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

• 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
• 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

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重要原因。最近的研究报告称，患有严重PcP的艾滋病患者死亡率高达50%，一项研究称PcP是艾滋病毒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关系比与机体负荷的关系更密切，通过使用艾滋病相关PcP的小鼠模型，我们直接证明了免疫介导的肺损伤在PcP的病理生理中起着核心作用。然而，病理免疫细胞被招募到肺部的机制在很大程度上仍然未知。PC与肺泡上皮（AECs）密切相互作用，这种相互作用导致趋化因子（称为趋化因子）的分泌，在PC感染期间，趋化因子可以将破坏性免疫细胞招募到肺部。我们假设AECs在PcP期间导致免疫介导的肺损伤通路中起关键作用，阻断该通路将减轻肺损伤并改善患者预后。本提案的具体目的是：1)确定pc刺激aec产生趋化因子的机制；2)确定AECs产生趋化因子是否调节免疫细胞向肺的募集；3)确定趋化因子受体在应答免疫细胞上的表达如何影响它们向肺的募集；4)确定趋化因子功能的治疗性调节是否能减轻pcp相关的肺损伤。我们将使用原代细胞培养和嵌合敲除小鼠模型的组合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向肺募集的影响，以及如何利用这种相互作用来减轻PcP期间的炎症损伤。PcP仍然是医疗界关注的一个重要问题。虽然由于抗生素预防，PcP的发病率已经下降，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治疗的患者）疾病和死亡的重要原因。抗生素治疗PcP并不总是能立即改善临床，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，提出的研究旨在增加我们对导致pcp相关肺损伤的机制的理解，并希望确定特定的治疗靶点。