GRANULOMATOUS LUNG INFLAMMATION

慢性肺部炎症的发生和维持是由于 激发剂，炎症介质， 白细胞和肺的结构细胞。与病因无关 肉芽肿性肺病通常具有特异性病理反应， 其特征在于激发和激活各种 白细胞群来定义肺的区域。具体目标 本节的目的是确定 其中1型或2型的表达和调节 细胞因子表型以下假设将得到解决，以支持 目的：募集和激活各种白细胞 特异性趋化因子支持的肉芽肿性病变 受体。当白细胞运输到肉芽肿性炎症部位时， 它们受到细胞因子和其他介体系统的影响， 趋化因子及其受体的表达。的表达 趋化因子受体在“采样”环境中是重要的， 趋化因子家族成员是特异性白细胞活化的关键 活动和继续招聘。拟议的研究将集中在 以下问题：1）表达的机制是什么？ CC 1型（Th 1）或2型（Th 2）细胞因子）？2)什么变化， 在CCR 1，CCR 2，CCR 3， 还是CCR 5基因敲除小鼠3)什么是趋化因子/趋化因子受体- 正常肺成纤维细胞或成纤维细胞 从1型或2型肉芽肿中分离的细胞可以调节白细胞 在肉芽肿发展过程中的反应性？（4）细胞的作用是什么？ 决定趋化因子和趋化因子受体的细胞间相互作用 在肉芽肿发展过程中的表达？趋化因子的表达和 趋化因子和趋化因子受体及其调节机制 将使用充分表征的肺肿瘤模型来研究表达 炎症在正常和基因敲除小鼠通过生物测定，ELISA，免疫， 组织化学、北方印迹或RT-PCR和原位杂交 分析。这项研究计划将表明趋化因子 它们的受体在启动和维持 肺部炎症，并将作为治疗的良好目标， 干预

The initiation and maintenance of chronic pulmonary inflammation is due to a dynamic interaction between an inciting agent, inflammatory mediators, leukocytes, and structural cells of the lung. Independent of the etiology granulomatous lung disease usually possess specific pathologic responses, which are characterized by th elicitation and activation of various leukocyte populations to define areas of the lung. The specific objective for this section of the Program Project is to determine the mechanisms whereby the expression and regulation of either a type 1 or type 2 cytokine phenotype. The following hypothesis will be addressed to support this objective: Recruitment and activation of various leukocyte populations to granulomatous lesions supported by specific chemokine receptors. As leukocytes traffick to sites of granulomatous inflammation, they are influenced by cytokines and other mediator systems, which dictate the expression of chemokines and chemokine receptors. The expression of chemokine receptors are important in "sampling" the environment for chemokine family members which are key for specific leukocyte activation events and continued recruitment. The proposed studies will focus on the following questions: 1) What are the mechanisms involved in the expression of CC type 1 (Th1) or type 2 (Th2) cytokines)? 2) what alterations in the normal development of these lung granulomas are found in CCR1, CCR2, CCR3, or CCR5 knockout mice? 3) What are the chemokine/chemokine receptor- dependent mechanisms by which normal lung fibroblasts or fibroblasts isolated from either type 1 or type 2 granulomas can regulate leukocyte reactivity during granuloma development? and 4) What is the role of cell- to-cell interactions which dictate chemokine and chemokine receptor expression during granuloma development? The expression of chemokines and chemokines and chemokine receptors and mechanisms that regulate their expression will be studied using well characterized models of lung inflammation in normal and knockout mice via bioassays, ELISAs, immuno- histochemistry, Northern blot or RT-PCR, and in situ hybridization analyses. The studies designed in this proposal will show that chemokines and their receptors play novel roles in the initiation and maintenance of pulmonary inflammation and will serve as excellent targets for therapeutic intervention.