OPIATE MODULATION OF PULMONARY INFECTION

阿片类药物调节肺部感染

• 批准号: 2749079
• 负责人: THOMAS William MOLITOR
• 金额: $ 28.02万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749079
• 关键词: Bacillus Calmette Guerin vaccine; Mycobacterium bovis; bacterial cytopathogenic effect; bactericidal immunity; cellular immunity; cytokine; cytotoxic T lymphocyte; disease /disorder model; drug abuse; histopathology; immunocytochemistry; in situ hybridization; microglia; monocyte; morphine; nervous system infection; newborn animals; northern blottings; pneumonia; swine; tuberculosis

DESCRIPTION: (Applicant's Abstract) Globally, tuberculosis (TB) is the leading cause of death from infectious disease. When infection disseminates from the lungs to the central nervous system (CNS), the mortality of TB, when untreated, approaches 100%. Medical conditions that impair cell-mediated immunity, including HIV infection, foster the development of disseminated TB, whereas immunization with Mycobacterium bovis BCG vaccine confers protection against dissemination to the CNS. Recent studies indicate that immunity against TB is mediated by T lymphocyte subpopulations, which inhibit the growth of the tubercle bacillus within tissue macrophages. Because of morphine's effects on cell-mediated immunity, opiate abuse has been suspected of increasing the susceptibility to TB. However, experimental studies examining whether morphine promotes the pathogenicity of either of the mycobacterial species that cause TB (M. tuberculosis or M. bovis) are lacking. The central hypothesis to be tested in the research proposed is that morphine promotes the immunopathogenesis of disseminated M. bovis infection. To test the hypothesis, both in vitro and in vivo experiments will be conducted using a swine model of disseminated TB. The specific aims are to: (1) characterize the effect of morphine in vitro on M. bovis infection of microglial cells and monocytes; (2) determine the effect of morphine dependence of non-immunized swine on the growth of M. bovis in microglial cells in vivo, and correlate these histopathologic findings with the clinical course of CNS infection; (3) characterize the effect of morphine in vitro on the anti-M. bovis activity of T lymphocyte subsets obtained from BCG-immunized swine; and (4) determine the effect of morphine in BCG-immunized swine on vaccine protection against CNS TB. Primary cultures of microglial cells and monocytes will be obtained from neonatal pigs. In addition to studying the effects of morphine in vitro on the interaction between M. bovis and these cell populations, the influence of morphine on the anti-mycobacterial activity of T lymphocyte subsets from immunized animals will be determined. A newly developed in vivo swine model of disseminated M. bovis infection will be used. We postulate that morphine administered to non-immunized swine will promote the development of CNS TB, whereas morphine administered to BCG-immunized swine will be associated with loss of the vaccine's protective effect against CNS TB. These studies will, for the first time, provide experimental evidence relevant to the clinical concern that opiate abuse fosters the pathogenesis of TB.

描述：（申请人摘要） 在全球范围内，结核病 (TB) 是传染性死亡的主要原因 疾病。 当感染从肺部传播到中枢神经时 系统（中枢神经系统），如果不治疗，结核病的死亡率接近 100%。 医疗的 损害细胞介导的免疫的疾病，包括艾滋病毒感染， 促进播散性结核病的发展，而免疫接种 牛分枝杆菌 BCG 疫苗可防止传播 中枢神经系统。 最近的研究表明，针对结核病的免疫力是由 T 介导的。 淋巴细胞亚群，抑制结核杆菌的生长 组织巨噬细胞内。 由于吗啡对细胞介导的作用 免疫力，滥用阿片类药物被怀疑会增加易感性 到结核病。 然而，实验研究检验吗啡是否促进 引起结核病的任何一种分枝杆菌的致病性（M. 结核病或牛分枝杆菌）缺乏。 待检验的中心假设 研究中提出吗啡可促进免疫发病机制 播散性牛支原体感染。 为了检验这一假设，在体外和 将使用猪模型进行体内实验 结核病。 具体目标是：（1）表征吗啡在 体外对牛支原体感染小胶质细胞和单核细胞的影响； (2)确定 未免疫猪的吗啡依赖性对支原体生长的影响。 体内小胶质细胞中的牛，并将这些组织病理学相关联 中枢神经系统感染临床病程的发现； (3) 表征 吗啡体外对抗 M 的影响。 牛T淋巴细胞活性 从 BCG 免疫猪获得的子集； (4) 确定效果 吗啡在卡介苗免疫猪中对中枢神经系统结核疫苗的保护作用。 小胶质细胞和单核细胞的原代培养物将从 新生猪。 除了研究吗啡在体外的影响 牛分枝杆菌和这些细胞群之间的相互作用，影响 吗啡对T淋巴细胞亚群抗分枝杆菌活性的影响 将确定免疫动物。 新开发的猪体内模型 将使用播散性牛支原体感染。 我们假设吗啡 对未免疫的猪施用会促进中枢神经系统结核的发展， 而给予 BCG 免疫猪的吗啡会与 疫苗失去对中枢神经系统结核的保护作用。 这些研究将， 首次提供与临床相关的实验证据 人们担心阿片类药物滥用会促进结核病的发病。