Chemokine regulation of immune cell recruitment during Pneumocystis pneumonia

肺孢子虫肺炎期间免疫细胞募集的趋化因子调节

基本信息

批准号：
7207945
负责人：
Terry W Wright
金额：
$ 37.87万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7207945
关键词：
AIDS-Related Pneumocystis Carinii Pneumonia Acquired Immunodeficiency Syndrome Adrenal Cortex Hormones Affect Alleles Alveolar Alveolar Macrophages Alveolus Anti-Inflammatory Agents Anti-inflammatory Antibiotic Prophylaxis Antibiotic Therapy Attenuated CCL2 gene CD8B1 gene Cause of Death Cell Communication Cells Cessation of life Chemotactic Factors Clinical Community Healthcare Cytokine Signaling Data Disease Epithelial Cells Functional disorder Genetic Variation Goals Human Immune Immune Targeting Immune response Immune system Immunocompromised Host Impairment Incidence Individual Infection Inflammation Inflammatory Injury Interruption Knock-out Localized Lung MAP Kinase Gene Malignant Neoplasms Mediating Modeling Morbidity - disease rate Mus Names Organism Outcome Pathologic Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Play Pneumocystis Pneumocystis carinii Pneumonia Pneumonia Primary Cell Cultures Production Property Range Rate Reaction Receptor Signaling Recruitment Activity Regulation Reporting Research Design Research Personnel Rodent Role Severities Signal Pathway Signal Transduction T-Lymphocyte TNF gene Therapeutic Tumor Necrosis Factor Receptor Variant alveolar epithelium antiretroviral therapy beta-Chemokines chemokine chemokine receptor design immunoregulation improved in vivo lung injury monocyte chemoattractant protein 1 receptor mortality mouse model mutant programs pulmonary function receptor expression respiratory response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Despite improved antiretroviral therapy, Pneumocystis carinii pneumonia (PcP) remains the most common AIDS-defining illness, and is a significant cause of AIDS-related morbidity and mortality. Recent studies have reported mortality rates as high as 50% for AIDS patients with severe PcP, and one study named PcP as the leading cause of death among HIV-infected patients. Importantly, the clinical severity of PcP correlates more closely with the level of inflammation than with organism burden, and using mouse models of AIDS-related PcP we have directly demonstrated that immune-mediated lung injury plays a central role in the pathophysiology of PcP. However, the mechanisms by which pathologic immune cells are recruited to the lung remain largely unknown. PC interacts closely with the alveolar epithelium (AECs), and this interaction results in the secretion of chemotactic factors called chemokines that could function to recruit damaging immune cells to the lung during PC infection. We hypothesize that AECs are critically involved in the pathway leading to immune-mediated lung injury during PcP, and that interrupting this pathway will alleviate lung injury and improve patient outcome. The Specific Aims of this proposal are designed to: 1) define the mechanism of Pc-stimulated chemokine production by AECs; 2) determine whether chemokine production by AECs modulates immune cell recruitment to the lung; 3) determine how chemokine receptor expression on responding immune cells affects their recruitment to the lung; and 4) determine whether therapeutic modulation of chemokine function alleviates PcP-related lung injury. We will use a combination of primary cell culture and chimeric knockout mouse models to definitively answer these questions. The long-term goals of this project are to understand the consequences of the Pc-AEC interaction for immune cell recruitment to the lung, and how this interaction may be exploited to alleviate inflammatory injury during PcP. PcP remains an important concern of the health care community. While the incidence of PcP has decreased due to antibiotic prophylaxis, it remains the most common AIDS-defining illness as well as a significant cause of disease and death in other immunocompromised patients such as those with cancer or who receive medications that suppress the immune system. Antibiotic treatment of PcP does not always result in immediate clinical improvement because the host's ongoing immune response is a major cause of PcP-related lung injury. Therefore the proposed studies are designed to increase our understanding of the mechanisms leading to PcP-related lung injury with the hope of identifying specific therapeutic targets.

描述（由申请人提供）：尽管抗逆转录病毒治疗有所改善，卡氏肺囊虫肺炎（PcP）仍然是最常见的艾滋病定义疾病，并且是艾滋病相关发病率和死亡率的一个重要原因。最近的研究报告称，患有严重 PcP 的 AIDS 患者死亡率高达 50%，一项研究将 PcP 列为 HIV 感染者死亡的主要原因。重要的是，PcP 的临床严重程度与炎症水平的相关性比与机体负荷的相关性更密切，并且使用 AIDS 相关 PcP 的小鼠模型，我们直接证明了免疫介导的肺损伤在 PcP 的病理生理学中发挥着核心作用。然而，病理性免疫细胞被招募到肺部的机制仍然很大程度上未知。 PC 与肺泡上皮 (AEC) 密切相互作用，这种相互作用导致称为趋化因子的趋化因子的分泌，这些趋化因子可以在 PC 感染期间将破坏性免疫细胞招募到肺部。我们假设 AEC 在 PcP 期间导致免疫介导的肺损伤的途径中发挥重要作用，并且中断该途径将减轻肺损伤并改善患者的预后。该提案的具体目标旨在： 1) 定义 AEC 刺激 Pc 产生趋化因子的机制； 2) 确定AEC产生的趋化因子是否调节免疫细胞向肺部的募集； 3) 确定应答免疫细胞上趋化因子受体的表达如何影响其向肺部的募集； 4) 确定趋化因子功能的治疗性调节是否可以减轻 PcP 相关的肺损伤。我们将结合使用原代细胞培养和嵌合敲除小鼠模型来明确回答这些问题。该项目的长期目标是了解 Pc-AEC 相互作用对免疫细胞募集到肺部的影响，以及如何利用这种相互作用来减轻 PcP 期间的炎症损伤。 PcP 仍然是医疗保健界的一个重要关注点。虽然由于抗生素预防，PCP 的发病率有所下降，但它仍然是最常见的艾滋病定义疾病，也是其他免疫功能低下患者（如癌症患者或接受抑制免疫系统药物的患者）患病和死亡的重要原因。 PcP 的抗生素治疗并不总能立即带来临床改善，因为宿主持续的免疫反应是 PcP 相关肺损伤的主要原因。因此，拟议的研究旨在增加我们对导致 PcP 相关肺损伤的机制的理解，以期确定具体的治疗靶点。