhydrolase

点击翻译按钮获取中文摘要

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.