LUNG LPS BINDING PROTEIN AND ARDS AFTER TRAUMA

创伤后肺 LPS 结合蛋白和 ARDS

• 批准号: 6017194
• 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 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6017194
• 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 （摘自申请人摘要）成人呼吸窘迫综合征 （ARDS）仍然是创伤和创伤后应激障碍中发病率和死亡率的主要原因。 危重病人。 ARDS被认为是由于局部 局部或全身性炎症级联反应的肺激活 损伤，导致肺组织损伤。 外伤后或革兰氏阴性 脓毒症时，来自细菌细胞壁的LPS结合到 单核细胞引起炎症介质的释放， 白细胞介素-1（IL-1）、白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）， 血小板活化因子和一氧化氮。 这些调解人被认为 导致创伤后ARDS的生理变化， 败血症 脂多糖结合蛋白（LBP），发现于血清和 局部产生，增强LPS与CD 14受体的结合。 的 申请人先前发现肺组织中LBP的产生增加 远距离伤害后 因此，LBP可能有助于过度放大 肺部炎症反应在存在少量的LPS。 控制肺LBP产生的机制及其在肺结核中的作用 创伤患者中ARDS的病理生理学仍不清楚。 目前的建议旨在调查和了解当地 创伤后肺组织中产生LBP。 申请人假设， 由于局部或全身性LBP引起的局部肺部LBP产生增加 损伤可能使肺易于过度激活 炎症系统导致更大的组织破坏。 因此他 目的是确定调节肺细胞产生LBP的因素， 体外和体内，并确定局部的功能作用， 在ARDS中产生肺LBP对宿主对LPS的反应。 这项赠款建议由两个阶段组成。 第一阶段将包括 一个训练计划。 通过完成核心课程 以及经常与初级和中级导师进行教学， 候选人将获得强大的知识基础，以及获得技术 在分子生物学、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.小王， 在做研究计划的时候 第二阶段将侧重于 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。 目标是让候选人 发展独立的研究领域。 (End摘要）