Role of Cytokines in Two Hit Organ Injury

细胞因子在两次击中器官损伤中的作用

• 批准号: 6466248
• 负责人: JEAN A NEMZEK
• 金额: $ 9.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6466248
• 关键词: adult respiratory distress syndrome; chemotaxis; cytokine; enzyme linked immunosorbent assay; gastric acid; genetically modified animals; histology; ileocolonic region; immunocytochemistry; immunoregulation; in situ hybridization; inflammation; laboratory mouse; lung injury; multiple organ failure; neutralizing antibody; peritonitis; septic shock

Description (provided by applicant): This Mentored Clinical Scientist Development Award has been prepared for Jean A. Nemzek, DVM, MS. Dr. Nemzek is a boarded veterinary surgeon with a broad research background. After a fellowship in Comparative Medicine at University of Michigan, Dr. Nemzek joined the faculty in the Department of Pathology and the Unit for Laboratory Animal Medicine. This dynamic environment offers many experts in the field of inflammation and deep commitment to new investigators. Dr. Nemzek?s long-term research objective is to combine clinical experience and a solid basic science background to advance understanding of immune modulators in sepsis, organ failure, and acute lung injury. To achieve that goal, Dr. Nemzek is aligned with an exceptional mentor, Dr. Daniel G. Remick. They have outlined a career plan with the scientific, technical, and administrative principles necessary for independence as an investigator. The proposed studies examine the effects of sequential insults on inflammatory responses. It is theorized that sequential hits prime the immune system promoting synergistic response. This theory prompted several "two-hit" studies of inflammation. However, these studies have conflicting results, probably due to the diversity, timing, and compartmentalization of the insults given. The hypothesis of this study is that the enhanced mortality resulting after two inflammatory hits, septic peritonitis followed by acid aspiration, is mediated by an increased proinflammatory cytokine response produced at the site of the first hit. The first specific aim will determine if the exaggerated effect on lethality after two insults is due to increases in peritoneal inflammation with insults given at different intervals. The second specific aim will determine if a similar effect is seen when severity of the insults is increased. Together these aims will directly test the hypothesis and begin to identify cytokine mediators. The third specific aim will determine if the cytokine responses primarily localized to the peritoneal compartment and quantify cytokine production. Finally, cytokine profiles relative to the compartmentalization, timing, and severity of the hits will be used to determine if altering cytokine levels will reduce inflammation and lethality. This will confirm the role of specific cytokines in sequential inflammation. Successful completion of these aims could impact current two hit theories and use of immune therapy in septic patients exposed to additional inflammatory insults.

描述（由申请人提供）：本指导临床科学家 发展奖已为Jean A. Nemzek，DVM，MS。Nemzek博士是 有着广泛研究背景的寄宿兽医后 密歇根大学比较医学研究员，Nemzek博士加入了 病理学系和实验动物单位的教员 药这种动态的环境提供了许多领域的专家， 炎症和对新研究人员的深刻承诺。尼姆泽克医生的长期 研究目标是将联合收割机的临床经验和坚实的基础科学相结合 背景为了进一步了解脓毒症、器官 失败和急性肺损伤。为了实现这一目标，Nemzek博士 与一位杰出的导师丹尼尔G.雷米克他们勾勒出了一个职业生涯 按照必要的科学、技术和管理原则进行规划 作为一个独立的调查员。拟议中的研究考察了 对炎症反应的影响。理论上认为 连续的攻击引发免疫系统，促进协同反应。这 这一理论引发了几项关于炎症的“两次打击”研究。但这些 研究结果相互矛盾，可能是由于多样性，时间， 对所受侮辱的区分。这项研究的假设是， 在两次炎症发作、脓毒性发作后， 腹膜炎，其次是酸吸入，是介导的增加 在第一次撞击部位产生的促炎细胞因子反应。的 第一个具体目标将决定是否对致命性产生夸大的影响， 两次损伤是由于腹膜炎症增加， 在不同的时间间隔。第二个具体目标将决定是否类似 当损害的严重程度增加时，可以看到效果。这些目标一起 将直接检验假设并开始鉴定细胞因子介体。的 第三个具体目标是确定细胞因子反应是否主要局限于 并量化细胞因子的产生。最后， 细胞因子谱相对于区室化，时间和严重性 这些命中将用于确定改变细胞因子水平是否会降低 炎症和致命性。这将证实特异性细胞因子的作用， 继发性炎症成功实现这些目标可能会产生影响。 当前两次打击理论和脓毒症患者免疫治疗的使用 更多的煽动性侮辱。