Pathogenesis of HIV-Related Emphysema: T Cells, smoking*

HIV 相关肺气肿的发病机制：T 细胞、吸烟*

• 批准号: 7123464
• 负责人: JAMES M BECK
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-29 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123464
• 关键词: HIV infections; Pneumocystis; T lymphocyte; cellular pathology; emphysema; genetically modified animals; helper T lymphocyte; host organism interaction; laboratory mouse; leukocyte count; respiratory disorder epidemiology; respiratory epithelium; smoking; tissue /cell culture; tobacco abuse

DESCRIPTION (provided by applicant): The advent of highly active anti-retroviral therapy (HAART) has permitted significant increases in survival and in quality of life in those HIV-infected individuals with access to advanced medical care and pharmaceuticals. With increased survival, and with effective prophylaxis and treatment for many previously lethal opportunistic infections, the manifestations of chronic diseases have become more prevalent in HIV-infected individuals. One such manifestation of chronic HIV infection is emphysema. Recent literature clearly documents the existence of accelerated emphysema, particularly in HIV-infected individuals who smoke cigarettes. The clinical literature has suggested that the CD8+ T cell may be important in the in the pathogenesis of HIV-related emphysema, but this relationship remains associational and speculative. Pneumocystis pneumonia remains an important cause of morbidity and mortality in HIV-infected individuals. Recently, the existence of carrier states for this infection have been identified, both in HIV-infected individuals and in those individuals who provide their care. Furthermore, Pneumocystis carriage is common in smokers with chronic obstructive pulmonary disease. Whether repeated bouts of Pneumocystis colonization or carriage contribute to lung damage, particularly in interaction with cigarette smoke, has not been investigated experimentally. Although HIV infection produces wide-ranging immunologic effects, depletion of CD4+ T cells remains the immunologic hallmark of HIV infection. Our laboratories have many years of experience studying the lungs of chronically CD4-depleted mice, as an immunologically valid animal model of HIV-induced immunosuppression. Furthermore, we have characterized the immunologic responses to chronic Pneumocystis infection in these CD4-depleted mice, a well-accepted animal model of this important opportunistic infection. In these investigations, the CD8+ T cell has emerged as an important mediator of lung inflammation and lung damage. Most recently, we have acquired expertise in the development and analysis of cigarette smoke-induced emphysema in mice. We hypothesize that, during persistent depletion of CD4+ T cells, chronic Pneumocystis colonization and cigarette smoke interact to cause emphysema. The development of emphysema is mediated by CD8+ T cells in the lung, and results from cytokine and perforin release. Furthermore, we hypothesize that CD8+ T cells drive the development of emphysema by damage to alveolar epithelial cells. RELEVANCE: Chronic manifestations of HIV infection, including emphysema, are likely to present increasing clinical challenges in the era of HAART, but the pathogenesis of HIV-related emphysema is not understood. Using immunologically relevant animal models, this project will investigate the pathogenesis of smoking-related emphysema during chronic immunosuppression, and will examine Pneumocystis as a relevant cofactor in the development of emphysema.

描述（由申请人提供）：高效抗逆转录病毒疗法（HAART）的出现使那些获得先进医疗护理和药物的HIV感染者的生存率和生活质量显著提高。随着存活率的提高，以及对许多以前致命的机会性感染的有效预防和治疗，慢性病的表现在艾滋病毒感染者中变得更加普遍。慢性HIV感染的一种表现是肺气肿。最近的文献清楚地证明了加速肺气肿的存在，特别是在吸烟的艾滋病毒感染者中。临床文献表明，CD 8 + T细胞可能在HIV相关性肺气肿的发病机制中起重要作用，但这种关系仍然存在关联性和推测性。肺孢子虫肺炎仍然是艾滋病毒感染者发病和死亡的重要原因。最近，已经确定了这种感染的携带者状态的存在，无论是在HIV感染者还是在提供护理的人中。此外，肺孢子虫携带在患有慢性阻塞性肺病的吸烟者中很常见。肺孢子虫的反复定植或携带是否会导致肺损伤，特别是与香烟烟雾的相互作用，尚未进行实验研究。虽然HIV感染产生广泛的免疫学效应，但CD 4 + T细胞的耗竭仍然是HIV感染的免疫学标志。我们的实验室拥有多年研究慢性CD 4耗竭小鼠肺部的经验，作为HIV诱导免疫抑制的免疫学有效动物模型。此外，我们的特点是慢性肺孢子虫感染的免疫反应，在这些CD 4-耗尽的小鼠，一个公认的动物模型，这种重要的机会性感染。在这些研究中，CD 8 + T细胞已成为肺部炎症和肺损伤的重要介质。最近，我们获得了香烟烟雾诱导的小鼠肺气肿的开发和分析方面的专业知识。我们假设，在持续的CD 4 + T细胞耗竭，慢性肺孢子虫定植和香烟烟雾相互作用，导致肺气肿。肺气肿的发展是由肺中的CD 8 + T细胞介导的，并且是细胞因子和穿孔素释放的结果。此外，我们假设CD 8 + T细胞通过损伤肺泡上皮细胞来驱动肺气肿的发展。相关性：HIV感染的慢性表现，包括肺气肿，可能在HAART时代提出越来越多的临床挑战，但HIV相关肺气肿的发病机制尚不清楚。利用免疫学相关的动物模型，本项目将调查慢性免疫抑制期间吸烟相关肺气肿的发病机制，并将研究肺孢子虫作为肺气肿发展的相关辅助因素。