NOVEL THERAPIES FOR MYCOBACTERIAL PNEUMONIA

分枝杆菌肺炎的新疗法

• 批准号: 2234428
• 负责人: William J Martin
• 金额: $ 26.79万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2234428
• 关键词: Mycobacterium avium; SCID mouse; alveolar macrophages; antibacterial agents; bacterial RNA; bacterial pneumonia; colony stimulating factor; confocal scanning microscopy; cytokine; drug /agent; drug delivery systems; enzyme linked immunosorbent assay; flow cytometry; inhalation drug administration; interferon gamma; interferons; laboratory mouse; liposomes; nonhuman therapy evaluation; oligonucleotides; phagocytosis; pulmonary surfactants; respiratory disorder chemotherapy; technology /technique development

Mycobacterial infections of the lung remain a serious world-wide problem. Due to a number of number of important cofactors, tuberculosis and other mycobacterial infections are increasing in frequency. New therapeutic options are necessary for multidrug resistant strains of TB as well as other mycobacteria such as M. avium. The longterm objective of this proposal is to develop fundamentally new therapeutic strategies to treat mycobacterial infections. In this proposal we will test the hypothesis that airway delivery of specific nonantibiotic agents will successfully augment attachment, phagocytosis and killing of TB or M. avium by alveolar macrophages (AMs). Since it is known that mycobacteria are rapidly engulfed by AMs and survive and replicate within this intracellular environment, the overall strategy will be to use novel methods of delivery as well as novel therapeutic agents to augment the clearance of mycobacteria by AMs. Two airway delivery methods currently available in our laboratory include: 1) intratracheal delivery using mechanical ventilation, and 2) aerosolization using an ultrasonic nebulizer in line with a "nose-only" device. Using a murine model of immunocompetent BALB/c mice as well as immunodeficient BALB/c mice (SCID and CD4 lymphocyte depleted), we will examine the following specific aims: 1) to determine if surfactant protein A (SP-A) will augment attachment/phagocytosis/killing of TB or M. avium by AMs, 2) to determine if proinflammatory cytokines/agents will augment attachment/phagocytosis/killing of TB or M. avium by AMs, 3) to determine if liposome-encapsulated oligonucleotides can be successfully delivered inside AMs to kill TB or M. avium organisms and 4) to determine if SP-A, proinflammatory cytokine/agents or competitive oligonucleotides are useful therapies for mycobacterial pneumonia. If successful, these studies should result in the development of new therapies and new modes of airway delivery to augment clearance of mycobacteria from the lower respiratory tract.

肺的分枝杆菌感染仍然是一个严重的全球问题。 由于许多重要的辅助因子，结核病和其他 分枝杆菌感染的频率正在增加。新治疗 选项对于TB的多药抗性菌株是必需的 其他分枝杆菌，例如大鸟。长期目标 建议是开发从根本上进行新的治疗策略来治疗 分枝杆菌感染。在此提案中，我们将检验假设 特定非抗生素剂的气道输送将成功 增强附件，吞噬作用和杀死结核病或雄性M.鸟 肺泡巨噬细胞（AMS）。由于已知分枝杆菌是 迅速被AMS吞没并在此内生存和复制 细胞内环境，总体策略将是使用新颖 分娩方法以及新型的治疗剂来增强 AMS清除分枝杆菌。目前两种气道交付方法 在我们的实验室中可用：1）使用气管内交付 机械通气和2）使用超声波 雾化器与“仅鼻子”设备一致。使用鼠模型 免疫能力的BALB/C小鼠以及免疫缺陷的BALB/C小鼠（SCID 和CD4淋巴细胞耗尽），我们将检查以下特定 目的：1）确定表面活性剂蛋白A（SP-A）是否会增加 AMS的附着/吞噬作用/杀死结核病或鸟杀。2）确定 如果促炎细胞因子/剂将增加 AMS的附着/吞噬作用/杀死结核病或大鸟杀死，3）确定 如果脂质体封装的寡核苷酸可以成功交付 在AM内杀死结核病或M. avium生物，4）确定SP-A是否，是否是 促炎性细胞因子/剂或竞争性寡核苷酸是 分枝杆菌肺炎的有用疗法。如果成功，这些 研究应导致新疗法和新模式的发展 呼吸道运送以增加下部的分枝杆菌清除 呼吸道。