Role of Cyclooxygenase-2-derived Prostanoids in Polymicrobial Sepsis

描述(由申请人提供)： 描述：脓毒症是一种疾病过程，其特征是对潜在感染的全身炎症反应。在美国，每年有75万人患上严重的脓毒症，尽管最近在重症监护方面取得了进展，但每年仍有超过21万人死亡。由腹内感染引起的多菌败血症在严重脓毒症病例中所占的比例越来越大，并且常常与大量的死亡率相关。环氧合酶-2(COX-2)是环氧合酶的诱导型亚型，在调节炎症和抗炎的先天免疫反应中起关键作用，COX-2衍生的前列腺素可能在多菌败血症时对胃肠道屏障的防御起着至关重要的作用。我们的总体假设是，COX-2在宿主对腹内多菌败血症的反应中起到保护作用。我们的初步数据表明，在腹膜炎诱导的多菌败血症的小鼠模型中，COX-2缺乏是有害的。环氧合酶-2基因缺陷小鼠在盲肠结扎和穿孔(CLP)后表现出夸大的死亡率、严重的回肠粘膜损伤、菌血症增加和重要器官种植增加。这项建议的具体目的是：1)研究COX-2衍生的前列腺素在腹膜炎诱导的多菌脓毒症小鼠模型中的作用；2)阐明在腹膜炎诱导的多菌脓毒症中介导COX-2保护作用的细胞类型(S)；以及3)确定COX-2在脓毒症中提供保护的机制。除了我们的科学目标，候选人还寻求一个正式的、有指导的培训计划，以发展成为一名成功的内科科学家所必需的技能。候选人是一位对脓毒症的病理生理学长期感兴趣的集约主义者。她建议的职业发展计划包括：1)与重症监护研究领域的成功领导者进行指导和合作；2)对研究与临床相关的脓毒症模型所需的各种技术进行基础培训；以及3)获得智力技能，以发展成为学术重症监护医学的独立研究员。 摘要：败血症是一种与严重感染相关的疾病，每年困扰75万人。目前还没有针对败血症的特效药，每年有20多万人死于这种毁灭性的疾病。这项建议的主要目标是确定COX-2酶在脓毒症期间是如何保护的，希望这项研究最终将导致这种经常致命的疾病的新疗法。 演出现场(S)：马萨诸塞州波士顿布里格姆妇女医院。 派：弗雷登堡，劳拉·伊丽莎白。

DESCRIPTION (provided by applicant): DESCRIPTION: Sepsis is a disease process characterized by a systemic inflammatory response to an underlying infection. In the United States, 750,000 people develop severe sepsis annually and despite recent advances in critical care, over 210,000 people die each year. Polymicrobial sepsis due to intra-abdominal infection accounts for a significant and growing percentage of cases of severe sepsis and is often associated with substantial mortality. Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, plays a pivotal role in modulating both the inflammatory and anti-inflammatory innate immune responses and COX-2-derived prostanoids may be vital to gastrointestinal barrier defense during polymicrobial sepsis. Our overall hypothesis is that COX-2 plays a protective role during the host response to intra-abdominal polymicrobial sepsis. Our preliminary data demonstrate that COX-2 deficiency is detrimental in a murine model of peritonitis-induced polymicrobial sepsis. COX-2 deficient mice exhibit exaggerated mortality, severe ileal mucosal damage, increased bacteremia, and enhanced seeding of vital organs following cecal ligation and puncture (CLP). The Specific Aims of this proposal are: 1) to investigate the role of COX-2-derived prostanoids in a murine model of peritonitis-induced polymicrobial sepsis; 2) to elucidate the cell type(s) responsible for mediating the protective effects of COX-2 during peritonitis-induced polymicrobial sepsis; and 3) to determine the mechanisms by which COX-2 affords protection during sepsis. In addition to our scientific goals, the candidate seeks a formal, mentored training program to develop the skills necessary to become a successful physician-scientist. The candidate is an intensivist with a long-standing interest in the pathophysiology of sepsis. Her proposed career development plan includes: 1) mentorship and collaboration with successful leaders in the field of critical care research; 2) fundamental training in a wide range of techniques necessary to study clinically relevant models of sepsis; and 3) acquiring the intellectual skills to develop into an independent investigator in academic critical care medicine. SUMMARY: Sepsis is a disease associated with severe infections that afflicts three quarters of a million people each year. There is no specific treatment for sepsis and over 200,000 people die annually of this devastating illness. The main goal of this proposal is to determine how the COX-2 enzyme is protective during sepsis with the hope that this research will eventually lead to new therapies for this frequently fatal disease. PERFORMANCE SITE(S): Brigham and Women's Hospital, Boston, MA. PI: Fredenburgh, Laura Elizabeth.