ROLE OF CYTOKINE METABOLISM IN OZONE IMMUNOTOXICITY

描述：(改编自《调查者摘要》)肺是一种主要的 环境污染物进入体内的途径。然而， 肺内的局部免疫细胞群可能在 它具有免疫活性，很可能是吸入污染物的毒性目标。 这项研究的目的是确定臭氧(03)的影响。 暴露于肺巨噬细胞(PAM)活动的关键方面 在诱导细胞介导的免疫(CMI)反应中。这与PAM有关 与细胞因子的相互作用，主要是干扰素(干扰素和 IFNAlpha)，以及与早期和晚期相关的事件的启动 PAM在CMI反应过程中的激活阶段 细菌病原体，单核细胞增多性李斯特氏菌。要使用的动物模型是 Fisher 344大鼠，将采用体内和体外暴露方案。 现有的数据库虽然稀少，但表明接触臭氧会改变 肺部抗菌素防御，总的来说，关于李斯特菌， 具体地说，以及PAM膜的动力学和各种官能化 受体介导的过程。然而，理解臭氧的影响 在暴露的PAM中，缺乏细胞因子介导的过程。假说 在这里提出的是，臭氧诱导PAM的能力的变化 参与CMI响应在机械上与 这些细胞形成并随后与免疫调节相互作用的能力 细胞因子，主要是干扰素。为了确保PAM是 在免疫功能改变的过程中受到影响的原始细胞， 臭氧对小鼠肺T淋巴细胞的影响 还将检查CMI响应的后期阶段，以寻找可能的变化 在细胞因子的形成/结合中。使用著名的李斯特氏菌宿主 阻力模型系统检测CMI功能，将大鼠暴露于臭氧中 分析了它们对亚致死性肺炎的抵抗力和肺清除 李斯特菌挑战赛。臭氧诱导的PAM-干扰素改变的关键作用 降低的CMI功能中的相互作用将通过检查空气- 暴露的大鼠在抗李斯特菌药物的特定阶段出现免疫功能丧失 回应。此外，PAM/T细胞在早期和晚期释放细胞因子 将评估耐药阶段，以及细胞因子结合的各个方面。 PAM结合后的干扰素代谢也将被研究，以澄清哪些干扰素 加工步骤可能主要受臭氧的影响。为了测量 臭氧诱导PAM细胞因子/干扰素代谢改变的最终意义 干扰素/细胞因子诱导的结构/功能终点的变化也将是 检查过了。PAM/T细胞在细胞因子形成、细胞因子/干扰素处理等方面的变化 细胞，然后将检查可诱导功能终点的变化 在臭氧过后李斯特氏菌耐药性的总体变化背景下 曝光。

DESCRIPTION: (Adapted from the Investigator's Abstract) The lungs are a major route for the introduction of environmental pollutants into the body. However, local immune cell populations within the lungs may play a pivotal role in immunocompetence and are likely targets for toxicity from inhaled pollutants. The objective of this study is to determine the effect from ozone (O3) exposure on critical aspects of pulmonary macrophage (PAM) activity involved in induction of the cell-mediated immune (CMI) response. This concerns PAM interactions with cytokines, primarily the interferons (IFNgamma and IFNalpha), and the initiation of events associated with the early and late stages of PAM activation during the course of a CMI reaction against a bacterial pathogen, Listeria monocytogenes. The animal model to be used is the Fisher 344 rat, and in vivo and in vitro exposure regimens will be employed. The existing, although sparse, database suggest that O3 exposure can alter pulmonary antimicrobial defense, in general, and with regards to Listeria, specifically, as well as PAM membrane dynamics and various functional receptor-mediated processes. However, an understanding of the effects of O3 upon cytokine-mediated processes in exposed PAM is lacking. The hypothesis proposed herein is that O3-induced alterations in the ability of PAM to participate in the CMI response are mechanistically linked to changes in the capacity of these cells to form and later interact with immunoregulatory cytokines, primarily the interferons. To be certain that the PAM are the primary cells affected during the course of altered immune function, the effects of O3 upon lung T-lymphocytes, cells critical to PAM priming in the later stages of the CMI response, will also be examined for possible changes in cytokine formation/binding. Using a well-established Listeria host resistance model system to examine CMI function, O3-exposed rats will be analyzed for their resistance to and pulmonary clearance of a sublethal Listeria challenge. The critical role of O3-induced altered PAM-IFN interactions in reduced CMI function will be illustrated by examining air- exposed rats rendered immunincompetent at a defined stage of the antilisterial response. In addition, cytokine release by PAM/T-cells at the early and late stages of resistance will be assessed, as will aspects of cytokine binding. Post-binding IFN metabolism by PAM will also be studied to clarify which IFN processing step might be predominantly affected by O3. In order to measure the ultimate implication from altered PAM cytokine/IFN metabolism, O3-induced changes in IFN/cytokine-inducible structural/functional endpoints will also be examined. All changes in cytokine formation, cytokine/IFN processing by PAM/T- cells, and changes in the inducible functional endpoints will then be examined in the context of the overall changes in Listeria resistance following O3 exposure.