Role of Cyclooxygenase-2-derived Prostanoids in Polymicrobial Sepsis

脓毒症是一种疾病过程，其特征在于对潜在感染的全身炎症反应。 在美国，每年有750，000人发展为严重脓毒症，尽管最近在严重脓毒症方面取得了进展， 每年有超过21万人死亡。腹腔内感染引起的多微生物败血症 严重脓毒症病例的显著且不断增加的百分比，并且通常与实质性的 mortality.环氧合酶-2（考克斯-2）是环氧合酶的诱导型异构体，在肿瘤的发生发展中起着关键作用。 调节炎性和抗炎性先天免疫应答以及考克斯-2衍生的 前列腺素类可能是至关重要的胃肠道屏障防御在多微生物败血症。我们的整体 假设考克斯-2在宿主对腹腔内多种微生物的反应中起保护作用 败血症我们的初步数据表明，考克斯-2缺乏是有害的小鼠模型， 腹膜炎引起的多微生物败血症考克斯-2缺陷小鼠表现出夸大的死亡率，严重的回肠 盲肠结扎后粘膜损伤、菌血症增加和重要器官播种增加， 穿刺（CLP）。本研究的具体目的是：1）研究考克斯-2-衍生物在肿瘤细胞中的作用， 腹膜炎诱导的多微生物脓毒症小鼠模型中的前列腺素类; 2）阐明细胞类型 负责介导腹膜炎诱导的多微生物脓毒症期间考克斯-2的保护作用;和 3)以确定考克斯-2在脓毒症期间提供保护的机制。除了我们的科学 目标，候选人寻求一个正式的，指导性的培训计划，以发展成为一个 成功的物理学家和科学家候选人是一个强化治疗师，长期以来对 脓毒症的病理生理学她建议的职业发展计划包括：1）指导和合作 与重症监护研究领域的成功领导者; 2）在广泛的基础培训， 研究脓毒症临床相关模型所需的技术;和3）获得智力技能， 发展成为学术重症监护医学的独立调查员。摘要：败血症是一种疾病 与每年折磨75万人的严重感染有关。没有 每年有超过20万人死于这种毁灭性疾病。主要目标 这项建议的一个重要目的是确定考克斯-2酶在脓毒症中的保护作用，希望这一点能够成为一个新的研究方向。 研究最终将为这种经常致命的疾病带来新的疗法。

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.