DIVERSE EFFECTS OF CHEMOKINES IN SYSTEMIC INFLAMMATION

脓毒症和急性肺损伤的临床表现往往是 细胞相互作用的结果，导致过度炎症 介体表达、白细胞活化和组织损伤。尽管 微生物抗生素、生物技术和 重症监护管理、败血症相关的发病率和死亡率 在过去的30年里，疾病并没有发生重大变化。临床上， 可用于治疗这些疾病的治疗选择是有限的， 这反映了对这些机制的理解不足， 是这些症状的基础微生物和随后的宿主 细胞因子应答已被确定为主要的致病因素， 导致多器官损伤的发生和持续。 最近的数据支持细胞因子和趋化因子具有 全身炎症发展过程中的多种活动， 急性肺损伤因此，我们的研究旨在了解 负责调节趋化因子的表达和活性 在急性全身性炎症的演变过程中， 本申请的长期目标。我们假设 细胞因子网络xp导致趋化因子MIP-2和 MCP-1可分别发挥炎症或免疫调节作用， 在全身性炎症发展过程中的作用。拟议 研究将集中在以下几个问题：1）什么是贡献 MCP-1和MIP-2对败血症和急性肺损伤病理的影响？ 2)MCP-1发挥作用的细胞和分子机制是什么？ 免疫调节对系统性免疫缺陷的影响 炎症和急性肺损伤3)免疫调节剂是如何 细胞因子白细胞介素-10（IL-10）调节MIP-2的表达 MCP-1？4)MCP-1和MCP-2的脓毒症反应的演变有何不同？ 1和CCR 2b（MCP-1受体）基因敲除小鼠相比，野生型小鼠？ 5)MCP-1的表达在人类脓毒症的发展过程中是否 与临床疾病相关吗在本节中，内毒素血症和盲肠 结扎/穿刺诱导的败血症将用于评估 MIP-2和MCP-1对器官损伤进展的贡献。机制 MIP-2和MCP-1的调节将通过生物测定，ELISA， 免疫组织化学、北方印迹或RT-PCR、原位杂交， mRNA稳定性和核连续分析。本研究中设计的研究 该提案将证明趋化因子MIP-2和MCP-1发挥不同的作用， 在介导多器官损伤发病机制中的作用。

The clinical manifestation of sepsis and acute lung injury is often the consequence of cell interactions, resulting in excessive inflammatory mediator expression, leukocyte activation, and tissue injury. In spite of advances in the development of microbial antibiotics, biotechnology, and critical care management, morbidity and mortality due to sepsis related disorders has not significantly changed in the past 30 years. Clinically, the therapeutic options available to treat these disorders are limited, which reflects an insufficient understanding of the mechanisms that underlie these symptoms. Microbial organisms and the subsequent host's cytokine response have been identified as major etiologic factors that contribute to the initiation and perpetuation of multi-organ injury. Recent data supports the concept that cytokines and chemokines possess diverse activities during the development of systemic inflammation and acute lung injury. Thus, our studies directed at understanding mechanisms responsible for regulating the expression and activities of chemokines during the evolution of acute systemic inflammation are the broad, long- term objectives of this application. We hypothesize that established cytokine networksxp result in the expression of the chemokines MIP-2 and MCP-1 which can respectively exert inflammatory or immunoregulatory effects during the evolution of systemic inflammation. The proposed studies will focus on the following questions: 1) What is the contribution of MCP-1 and MIP-2 to the pathology of septicemia and acute lung injury? 2) What is the cellular and molecular mechanism whereby MCP-1 exerts an immunoregulatory effect on the evolution on the evolution of systemic inflammation and acute lung injury? 3) How does the immunomodulatory cytokine interleukin-10 (IL-10) diversely regulate the expression of MIP-2 and MCP-1? 4) How does the evolution of the septic response differ in MCP- 1 and CCR2b (MCP-1 receptor) knockout mice, as compared to wild-type mice? 5) Does the expression of MCP-1 during the development of sepsis in humans correlate with clinical disease? In this section, endotoxemia and cecal ligation/puncture-induced septicemia will be utilized to assess the contribution of MIP-2 and MCP-1 to evolving organ injury. Mechanisms for the regulation of MIP-2 and MCP-1 will be studied via bioassays, ELISAs, immuno-histochemistry, Northern blot or RT-PCR, in situ hybridization, mRNA stability and nuclear run-on analyses. The studies designed in this proposal will demonstrate that the chemokines MIP-2 and MCP-1 play diverse roles in mediating the pathogenesis of multi-organ injury.