IMMUNOMODULATION OF MACROPHAGES FOLLOWING TRAUMA

创伤后巨噬细胞的免疫调节

• 批准号: 3305344
• 负责人: Ronald Vitt Maier
• 金额: $ 15.03万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3305344
• 关键词: adult respiratory distress syndrome; alveolar macrophages; arachidonate; cell mediated cytotoxicity; diagnostic respiratory lavage; endotoxins; high performance liquid chromatography; human tissue; immunosuppression; inflammation; interferon gamma; laboratory rabbit; platelet activating factor; second messengers; trauma

Alterations in macrophage function following trauma contribute both to an enhanced susceptibility to infection and sepsis, and to the pathogenesis of multiple organ dysfunction and failure, particularly adult respiratory distress syndrome (ARDS). Paradoxically, both enhancement of the macrophage immunoinflammatory response to correct post injury defects and suppression of a systemic macrophage immunoinflammatory response, following severe trauma and sepsis, have been advocated as therapy in the critically ill patient at risk for ARDS. The long term goals of the present proposal are to further elucidate the cellular mechanisms involved in the immunomodulation of the alveolar macrophage following trauma in order to better define and direct therapy in the patient at risk. Hypothesis: Metabolism of the alveolar macrophage membrane lipid arachidonic acid produces extracellular mediators of inflammation and major intracellular second messengers that modulate the macrophage immunoinflammatory response. This intracellular system modulates the macrophage response to stimulation by 1.) inflammatory mediators, such as endotoxin and macrophage inflammatory peptides. 2.) immunomodulation by priming (gamma interferon and platelet activating factor) and suppressive (non-steroidal anti-inflammatory drugs and lazaroids) agents, and 3.) autocroid augmentation of macrophage function by macrophage generated inflammatory mediators (tumor necrosis factor and platelet activating factor). To test this hypothesis the following specific aims will be pursued: 1.) Arachidonic acid metabolites involved in signal transduction during inflammatory stimulation of the macrophage will be identified. 2.) The interaction of arachidonic acid metabolites with the phosphoinositol signal transduction pathway following macrophage stimulation will be investigated. 3.) The effect of immunomodulators on arachidonic acid metabolism and subsequent inflammatory mediator production by control and stimulated macrophages will be elucidated. 4.) Involvement of arachidonic acid in signal transduction of macrophage products functioning as autocrine self- augmenting mediators will be delineated. 5.) The effect of alterations in arachidonic acid metabolism on the pathophysiologic response to macrophage stimulation will be investigated in vivo in a rabbit model. 6.) Determination of similar cellular mechanisms in the human system will be studied utilizing circulating and bronchoalveolar lavage alveolar macrophages from normal volunteers and patients with ARDS. The elucidation of the cellular mechanisms involved in the up- and down- regulation of macrophage function in the post injury state and the subsequent response to inflammatory mediators will help direct the development of appropriate safe therapeutic interventions.

创伤后巨噬细胞功能的改变有助于 增强对感染和脓毒症的易感性， 多器官功能障碍和衰竭，尤其是成人呼吸道 窘迫综合征（ARDS）。 巧合的是， 巨噬细胞免疫炎症反应，以纠正损伤后缺陷， 抑制全身巨噬细胞免疫炎症反应， 严重创伤和脓毒症，已被提倡作为治疗的关键 有ARDS风险的病人。 本提案的长期目标 是为了进一步阐明参与的细胞机制， 创伤后肺泡巨噬细胞的免疫调节， 更好地定义和指导处于风险中的患者的治疗。 假设：肺泡巨噬细胞膜脂质代谢 花生四烯酸产生细胞外炎症介质， 调节巨噬细胞的细胞内第二信使 免疫炎症反应。 这种细胞内系统调节 巨噬细胞对刺激的反应1.）炎症介质，如 内毒素和巨噬细胞炎性肽。 2.）的情况。免疫调节 预处理（γ干扰素和血小板活化因子）和抑制 （非甾体抗炎药和拉扎类化合物）剂，和3.） 通过产生巨噬细胞自动增强巨噬细胞功能 炎症介质（肿瘤坏死因子和血小板活化 因素）。 为了检验这一假设，将追求以下具体目标：1）。 花生四烯酸代谢产物参与细胞周期信号转导 将鉴定巨噬细胞的炎性刺激。 2.）的情况。的 花生四烯酸代谢物与磷酸肌醇信号的相互作用 将研究巨噬细胞刺激后的转导途径。 3.）第三章免疫调节剂对花生四烯酸代谢的影响， 随后通过控制和刺激炎症介质产生 巨噬细胞将被阐明。 4.）花生四烯酸参与 巨噬细胞自分泌产物的信号转导 将划定扩大调解人。 5.）改变的影响 花生四烯酸代谢对巨噬细胞病理生理反应的影响 将在兔模型中体内研究刺激。 6.） 在人类系统中确定类似的细胞机制将是 研究利用循环和支气管肺泡灌洗肺泡 来自正常志愿者和患有ARDS的患者的巨噬细胞。 阐明了参与上下运动的细胞机制- 调节巨噬细胞在损伤后的功能， 随后对炎症介质的反应将有助于引导 制定适当的安全治疗干预措施。