IMMUNOMODULATION OF MACROPHAGES FOLLOWING TRAUMA

创伤仍然是美国人死亡和残疾的主要原因，而且 1至45岁年龄组死亡的头号原因 以及总体而言生产年限的损失。反过来，主要原因是 创伤后晚期死亡的原因是器官功能障碍，包括急性呼吸窘迫综合征， 导致多器官衰竭综合征(MOF)和死亡。初级阶段 ARDS和MOFS的病因是临床上的“脓毒症综合征”或全身性 导致播散性组织损伤的炎症反应综合征(SIRS) 和器官功能障碍。长寿的，高度多样化的组织固定 巨噬细胞是正常细胞和正常细胞的重要中枢协调者 异常的宿主免疫炎症反应，并对 “恶性全身性炎症”的诱发和持续 巨噬细胞被“启动”并被激活。 炎性环境中的多种刺激因素。直到现在才有治疗效果 方法侧重于控制或抑制单组分的 整体的炎症反应。然而，由于炎症 响应充满了冗余和反馈放大 机制，将我们的重点扩大到更广泛的控制是很有吸引力的 炎症性损伤。为了实现这一目标，我们建议更好地界定 巨噬细胞活化的细胞机制及其治疗研究进展 基于对过度侵袭性巨噬细胞的调节的干预 免疫炎症反应。 假设：异常的巨噬细胞炎症反应是可以调节的 通过操纵细胞信号转导机制来控制 炎症介质基因。这些巨噬细胞的阐明和调控 细胞机制将允许开发安全的治疗方法 有可能预防ARDS、多器官功能衰竭和死亡的干预措施。 为了验证这一假设，我们将追求以下具体目标：L。 描绘并确认巨噬细胞-内毒素信号的建议成分 转导途径，2.)阐明“启动”的分子机制 (重新编程)和/或巨噬细胞反应的自分泌增强， 3.)确定选择性修改绑定的可行性和效果 刺激性(CD14)和非刺激性(清道夫， 酰基-低密度脂蛋白)受体。研究磷脂的贡献 代谢到巨噬细胞活化，5.)评价钙调素 (CA-CaM)途径参与巨噬细胞活化；测试……的能力 抗氧化剂改变炎症刺激信号转导 巨噬细胞。 巨噬细胞应答的调控机制研究进展 炎症刺激将使治疗干预措施的发展成为可能 有益地调节过多的巨噬细胞和随后的宿主 自动破坏性反应。

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.