Chemokine regulation of immune cell recruitment

尽管抗逆转录病毒治疗有所改善，但卡氏肺孢子虫肺炎（PcP）仍然是最常见的肺炎。 常见的艾滋病定义疾病，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，患有严重PcP的艾滋病患者的死亡率高达50%， 一项研究将PcP列为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相关性比与生物体负荷的相关性更密切， 使用艾滋病相关的PcP小鼠模型，我们直接证明了免疫介导的 肺损伤在PcP的病理生理学中起中心作用。然而， 病理性免疫细胞被募集到肺中的情况在很大程度上仍然未知。PC与 肺泡上皮细胞（AEC），这种相互作用导致分泌趋化因子，称为 在PC感染期间，趋化因子可以起到将破坏性免疫细胞募集到肺部的作用。我们 假设AEC在导致免疫介导的肺损伤的途径中起关键作用 在PcP过程中，中断这一途径将减轻肺损伤并改善患者预后。 本研究的具体目的是：1）明确Pc刺激的细胞凋亡机制， 2）确定由AEC产生的趋化因子是否调节 免疫细胞募集到肺; 3）确定趋化因子受体表达如何响应 免疫细胞影响它们向肺的募集;和4）确定免疫细胞的治疗性调节是否影响免疫细胞的功能。 趋化因子功能可解释PCP相关的肺损伤我们将结合原代细胞培养 和嵌合基因敲除小鼠模型来明确回答这些问题。长期目标是 项目是为了了解免疫细胞募集的Pc-AEC相互作用的后果， 肺，以及如何利用这种相互作用，以减轻炎症损伤在PcP。 PcP仍然是卫生保健界的一个重要关注点。虽然PcP的发病率 由于抗生素预防，它仍然是最常见的艾滋病定义疾病， 其他免疫功能低下患者（如癌症患者）的重要疾病和死亡原因 或者接受抑制免疫系统的药物治疗。抗生素治疗PcP不 总是导致立即的临床改善，因为宿主的持续免疫反应是一个 PCP相关肺损伤的主要原因。因此，拟议的研究旨在增加我们的 了解导致PcP相关肺损伤的机制， 治疗目标

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. Thereforethe 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.