Pneumocystis jirovecii and macrophages in COPD

描述（由申请人提供）： 气道炎症、气道重塑、微生物定植和实质破坏是慢性阻塞性肺疾病（COPD）的标志。除吸烟外，感染性病原体也可能导致COPD患者肺功能下降。COPD患者的炎症过程显示出与耶氏肺孢子虫（PC）相似的炎症介质和免疫细胞参与的独特模式。现在已经出现了关于巨噬细胞表型在COPD患者中的重要性的证据。巨噬细胞占从COPD患者的支气管肺泡灌洗中回收的炎性细胞的大部分，并且定位于肺泡破坏部位。此外，IL-4/IL-13交替激活的巨噬细胞表型（AAM）与几种慢性肺部疾病有关。我们建议在这项研究中，以评估AAM和PC之间的关系，在肺组织研究联盟的COPD患者的肺。在3个目标中，我们将1）将PC定殖与肺组织样品中AAM的存在相关联，2）通过免疫组织化学确定PC的存在如何与巨噬细胞表型和纤维化的精确定位相关联，以及3）确定PC负荷和AAM如何与临床结果测量相关联。该项目将研究一种新的发病机制，这可能为COPD患者未来的潜在治疗干预提供靶点。公共卫生相关性：慢性阻塞性肺疾病（COPD）影响着2400万美国人，并导致慢性、危及生命的肺部疾病。它最近被描述，肺孢子虫（PC）感染可能是一个重要的因素，在疾病的进展。本研究将探讨PC感染通过诱导巨噬细胞的交替活化而促进COPD患者肺纤维化的假说。我们已经在小鼠模型中证明，PC使巨噬细胞反应朝向这种促纤维化表型极化。建立PC感染和替代性巨噬细胞活化之间的相关性将导致识别可能减缓这些患者肺纤维化和功能下降的发展的治疗干预。(End摘要）

DESCRIPTION (provided by applicant): Airway inflammation, airway remodeling, colonization with microorganisms, and parenchymal destruction are hallmarks of chronic obstructive pulmonary disease (COPD). In addition to cigarette smoking, infectious pathogens likely contribute to the decline in pulmonary function in COPD patients. The inflammatory process in patients with COPD displays a distinct pattern of inflammatory mediators and immune cells that are involved that are similar to the pattern seen in response to Pneumocystis jiroveci (PC). Evidence has now emerged on the importance of macrophage phenotype in COPD patients. Macrophages account for the majority of inflammatory cells recovered from bronchoalveolar lavage from COPD patients and are localized to sites of alveolar destruction. Further, the IL-4/IL-13 alternatively activated macrophage phenotype (AAM) has been implicated in several chronic lung diseases. We propose in this study to evaluate the relationship between the AAM and PC in lungs of COPD patients in the Lung Tissue Research Consortium. In 3 Aims we will 1) correlate PC colonization with the presence of AAMs in lung tissue samples, 2) determine through immunohistochemistry how the presence of PC correlates to the precise localization of macrophage phenotype and fibrosis, and 3) determine how PC burden and AAMs correlate to clinical outcome measurements. This project will investigate a novel mechanism of pathogenesis which may provide targets for potential future therapeutic interventions for patients with COPD. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic obstructive pulmonary disease (COPD) affects 24 million Americans and causes chronic, life- threatening lung disease. It has recently been described that Pneumocystis jiroveci (PC) infection may be an important factor in the progression of the disease. This project will investigate the hypothesis that PC infection worsens pulmonary fibrosis development in patients with COPD through induction of alternative macrophage activation. We have demonstrated in mouse models that PC polarizes the macrophage response toward this pro-fibrotic phenotype. Establishing a correlation between PC infection and alternative macrophage activation will lead to the identification of therapeutic interventions that possibly will slow the development of pulmonary fibrosis and functional decline in these patients. (End of Abstract)