Chemokine regulation of immune cell recruitment

描述(申请人提供)：尽管抗逆转录病毒治疗得到了改进，卡氏肺孢子虫肺炎(PCP)仍然是最常见的艾滋病定义疾病，也是与艾滋病相关的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的艾滋病患者的死亡率高达50%，其中一项研究将PCP列为艾滋病毒感染患者的主要死亡原因。重要的是，PCP的临床严重程度与炎症程度的关系比与机体负担的关系更密切，我们利用艾滋病相关性PCP的小鼠模型直接证明了免疫介导的肺损伤在PCP的病理生理学中起着核心作用。然而，病理性免疫细胞被招募到肺中的机制在很大程度上仍不清楚。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的分泌，这种趋化因子可以在PC感染期间将受损的免疫细胞招募到肺中。我们假设血管内皮细胞在PCP期间导致免疫介导的肺损伤的途径中起关键作用，阻断这一途径将减轻肺损伤并改善患者的预后。这项建议的具体目的是：1)明确PC刺激的AECs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的募集；3)确定免疫细胞上趋化因子受体的表达如何影响其向肺的募集；以及4)确定趋化因子功能的治疗调节是否减轻PCP相关的肺损伤。我们将使用原代细胞培养和嵌合基因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募集到肺的影响，以及如何利用这种相互作用来减轻PCP期间的炎性损伤。五氯苯酚仍然是医疗界关注的一个重要问题。虽然由于抗生素的预防，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，也是其他免疫功能受损患者(如癌症患者或接受抑制免疫系统的药物治疗的患者)疾病和死亡的重要原因。PCP的抗生素治疗并不总是立即导致临床改善，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，建议的研究旨在增加我们对五氯苯酚相关肺损伤机制的理解，希望确定特定的治疗靶点。

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.