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750，000人患上严重败血症，尽管最近在重症监护方面取得了进展，但每年仍有超过210，000人死亡。由于腹腔内感染引起的多微生物败血症占严重败血症病例的显著且不断增长的百分比，并且通常与大量死亡率相关。环氧合酶-2（考克斯-2）是环氧合酶的诱导型，在炎症和抗炎天然免疫反应中起着关键作用，考克斯-2衍生的前列腺素类化合物可能在多菌性脓毒症的胃肠道屏障防御中起重要作用。我们的总体假设是，考克斯-2在宿主对腹腔内多微生物脓毒症的反应中起保护作用。我们的初步数据表明，考克斯-2缺陷是有害的小鼠模型腹膜炎诱导的多微生物败血症。考克斯-2缺陷小鼠表现出过高的死亡率，严重的回肠粘膜损伤，菌血症增加，盲肠结扎和穿刺（CLP）后重要器官的接种增加。该提案的具体目的是：1）研究考克斯-2衍生的前列腺素类在腹膜炎诱导的多微生物脓毒症小鼠模型中的作用; 2）阐明在腹膜炎诱导的多微生物脓毒症期间负责介导考克斯-2保护作用的细胞类型;和3）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外，候选人还寻求正式的、有指导的培训计划，以培养成为一名成功的医生兼科学家所需的技能。候选人是一名重症监护医师，长期对脓毒症的病理生理学感兴趣。她提出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）研究败血症临床相关模型所需的广泛技术的基础培训; 3）获得智力技能，发展成为学术重症监护医学的独立研究者。 脓毒症是一种与严重感染相关的疾病，每年折磨着75万人。败血症没有具体的治疗方法，每年有超过20万人死于这种毁灭性的疾病。这项提案的主要目标是确定考克斯-2酶是如何在脓毒症中起保护作用的，希望这项研究最终能为这种经常致命的疾病带来新的治疗方法。 表演地点：Brigham and Women's Hospital，Boston，MA。 PI：Fredenburgh，Laura Elizabeth.

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.