Aveolar Macrophage Apoptosis and Pneumocystis

肺泡巨噬细胞凋亡和肺孢子虫

• 批准号: 7568203
• 负责人: CHAO-HUNG LEE
• 金额: $ 35.91万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568203
• 关键词: Acquired Immunodeficiency Syndrome; Alveolar Macrophages; Alveolus; Animals; Apoptosis; Apoptotic; Bronchoalveolar Lavage Fluid; Cells; Cessation of life; Cytoplasm; Data; Disease Progression; Down-Regulation; Ensure; Epithelial Cells; Excretory function; Genes; Goals; Human; Immune system; Individual; Infection; Inhibition of Apoptosis; Lead; Ligands; Lung; Mediating; Membrane Potentials; Mitochondria; Modeling; Monitor; Mus; Organism; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Pneumonia; Polyamine Catabolism; Polyamines; Rattus; Reactive Oxygen Species; Research; Research Personnel; Resistance; Role; Source; Spermidine; Steroids; Stimulus; Testing; cell type; cytochrome c; human disease; immunosuppressed; macrophage; mitochondrial membrane; pneumocyte; programs; receptor; research study; rosin; transcription factor; uptake

Pneumocystis carinii (P. jiroveci in human disease) causes a severe pneumonia in irnmunocornprornised individuals, such as those with AIDS. The number of alveolar macrophages is decreased in humans with Pneumocystis pneumonia (Pep). In rat and mouse Pep models, alveolar macrophage number is decreased by approximately 60% mainly due to the increased rate of apoptosis in alveolar macrophages. During Pep, polyamine (spermidine, acetylspermine, and acetylspermidine) levels are greatly increased in the alveoli and alveolar macrophages. Bronchoalveolar lavage (BAL) fluids from animals with Pep are able to induce apoptosis in normal alveolar macrophages, and depletion of polyamines from these BAL fluids abrogates their ability to induce apoptosis. This proposal will use steroid-immunosuppressed rats and L3T4 cell- depleted mice to test the hypothesis that alveolar macrophages apoptosis is caused directly by polyamines or indirectly by reactive oxygen species that are generated as the result of polyamine catabolism during Pep. Experiments will be performed to determine whether the polyamines present in the alveoli and alveolar macrophage during Pep are derived from Pneumocystis organisms, alveolar macrophages, and/or lung epithelial cells. The levels of each specific polyamine needed to induce apoptosis in alveolar macrophages will be determined. Changes in polyamine uptake by alveolar macrophages will also be assessed. The relationship between increased levels of reactive oxygen species and polyamines will be investigated. Pro- and anti-apoptosisfactors that are involved in the apoptosis will be identified, and effects of polyamines on the expression and the activity of these factors will be investigated. The involvement of extrinsic and intrinsic (mitochondrial) apoptosis pathways will be studied by identifying factors that alter mitochondrial membrane potential leading to release of cytochrome c to the cytoplasm and the contribution of death receptors and their ligands to the apoptosis. Effects of down regulation of anti-apoptotic factors on the resistance of alveolar macrophage to polyamine-mediated, Pneumocystis-induced apoptosis will also be investigated. Since preliminary studies in both rats and mice with Pep indicate that inhibition of apoptosis in alveolar macrophages ameliorates disease progression or even resolves the infection, the proposed studies may lead to new treatments for Pneumocystis pneumonia.

卡氏肺孢子虫（人类疾病中的Jiroveci肺孢子虫）导致免疫缺陷型严重肺炎 例如艾滋病患者。人的肺泡巨噬细胞数量减少， 肺孢子虫肺炎（Pep）。在大鼠和小鼠Pep模型中，肺泡巨噬细胞数量减少， 约60%，主要是由于肺泡巨噬细胞凋亡率的增加。在Pep期间， 肺泡中的多胺（亚精胺、乙酰精胺和乙酰亚精胺）水平大大增加， 肺泡巨噬细胞来自Pep动物的支气管肺泡灌洗液（BAL）能够诱导 正常肺泡巨噬细胞的凋亡，以及这些BAL液中多胺的耗竭， 它们诱导细胞凋亡的能力。该提案将使用类固醇免疫抑制大鼠和L3 T4细胞， 耗尽小鼠来检验肺泡巨噬细胞凋亡是由多胺直接引起的假设 或间接地通过在Pep过程中作为多胺催化剂的结果而产生的活性氧物质。 将进行实验以确定多胺是否存在于肺泡和肺泡上皮细胞中。 PEP期间的巨噬细胞来源于肺孢子虫生物体、肺泡巨噬细胞和/或肺 上皮细胞诱导肺泡巨噬细胞凋亡所需的各种特异性多胺水平 将被确定。还将评估肺泡巨噬细胞摄取多胺的变化。的 将研究活性氧物质和多胺水平增加之间的关系。亲- 和参与细胞凋亡的抗凋亡因子，以及多胺对细胞凋亡的影响。 将研究这些因子的表达和活性。外在和内在的参与 （线粒体）凋亡途径将通过鉴定改变线粒体膜的因素来研究 可能导致细胞色素c释放到细胞质和死亡受体的贡献， 它们的配体对细胞凋亡的影响。抗凋亡因子下调对肝癌细胞耐药的影响 还将研究肺泡巨噬细胞对多胺介导的肺孢子虫诱导的细胞凋亡的影响。 由于在大鼠和小鼠中对PEP的初步研究表明， 巨噬细胞改善疾病进展甚至解决感染，拟议的研究可能 导致肺孢子虫肺炎的新疗法。

项目成果

Polyamine transport as a target for treatment of Pneumocystis pneumonia.

多胺转运作为治疗肺孢子虫肺炎的靶点。

• DOI: 10.1128/aac.00662-09
• 发表时间: 2009
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Liao,Chung-Ping;Phanstiel4th,Otto;Lasbury,MarkE;Zhang,Chen;Shao,Shoujin;Durant,PamelaJ;Cheng,Bi-Hua;Lee,Chao-Hung
• 通讯作者: Lee,Chao-Hung