Pneumocystis and COPD in a Simian Model of AIDS

描述（由申请人提供）： HIV感染患者发生肺气肿的风险增加;然而，与易感性增加相关的机制尚未确定。 感染性病原体可能通过上调肺中的炎症介质而促进肺气肿的发展，这些炎症介质与香烟烟雾一起促进肺病理学。 在人类受试者和非人灵长类动物AIDS模型中的研究表明，对机会病原体肺孢子虫（Pc）定殖的炎症反应与肺气肿的炎症反应相似，并且特征在于CD 8 + T细胞、中性粒细胞和巨噬细胞的流入。 我们已经显示了高频率的殖民化Pc在阻塞性肺疾病的进展，HIV感染，我们开发了一个非人灵长类动物模型的Pc感染猴免疫缺陷病毒（SIV）感染的猕猴。 与SIV感染的猴子相比，SIV/Pc共感染的猴子显示肺功能进行性下降。 阻塞性肺病发生在急性Pc肺炎（PCP）发作之前，其特征是肺泡气腔扩大，对支气管扩张剂激发无反应。 我们假设，在艾滋病免疫功能障碍的背景下，Pc定植诱导炎症反应，导致肺功能和结构的变化类似于肺气肿。 在灵长类动物模型中，我们有一个独特的机会来直接测试这个假设。 本研究的具体目的是：1）验证艾滋病模型中Pc定植导致肺功能进行性丧失和发展为艾滋病相关肺气肿的假设; 2）阐明Pc定植诱导的慢性炎症导致组织破坏和肺功能异常的机制; 3）验证在该模型中干预Pc定殖过程将改善肺损伤的假设。 相关性：检验肺孢子虫是HIV相关肺气肿进展的辅助因素这一假设很重要，因为获得的信息将导致干预措施的发展，以预防与Pc定植阻塞性肺损伤相关的肺损伤。

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.