DIVERSE EFFECTS OF CHEMOKINES IN SYSTEMIC INFLAMMATION

脓毒症和急性肺损伤的临床表现通常是 细胞相互作用的结果，导致过度炎症 中介物表达、白细胞活化和组织损伤。尽管 微生物抗生素、生物技术和生物工程的发展进展 重症监护管理、脓毒症相关的发病率和死亡率 在过去的30年里，疾病并没有明显的变化。在临床上， 可用于治疗这些疾病的治疗选择有限， 这反映了对这些机制的了解不足 这是这些症状的基础。微生物和后续寄主的 细胞因子反应已被确定为主要的致病因素 有助于多器官损伤的开始和持续。 最近的数据支持细胞因子和趋化因子具有的概念 全身炎症发生和发展过程中的各种活动 急性肺损伤。因此，我们的研究旨在了解机制 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，广泛、长期- 本申请的期限目标。我们假设已经建立了 细胞因子网络导致趋化因子MIP-2和 单核细胞趋化蛋白-1可分别发挥炎症或免疫调节作用 在全身炎症演变过程中的作用。建议数 研究将集中在以下几个问题上：1)贡献是什么 MCP-1和MIP-2在败血症和急性肺损伤病理中的作用 2)MCP-1发挥作用的细胞和分子机制是什么？ 免疫调节在系统进化中的作用 炎症和急性肺损伤？3)免疫调节是如何 细胞因子IL-10对MIP-2表达的多种调节作用 和MCP-1？4)败血症反应的进化在MCP- 1和CCR2b(MCP-1受体)基因敲除小鼠与野生型小鼠相比？ 5)单核细胞趋化蛋白-1在人类脓毒症发病过程中的表达 与临床疾病有关联吗？在本节中，内毒素血症和盲肠 结扎/穿刺性败血症将被用来评估 MIP-2和MCP-1在进行性器官损伤中的作用实现以下目标的机制 MIP-2和MCP-1的调控将通过生物检测、ELISA、 免疫组织化学、Northern印迹或RT-PCR、原位杂交、 信使核糖核酸的稳定性和核连续分析。在这里设计的研究 提案将证明趋化因子MIP-2和MCP-1发挥不同的作用 在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.