IMMUNOMODULATION OF MACROPHAGES FOLLOWING TRAUMA

创伤后巨噬细胞的免疫调节

• 批准号: 6749535
• 负责人: Ronald Vitt Maier
• 金额: $ 32.64万
• 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 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6749535
• 关键词: adult respiratory distress syndrome; alveolar macrophages; biological signal transduction; bronchoscopy; cell line; clinical research; cytokine receptors; gene expression; human subject; immunoprecipitation; inflammation; interleukin 1; interleukin 10; interleukin 8; laboratory rabbit; leukocyte activation /transformation; lipopolysaccharides; mitogen activated protein kinase; patient oriented research; phosphoprotein phosphatase; receptor expression; tissue /cell culture; toll like receptor; trauma; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): The major cause of delayed deaths following severe trauma is multiple organ dysfunction syndrome (MODS), including acute respiratory distress syndrome (ARDS). The underlying etiology of MODS is Ithought to be an excessive systemic inflammatory response syndrome (SIRS) causing disseminated tissue injury. The monocyte/macrophage (MPh) is a central coordinator of both the normal and aberrant host immuno-inflammatory response and is thought to be crucial for the induction and persistence of this "malignant systemic inflammatory response." The MPh is either "primed" or immunosuppressed, dependent upon the phase of injury recovery, and produces a dysfunctional innate immune response to the multiple stimuli in the inflammatory milieu. Previous therapeutic approaches have focused on inhibition of single mediators of the host response. However, since the inflammatory response is replete with redundance and feedback amplification loops, it is theoretically more appealing to broaden our focus to more globally control the inflammatory injury and, thus, improve patient outcome. Hypothesis: the aberrant dysfunctional Mo immuno-inflammatory response can be modulated by manipulation of the cellular signal transduction mechanisms that control the expression of multiple inflammatory mediator genes. Elucidation and control of these MPh cellular mechanisms will target the potential development of safe, therapeutic interventions to potentially prevent ARDS, MODS and death in these critically ill patients. The following specific aims will be pursued: 1) delineate selective activation patterns of intracellular signal transduction pathways (MAPK family) to varying stimuli and cell specificity; 2) investigate signal initiation processes (including TLR-4, IRAK and PYK-2) and the need for an intact cytoskeleton; 3) identify potential response regulators, including CaMK, PKA and PKC; 4) elucidate the endogenous counter-regulatory mechanisms, including kinase-specific phosphatases; and 5) correlate signal activation pathways with subsequent genomic and proteomic response profiles.

描述（由申请人提供）： 严重创伤后迟发性死亡的主要原因是多器官功能障碍综合征（MODS），包括急性呼吸窘迫综合征（ARDS）。MODS的潜在病因被认为是一种过度的全身炎症反应综合征（SIRS）引起的播散性组织损伤。单核细胞/巨噬细胞（MPh）是正常和异常宿主免疫炎症反应的中心协调者，被认为是诱导和持续这种“恶性全身炎症反应”的关键。MPh是“引发”或免疫抑制的，取决于损伤恢复的阶段，并对炎症环境中的多种刺激产生功能失调的先天免疫应答。先前的治疗方法集中于抑制宿主反应的单一介质。然而，由于炎症反应充满了冗余和反馈放大回路，理论上更有吸引力的是扩大我们的关注点，以更全面地控制炎症损伤，从而改善患者的预后。假设：异常的功能障碍性Mo免疫炎症反应可以通过控制多种炎症介质基因表达的细胞信号转导机制的操纵来调节。这些MPh细胞机制的阐明和控制将针对安全的治疗干预的潜在发展，以潜在地预防这些危重患者的ARDS、MODS和死亡。本研究的主要目的是：1）阐明细胞内信号转导通路的选择性激活模式（MAPK家族）对不同刺激和细胞特异性的反应; 2）研究信号起始过程（包括TLR-4、IRAK和PYK-2）和对完整细胞骨架的需要; 3）鉴定潜在的反应调节剂，包括CaMK、PKA和PKC; 4）阐明内源性反调节机制，包括激酶特异性磷酸酶;和5）将信号激活途径与随后的基因组和蛋白质组反应谱相关联。