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.

脓毒症和急性肺损伤的发生和维持依赖于多种不清楚的细胞和分子机制，这些机制可能是由于先天免疫应答过度或失败以及随后的细胞因子风暴而触发的。这些过程启动了一系列事件，这些事件显著促进了该综合征的病理学，包括生理学改变、免疫抑制和愈合受损。我们的初步数据支持这样的概念，即在实验性脓毒症期间，CCR 4和TARC/CCL 17（Thrombin and activated-regulated chemokine）对先天免疫应答和随后的下游免疫系统都具有新的生物学活性。基于这些数据，我们假设TARC：CCR 4的表达，通过结构驻留细胞， 白细胞分别是脓毒症反应的关键调节组分。这在机制上通过调节早期细胞因子表达、toll样受体（TLR）表达和白细胞活化和诱导而发生。在这些初始反应期间CCR 4和TARC的表达对随后的脓毒症病理学具有深远的影响。本研究的主要目的是：1）研究CCR 4和TARC在实验性脓毒症发生发展过程中的时程、表达量和细胞来源; 2）确定TARC和CCR 4表达通过影响特异性细胞因子表达谱、白细胞活化和诱导以及TLR表达来调节实验性脓毒症的机制; 3）评估常驻的、结构细胞衍生的TARC在调节实验性脓毒症中的先天性和随后的全身性炎症反应中的贡献;以及4）研究从患有临床定义的脓毒症的患者回收的细胞和流体的CCR 4和TARC的表达，并将表达模式与疾病的表征阶段相关联。在本申请中将使用许多重要工具来确定TARC：CCR 4诱导调节的细胞和分子机制，包括使用CCR 4-/-小鼠。脓毒症的实验系统和临床标本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免疫反应的重要机制贡献以及这些相互作用如何影响脓毒症的各个阶段。