Pneumocystis jirovecii and macrophages in COPD

描述(由申请人提供)： 呼吸道炎症、气道重塑、微生物定植和实质破坏是慢性阻塞性肺疾病(COPD)的特征。除了吸烟，传染性病原体可能还会导致COPD患者肺功能的下降。慢性阻塞性肺疾病患者的炎症过程显示出一种独特的炎症介质和免疫细胞模式，这些炎症介质和免疫细胞参与的模式类似于对吉罗维氏肺孢子虫(PC)的反应模式。现在有证据表明巨噬细胞表型在COPD患者中的重要性。从COPD患者的支气管肺泡灌洗中回收的炎性细胞中，巨噬细胞占大多数，并且定位于肺泡破坏的部位。此外，IL-4/IL-13交替激活的巨噬细胞表型(AAM)与多种慢性肺部疾病有关。在这项研究中，我们建议评估肺组织研究联盟中COPD患者肺中AAM和PC之间的关系。在三个目标中，我们将1)将PC定植与肺组织样本中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，这可能为未来COPD患者的潜在治疗干预提供靶点。公共卫生相关性：项目叙述慢性阻塞性肺疾病(COPD)影响2400万美国人，并导致慢性、危及生命的肺部疾病。最近有报道称，吉罗维氏肺孢子虫(PC)感染可能是该病发展的一个重要因素。该项目将调查PC感染通过诱导替代巨噬细胞激活而加重COPD患者肺纤维化发展的假说。我们已经在小鼠模型中证明了PC极化了巨噬细胞对这种促纤维化表型的反应。建立PC感染和替代巨噬细胞激活之间的相关性将导致确定可能减缓这些患者的肺纤维化和功能下降的治疗干预措施。(摘要结束)

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)