Role of Cyclooxygenase-2-derived Prostanoids in Polymicrobial Sepsis

环氧合酶 2 衍生的前列腺素在多种微生物脓毒症中的作用

• 批准号: 7922806
• 负责人: LAURA ELIZABETH FREDENBURGH
• 金额: $ 10.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922806
• 关键词: Abdominal Infection; Accounting; Adrenal Cortex Hormones; Adrenal gland hypofunction; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Bacteremia; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Boston; Cells; Cessation of life; Coagulation Process; Collaborations; Critical Care; Data; Development Plans; Disease; Eicosanoids; Endotoxemia; Enterocytes; Enzymes; Epithelial Cells; Exhibits; Fibrin; Functional disorder; Goals; Gram-Negative Bacteria; HMGB1 Protein; Hematogenous; Hospitals; Hypotension; Hypoxia; Immune response; Immune system; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intestines; Intra-abdominal; Invaded; Lead; Ligation; Lipopolysaccharides; Lung; Mediating; Mediator of activation protein; Medical; Medicine; Mentors; Mentorship; Microbe; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Organ; Peptidoglycan; Peritonitis; Phagocytosis; Physicians; Play; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Puncture procedure; Refractory; Relative (related person); Research; Research Personnel; Resolution; Role; Scientist; Sepsis; Septic Shock; Series; Stimulus; Techniques; Tissues; Training; Training Programs; United States; Ventilator; Wild Type Mouse; Woman; activated Protein C; base; career development; cell type; clinically relevant; cost; cyclooxygenase 1; cyclooxygenase 2; cytokine; gastrointestinal; glycemic control; hemodynamics; improved; interest; killings; microbial; mortality; pathogen; performance site; programs; protective effect; receptor; response; skills

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.

描述（由申请人提供）： 描述：脓毒症是一种以对潜在感染的全身炎症反应为特征的疾病过程。在美国，每年有 750,000 人患上严重脓毒症，尽管重症监护近来取得了进展，但每年仍有超过 210,000 人死亡。腹内感染引起的多种微生物败血症在严重败血症病例中所占比例显着且不断增加，并且通常与大量死亡率相关。环氧合酶-2 (COX-2) 是环氧合酶的诱导亚型，在调节炎症和抗炎先天免疫反应中发挥着关键作用，COX-2 衍生的前列腺素可能对多种微生物脓毒症期间的胃肠道屏障防御至关重要。我们的总体假设是 COX-2 在宿主对腹内多种微生物败血症的反应过程中发挥保护作用。我们的初步数据表明，COX-2 缺乏对腹膜炎诱导的多种微生物败血症的小鼠模型是有害的。 COX-2缺陷小鼠在盲肠结扎穿刺（CLP）后表现出过高的死亡率、严重的回肠粘膜损伤、菌血症增加以及重要器官的播种增加。该提案的具体目标是：1）研究 COX-2 衍生的前列腺素类在腹膜炎诱导的多种微生物败血症的小鼠模型中的作用； 2) 阐明在腹膜炎诱导的多种微生物败血症期间负责介导COX-2保护作用的细胞类型； 3) 确定 COX-2 在败血症期间提供保护的机制。除了我们的科学目标之外，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师科学家所需的技能。该候选人是一名重症监护医师，对脓毒症的病理生理学有着长期的兴趣。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) 研究脓毒症临床相关模型所需的各种技术的基础培训； 3) 获得发展成为学术重症监护医学独立研究者的智力技能。 摘要：脓毒症是一种与严重感染相关的疾病，每年影响一百万人中的四分之三。败血症没有具体的治疗方法，每年有超过 200,000 人死于这种毁灭性的疾病。该提案的主要目标是确定 COX-2 酶在败血症期间如何发挥保护作用，希望这项研究最终能为这种常见致命疾病带来新的疗法。 演出地点：马萨诸塞州波士顿布莱根妇女医院。 PI：弗雷登堡，劳拉·伊丽莎白。