LUNG LPS BINDING PROTEIN AND ARDS AFTER TRAUMA

创伤后肺 LPS 结合蛋白和 ARDS

• 批准号: 6182757
• 负责人: RICHARD D KLEIN
• 金额: $ 12.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6182757
• 关键词: adult respiratory distress syndrome; bacterial polysaccharides; binding proteins; biological signal transduction; cytokine; gel mobility shift assay; histopathology; immunoprecipitation; in situ hybridization; inflammation; laboratory rat; lipopolysaccharides; lung injury; polymerase chain reaction; radiotracer; respiratory epithelium; tissue /cell culture; transfection

DESCRIPTION (Adapted from applicants' abstract) The adult respiratory distress syndrome (ARDS) is still a major cause of morbidity and mortality among trauma and critically ill patients. ARDS is believed to be the result of local pulmonary activation of the inflammatory cascade after local or systemic injury, leading to lung tissue damage. After trauma or gram negative sepsis, LPS from the bacterial cell wall binds to CD14 receptors on mononuclear cells causing the release of inflammatory mediators such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), Tumor Necrosis Factor-a (TNF-a), platelet activating factor and nitric oxide. These mediators are believed to be responsible for the physiologic changes seen in ARDS after trauma or sepsis. Lipopolysaccharide binding protein (LBP), found in serum and produced locally, enhances the binding of LPS to CD14 receptor. The applicant has previously found elevated LBP production in pulmonary tissue after distant injury. LBP may therefore contribute to over amplification of the lung inflammatory response in the presence of minute amounts of LPS. The mechanism by which lung LBP production is controlled and its role in the pathophysiology of ARDS in traumatized patients remains unknown. The current proposal seeks to investigate and understand the role of locally produced LBP in lung tissue after trauma. The applicant hypothesizes that elevated local pulmonary production of LBP as a result of local or systemic injury may predispose the lung to an overwhelming activation of the inflammatory system leading to greater tissue destruction. He therefore aims to define the factors regulating LBP production by pulmonary cells in vitro as well as in vivo and to determine the functional role of locally produced pulmonary LBP on host responses to LPS in ARDS. This grant proposal is composed of two phases. The first phase will consist of a training plan. Through the completion of a core curriculum of courses and frequent didactic sessions with both primary and secondary mentors, the candidate will acquire a strong knowledge base as well as obtain technical expertise in the fields of molecular biology, cell biology and genetics. The candidate will gain critical knowledge of advanced and complex techniques under the tutelage of the primary mentor, Dr. Stewart C. Wang, while working on the research proposal. The second phase will focus on completing the specific aims of the application and allow the candidate to gain a broader range of scientific knowledge. The goal is for the candidate to develop independent areas of research. (End of Abstract)

描述 （改编自申请人的摘要）成人呼吸窘迫综合征 （ARDS）仍然是创伤和创伤患者发病和死亡的主要原因 危重病人。 ARDS被认为是当地疾病的结果 局部或全身后肺部炎症级联激活 损伤，导致肺组织损伤。 外伤或革兰氏阴性后 败血症时，细菌细胞壁的 LPS 与 CD14 受体结合 单核细胞导致炎症介质的释放，例如 白细胞介素-1 (IL-1)、白细胞介素-6 (IL-6)、肿瘤坏死因子-a (TNF-a)、 血小板活化因子和一氧化氮。 这些调解人相信 造成创伤后 ARDS 中出现的生理变化或 败血症。 脂多糖结合蛋白 (LBP)，存在于血清和 局部产生，增强 LPS 与 CD14 受体的结合。 这 申请人之前曾发现肺组织中 LBP 产量升高 远处受伤后。 因此，LBP 可能会导致过度放大 微量 LPS 存在下的肺部炎症反应。 肺 LBP 产生的控制机制及其在 创伤患者 ARDS 的病理生理学仍不清楚。 当前的提案旨在调查和了解当地的作用 创伤后肺组织中产生LBP。 申请人假设 由于局部或全身性的原因，局部肺部产生 LBP 升高 损伤可能会使肺部过度激活 炎症系统导致更大的组织破坏。 他因此 目的是确定调节肺细胞 LBP 产生的因素 体外和体内并确定局部的功能作用 ARDS 中宿主对 LPS 的反应产生肺 LBP。 该拨款提案由两个阶段组成。 第一阶段将包括 的培训计划。 通过完成核心课程 以及与小学和中学导师的频繁教学会议， 候选人将获得强大的知识基础并获得技术 分子生物学、细胞生物学和遗传学领域的专业知识。 候选人将获得先进和复杂的关键知识 在主要导师 Stewart C. Wang 博士的指导下学习技术， 在研究研究计划的同时。 第二阶段将重点关注 完成申请的具体目标并允许候选人 获得更广泛的科学知识。 目标是为候选人 发展独立的研究领域。 （摘要完）