ROLE OF CYTOKINE METABOLISM IN OZONE IMMUNOTOXICITY

细胞因子代谢在臭氧免疫毒性中的作用

• 批准号: 2691432
• 负责人: Richard B Schlesinger
• 金额: $ 26.52万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2691432
• 关键词: Listeria; air pollution; alveolar macrophages; bactericidal immunity; cellular immunity; cytokine; immunotoxicity; interferons; laboratory rat; leukocyte activation /transformation; metabolism; ozone; protein biosynthesis; respiratory infections

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.

描述：（改编自研究者摘要）肺是一个主要的 将环境污染物引入体内的途径。然而，在这方面， 肺内的局部免疫细胞群可能在 免疫能力并且可能是吸入污染物毒性的目标。 本研究的目的是确定臭氧（O3）的影响 肺巨噬细胞（PAM）活性的关键方面， 诱导细胞介导的免疫（CMI）反应。这关系到PAM 与细胞因子的相互作用，主要是干扰素（IFN γ和 IFN α），以及与早期和晚期 PAM活化的阶段，在CMI反应过程中， 细菌病原体，单核细胞增生李斯特菌。使用的动物模型是 将采用Fisher 344大鼠以及体内和体外暴露方案。 现有的数据库（虽然稀少）表明，O3暴露可以改变 肺部的抗菌防御，一般来说，以及关于李斯特菌， 具体地，以及PAM膜动力学和各种功能 受体介导的过程。然而，对O3影响的理解 在暴露的PAM中缺乏对精氨酸介导的过程的影响。的假设 本文提出的是，O3诱导的PAM能力的改变， 参与CMI反应的人在机械上与 这些细胞形成并随后与免疫调节因子相互作用的能力 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， O3对肺T淋巴细胞的影响，肺T淋巴细胞是肺中PAM引发的关键细胞， 还将对CMI响应的后期阶段进行审查，以确定可能的变化 在细胞因子形成/结合中。利用一个成熟的李斯特菌宿主 阻力模型系统，以检查CMI功能，O3暴露大鼠将 分析了它们对亚致死浓度的 李斯特菌挑战。O3诱导的PAM-IFN改变的关键作用 减少CMI功能的相互作用将通过检查空气- 暴露的大鼠在确定的抗病毒治疗阶段表现出免疫功能不全， 反应此外，PAM/T-细胞在早期和晚期的细胞因子释放 将评估抗性的阶段以及细胞因子结合的方面。 还将研究PAM的结合后IFN代谢，以澄清哪种IFN 处理步骤可能主要受O3影响。为了测量 O3诱导PAM细胞因子/IFN代谢改变的最终意义 IFN/干扰素诱导的结构/功能终点的变化也将被 考察细胞因子形成、细胞因子/IFN通过PAM/T- 细胞，然后将检查诱导功能终点的变化 在O3暴露后李斯特菌耐药性总体变化的背景下， exposure.