Dynamic Effects of Chemokines on Systematic inflammation

脓毒症和急性肺损伤的发生和维持依赖于各种不同的细胞和分子机制，这些机制很可能是由不堪重负或失败的先天免疫反应和随后的细胞因子风暴引发的。这些过程启动了一系列事件，这些事件对这种综合征的病理有重要贡献，包括生理改变、免疫抑制和愈合障碍。我们的初步数据支持这一概念，即在实验性脓毒症期间，CCR4和TARC/CCL17(胸腺和激活的调节趋化因子)在先天免疫反应和随后的下游免疫系统中都具有新的生物活性。基于这些数据，我们假设TARC：CCR4的表达，通过结构驻留细胞和 白细胞分别是败血症反应的关键调节成分。其机制是通过调节早期细胞因子的表达、Toll样受体(TLR)的表达以及白细胞的激活和激发来实现的。CCR4和TARC在这些初始反应中的表达对随后的脓毒症病理有深远的影响。我们的研究将集中于以下具体目标：1)探讨CCR4和TARC在实验性脓毒症发生发展过程中的时程、表达幅度和细胞来源；2)确定TARC和CCR4的表达通过影响特定的细胞因子表达谱、白细胞的激活和诱导以及TLR的表达而调节实验性脓毒症进展的机制；3)评估驻留的结构细胞来源的TARC在调节实验性脓毒症的先天和随后的全身炎症反应中的作用；4)研究CCR4和TARC在临床明确的脓毒症患者的细胞和体液中的表达，并与疾病的不同阶段相关联。在这一应用中，将使用一些重要的工具来确定TARC：CCR4诱导的调节的细胞和分子机制(S)，包括使用CCR4-/-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在进化的免疫反应中的重要机制贡献，以及这些相互作用如何影响脓毒症的不同阶段。

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.