IMMUNODULATION OF MACROPHAGE FOLLOWING TRAUMA

创伤仍然是美国死亡和残疾的主要原因， 1至45岁年龄组的头号死亡原因 以及生产性寿命的总体损失。反过来，主要原因 创伤后晚期死亡的原因是器官功能障碍，包括ARDS， 导致多器官衰竭综合征（MOFS）和死亡。主 ARDS和MOFS的病因是临床“脓毒症综合征”或全身性 炎症反应综合征（SIRS）导致播散性组织损伤 和器官功能障碍寿命长，高度多样化的组织固定 巨噬细胞是一个重要的中央协调员， 异常的宿主免疫炎症反应，并负责 “恶性全身性炎症”的诱导和持续 在MOFS中看到的“响应”。巨噬细胞是“启动”和激活的， 炎症环境中的多种刺激。到目前为止治疗 方法集中在控制或抑制单组分的 整体炎症反应。然而，由于炎症 反应是如此充满了冗余和反馈放大 机制，它呼吁扩大我们的重点，以更普遍的控制 炎性损伤。为了实现这一目标，我们建议更好地定义 巨噬细胞活化的细胞机制和开发治疗 基于调节过度侵袭性巨噬细胞的干预措施 免疫炎症反应。 假设：异常的巨噬细胞炎症反应可以被调节 通过操纵细胞信号转导机制， 炎症介质基因。阐明和控制这些巨噬细胞 细胞机制将允许开发安全的治疗方法， 可能预防ARDS、MOFS和死亡的干预措施。 为了检验这一假设，将追求以下具体目标： 描绘并确认巨噬细胞-LPS信号的拟议成分 转导途径，2.）阐明“引发”的分子机制 （重编程）和/或巨噬细胞应答的自分泌增强， 3.）第三章确定选择性修改绑定的可行性和效果 以及刺激性（CD 14）和非刺激性（清除剂， 酰基-LDL）受体4.）研究磷脂的贡献 代谢至巨噬细胞活化，5.）评价钙-钙调素 （Ca-CaM）途径，和6.）测试的能力 抗氧化剂改变炎症刺激信号转导， 巨噬细胞 阐明控制巨噬细胞对 炎症刺激将允许开发治疗干预 以有益地调节过量的巨噬细胞和随后的宿主 自我毁灭反应。

Trauma remains a major cause of death and disability in America, and, the number one cause of mortality in the one to forty-five year old age group and for loss of productive years of life overall. In turn, the major cause of late death following trauma is organ dysfunction, including ARDS, leading to multiple organ failure syndrome (MOFS) and death. The primary etiology of ARDS and MOFS is the clinical "sepsis syndrome" or systemic inflammatory response syndrome (SIRS) causing disseminated tissue injury and organ dysfunction. The long lived, highly diverse tissue-fixed macrophage is a crucial central coordinator of both the normal and aberrant host immunoinflammatory response and is responsible for the induction and persistence of the "malignant systemic inflammatory response" seen in MOFS. The macrophage is both "primed" and activated by a multitude of stimuli in the inflammatory milieu. Until now therapeutic approaches have focused on control or inhibition of single components of the overall inflammatory response. However, since the inflammatory response is so replete with redundance and feedback amplification mechanisms, it is appealing to broaden our focus to more generally control the inflammatory injury. To achieve this goal, we propose to better define the cellular mechanisms of macrophage activation and develop therapeutic interventions based on modulation of the over-aggressive macrophage immunoinflammatory response. Hypothesis: The aberrant macrophage inflammatory response can be modulated by manipulation of cellular signal transduction mechanisms that control inflammatory mediator genes. Elucidation and control of these macrophage cellular mechanisms will permit development of safe therapeutic interventions to potentially prevent ARDS, MOFS and death. To test this hypothesis the following specific aims will be pursued: l.) delineate and confirm the proposed components of the macrophage-LPS signal transduction pathway, 2.) elucidate the molecular mechanisms of "priming" (reprogramming) and/or autocrine augmentation of the macrophage response, 3.) determine the feasibility and effects of selectively modifying binding and uptake of LPS by stimulatory (CD14) and non-stimulatory (scavenger, acyl-LDL) receptors 4.) investigate the contribution of phospholipid metabolism to macrophage activation, 5.) evaluate the calcium-calmodulin (Ca-CaM) pathway in macrophage activation, and 6.) test the ability of antioxidants to alter inflammatory stimulus-signal transduction in the macrophage. Elucidation of the mechanisms controlling the macrophage response to inflammatory stimuli will permit development of therapeutic interventions to beneficially modulate the excessive macrophage and the subsequent host auto-destructive responses.