Pneumocystis and COPD in a Simian Model of AIDS

描述(由申请人提供)： 感染艾滋病毒的患者患肺气肿的风险增加；然而，与易感性增加相关的机制尚未确定。感染因素可能通过上调肺内炎症介质的表达来促进肺气肿的发展，这些炎症介质与香烟烟雾协同作用，促进肺部病理。在人类和非人类灵长类动物模型中的研究表明，条件致病菌肺孢子虫(Pc)对定植的炎症反应类似于肺气肿，其特征是CD8+T细胞、中性粒细胞和巨噬细胞的涌入。在人类免疫缺陷病毒(SIV)感染的猕猴中，我们建立了Pc感染的非人灵长类动物模型，表明Pc在阻塞性肺疾病的进展中具有高的定植频率。与SIV感染的猴子相比，SIV/Pc混合感染的猴子表现出肺功能的进行性下降。阻塞性肺病发生在急性肺炎性肺炎(PCP)之前，以肺泡扩大为特征，对支气管扩张剂攻击无反应。我们推测，在艾滋病免疫功能障碍的背景下，Pc定植引起炎症反应，导致肺功能和结构的改变，类似于肺气肿。在灵长类动物模型中，我们有一个独特的机会来直接检验这一假设。这一建议的具体目的是：1)验证Pc在艾滋病模型中的定植导致肺功能进行性丧失和艾滋病相关性肺气肿的假说；2)阐明Pc定植引起的慢性炎症导致组织破坏和肺功能异常的机制；3)检验在该模型中对Pc定植过程进行干预将改善肺损伤的假说。 相关性：检验肺孢子虫是HIV相关性肺气肿进展的辅助因素这一假设很重要，因为所获得的信息将导致开发干预措施，以防止与Pc定植相关的肺损伤。

DESCRIPTION (provided by applicant): HIV-infected patients are at increased risk for the development of emphysema; however the mechanisms associated with increased susceptibility have not been defined. Infectious agents may contribute to the development of emphysema by up-regulating inflammatory mediators in the lung that act in concert with cigarette smoke to promote lung pathology. Studies in human subjects and non-human primate models of AIDS suggest that the inflammatory response to colonization by the opportunistic pathogen, Pneumocystis (Pc) is similar to that of emphysema, and is characterized by influx of CD8+ T cells, neutrophils and macrophages. We have shown a high frequency of colonization by Pc in the progression of obstructive lung disease in HIV infections, we developed a non-human primate model of Pc infection in simian immunodeficiency virus (SIV)-infected macaques. SIV/Pc co-infected monkeys show progressive decline in pulmonary function compared to SIV-infected monkeys. Obstructive pulmonary disease occurs prior to the onset of acute Pc pneumonia (PCP), is characterized by enlarged alveolar airspaces and is not responsive to bronchodilator challenge. We hypothesize that in the context of AIDS-immune dysfunction, Pc colonization induces inflammatory responses leading to changes in pulmonary function and architecture similar to that seen in emphysema. In the primate model, we have a unique opportunity to test this hypothesis directly. The specific aims of this proposal are: 1) to test the hypothesis that Pc colonization in a model of AIDS leads to progressive loss of pulmonary function and development of AIDS-associated emphysema; 2) to elucidate the mechanisms whereby chronic inflammation induced by Pc colonization leads to tissue destruction and pulmonary function abnormalities; 3) to test the hypothesis that intervention in the course of Pc colonization in this model will ameliorate pulmonary damage. Relevance: Testing the hypothesis that Pneumocystis is a co-factor in the progression of HIV-associated emphysema is important because the information gained will lead to the development of intervention to prevent lung injury associated with Pc colonization obstructive lung damage.