Chemokine regulation of immune cell recruitment

尽管抗逆转录病毒治疗有所改进，但卡氏肺孢子虫肺炎(PCP)仍然是最常见的 这是一种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。 最近的研究报告了患有严重PCP的艾滋病患者的死亡率高达50%，以及 一项研究指出，PCP是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相关性比与机体负担的相关性更密切， 利用与艾滋病相关的PCP小鼠模型，我们直接证明了免疫介导的 肺损伤在PCP的病理生理机制中起核心作用。然而，通过这些机制 病理免疫细胞被招募到肺中的情况在很大程度上仍不清楚。PC与 肺泡上皮(AECs)，这种相互作用导致趋化因子的分泌，称为 在PC感染期间，趋化因子可以将破坏性的免疫细胞招募到肺中。我们 假设血管内皮细胞在导致免疫介导的肺损伤的途径中起关键作用 在PCP期间，阻断这一通路将减轻肺损伤，改善患者预后。 该方案的具体目的是：1)明确Pc刺激的机制 AECs产生趋化因子；2)确定AECs产生的趋化因子是否调节 免疫细胞向肺内募集；3)确定趋化因子受体如何在应答中表达 免疫细胞影响它们向肺的募集；以及4)决定是否治疗调节 趋化因子功能减轻PCP相关性肺损伤。我们将使用原代细胞培养的组合 和嵌合基因敲除小鼠模型来明确回答这些问题。这样做的长期目标是 该项目旨在了解Pc-AEC相互作用对免疫细胞招募的影响 肺，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。而PCP的发病率有 由于抗生素预防而减少，它仍然是最常见的定义艾滋病的疾病，以及 其他免疫功能低下患者的重要疾病和死亡原因，如癌症患者 或者接受抑制免疫系统的药物。PCP的抗生素治疗不起作用 总是导致立即的临床改善，因为宿主正在进行的免疫反应是 五氯酚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PCP相关肺损伤的发病机制，以期明确具体的致病机制 治疗靶点。

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.