Dynamic Effects of Chemokines on Systematic inflammation

趋化因子对系统炎症的动态影响

• 批准号: 7108652
• 负责人: Steven Lynn Kunkel
• 金额: $ 26.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7108652
• 关键词: cellular pathology; chemokine; cytokine receptors; human subject; immunity; immunocytochemistry; in situ hybridization; inflammation; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; lung injury; molecular pathology; pathologic process; polymerase chain reaction; septicemia; time resolved data; toll like receptor; western blottings

The initation and maintenance of sepsis and acute lung injury are dependent upon a diverse collection of ill-understood cellular and molecular mechanisms, which are likely triggered as a result of an overwhelmed or failed innate immune response and a subsequent cytokine storm. These processes set in motion a cascade of events which significantly contribute to the pathology of this syndrome, including altered physiology, immunosuppression, and impaired healing. Our preliminary data support the concept that during experimental sepsis CCR4 andTARC/CCL17(Thymus and activated-regulated chemokine), possess novel biological activities on both the innate immune response and subsequent down-stream immune systems. Based on these data, we hypothesize that TARC:CCR4 expression, by structural resident cells and leukocytes, respectively, are key regulatory components of the septic response. This mechanistically occurs by modulating early cytokine expression, toll-like receptor (TLR) expression and leukocyte activation and elicitation. The expression of CCR4 and TARC during these initial responses have profound effects on subsequent sepsis pathology. Our studies will focus on the following Specific Aims: 1) to investigate the time-course, magnitude of expression, and cellular sources of CCR4 and TARC during the evolution of experimental sepsis; 2) to determine the mechanistic role by which TARC and CCR4 expression can regulate the progression of experimental sepsis by influencing specific cytokine expression profiles, leukocyte activation and elicitation, and TLR expression; 3) to assess the contribution of resident, structural cell-derived TARC in regulating the innate and subsequent systemic inflammatory response in experimental sepsis; and 4) to investigate the expression of CCR4 and TARC by cells and fluids recovered from patients with clinically defined sepsis and correlate the expression patterns with characterized phases of disease. A number of important tools will be used in this application to determine the cellular and molecular mechanism(s) of TARC:CCR4 induced regulation, including the use of CCR4-/- mice. Both experimental systems of sepsis and clinical specimens will be used to achieve our long term objective, which is to demonstrate the important mechanistic contribution of chemokine receptors and their ligands to the evolving immune response and how these interactions impact on the various phases of sepsis.

败血症和急性肺损伤的造成和维持取决于多样化的细胞和分子机制的收集，这些机制可能是由于不知所措或失败的先天免疫反应以及随后的细胞因子风暴而触发的。这些过程使一系列级联的事件造就了该综合征的病理，包括改变生理学，免疫抑制和愈合受损。我们的初步数据支持以下概念：在实验性败血症CCR4和TARC/CCL17（胸腺和激活调节的趋化因子）期间，在先天免疫反应和随后的下游免疫系统上具有新颖的生物学活性。基于这些数据，我们假设TARC：CCR4表达，结构性居民细胞和 白细胞分别是化粪池反应的关键调节成分。从机械上讲，通过调节早期细胞因子表达，Toll样受体（TLR）表达和白细胞激活和诱导来发生。在这些初始反应中，CCR4和TARC的表达对随后的败血症病理具有深远的影响。我们的研究将重点介绍以下特定目的：1）研究实验性败血症的演变过程中CCR4和TARC的时间顺序，表达的大小以及细胞来源； 2）确定TARC和CCR4表达可以通过影响特异性细胞因子表达谱，白细胞激活和诱导以及TLR表达来调节实验性败血症的进展的机械作用； 3）评估居民，结构细胞衍生的TARC在调节实验性败血症中先天和随后的全身性炎症反应方面的贡献； 4）研究从临床定义的败血症患者中回收的细胞和液体来研究CCR4和TARC的表达，并将表达模式与疾病的特征阶段相关联。在本应用中将使用许多重要的工具来确定TARC：CCR4诱导调节的细胞和分子机制，包括使用CCR4 - / - 小鼠。败血症和临床标本的实验系统都将用于实现我们的长期目标，即证明趋化因子受体及其配体对不断发展的免疫反应的重要机械贡献以及这些相互作用如何影响败血症的各个阶段。