MICA: Key mechanisms underlying inhaled GM-CSF's enhancement of phagocytosis and bacterial clearance by human alveolar macrophages.

MICA：吸入 GM-CSF 增强人肺泡巨噬细胞吞噬作用和细菌清除的关键机制。

• 批准号: MR/X005046/1
• 负责人: John Simpson
• 金额: $ 128.98万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX005046%2F1
• 关键词: MICA; Key; mechanisms; underlying; inhaled

Despite the widespread availability of antibiotics, infection deep in the lung (pneumonia) remains an important cause of death in older people, as well as in critically ill patients in intensive care units.Our lungs contain a population of cells that sit in the air pockets of the lung and sense the presence of bugs. These cells are called alveolar macrophages (AMs). When AMs sense bugs in the lung, they kill them and if necessary send signals to the wider immune system for more help. Our study wishes to find out if AMs work less well as we get older, or when we are critically ill, as this may explain why we become susceptible to pneumonia. We know that a natural chemical in the body, called granulocyte-macrophage colony-stimulating factor (GM-CSF), maintains the health of our AMs. A further aim of our study is to determine whether giving GM-CSF as an inhaled drug, directly into the lung, might boost the function of AMs. If it does, this would provide the impetus for further research to see if GM-CSF could be given to people at very high risk of pneumonia (for example those in intensive care units), to prevent infection. This may have great advantages, because GM-CSF is not an antibiotic. The very heavy use of antibiotics in intensive care units has led to the emergence of "superbugs" that are not killed by antibiotics, and there is an urgent need to develop safe treatments that might boost immune cells such as AMs, instead of relying entirely on antibiotics.Nearly all of our information on how GM-CSF improves the function of AMs comes from studies in mice. We need to understand better how human AMs kill bugs, we need to know if this goes wrong as we get older or become critically unwell, and we need to know if GM-CSF can improve things. These issues have driven the design of our study.We shall ask 20 young volunteers (aged 18-30) and 20 older volunteers (60 or over) to come to the hospital on three days. On day one and day two they will inhale GM-CSF or a placebo, but neither they nor the research team will know which they inhaled. Each session will last about an hour. On day three they will come back for a telescope test of the lungs (bronchoscopy), where they are closely monitored and fluid is instilled into the a small area of the lung and gently sucked back. The fluid sucked back contains millions of AMs. The test lasts about 20 minutes and the person rests in hospital afterwards for a few hours before going home. Separately, a group of critically ill patients in the ICU will have the same protocol, i.e. GM-CSF or placebo on days 1 and 2, and bronchoscopy on day 3. In a final variation, the young volunteers will come back at least one month later, and have the same procedures done again, except that if they received GM-CSF first time round they will receive placebo the second time, and vice versa.We can take the AMs to the lab and study how well they eat bugs. We can block the function of specific molecules in the AMs and if this prevents the anti-bug effects we can infer that these molecules must be important for AM function. This way we shall build up a profile of the key molecules at the surface of the AM ("receptors") or inside the AM. Once we have the results we can "unblind" ourselves to find out who had GM-CSF and who had placebo. In this way we can piece together the answers to our questions - how do human AMs get rid of bugs? Do ageing and critical illness reduce the function of AMs and, if so, how? Does GM-CSF restore good function to AMs?The study will generate entirely new information on the function of human AMs. If GM-CSF is safe and boosts AM function we shall take this information forward to work out if inhaled GM-CSF can effectively and safely prevent pneumonia in patients who are at highest risk.

尽管抗生素广泛使用，但肺部深部感染（肺炎）仍然是老年人和重症监护室重症患者死亡的重要原因。我们的肺部含有一群细胞，这些细胞位于肺部的气囊中，并感知细菌的存在。这些细胞被称为肺泡巨噬细胞（AM）。当AM感觉到肺部的细菌时，它们会杀死它们，并在必要时向更广泛的免疫系统发送信号以寻求更多帮助。我们的研究希望找出AM是否随着我们年龄的增长或当我们病重时工作得不好，因为这可能解释为什么我们容易患上肺炎。我们知道，体内有一种天然化学物质，称为粒细胞-巨噬细胞集落刺激因子（GM-CSF），可以维持AM的健康。我们研究的另一个目的是确定是否给予GM-CSF作为吸入药物，直接进入肺部，可能会增强AM的功能。如果是这样，这将为进一步的研究提供动力，看看GM-CSF是否可以给予肺炎风险非常高的人（例如重症监护病房的人），以预防感染。这可能有很大的优势，因为GM-CSF不是抗生素。重症监护病房大量使用抗生素导致抗生素无法杀死的“超级细菌”出现，因此迫切需要开发安全的治疗方法，以增强AM等免疫细胞的功能，而不是完全依赖抗生素。几乎所有关于GM-CSF如何改善AM功能的信息都来自小鼠研究。我们需要更好地了解人类AM如何杀死细菌，我们需要知道当我们变老或变得严重不适时，这是否会出错，我们需要知道GM-CSF是否可以改善情况。这些问题推动了我们的研究设计。我们将邀请20名年轻志愿者（18-30岁）和20名老年志愿者（60岁或以上）在三天内来到医院。在第一天和第二天，他们将吸入GM-CSF或安慰剂，但他们和研究小组都不知道他们吸入了什么。每节约一小时。在第三天，他们将回来进行肺的望远镜测试（支气管镜检查），在那里他们被密切监测，液体被滴入肺的一个小区域并轻轻吸回。吸回的液体中含有数百万的AM。测试持续约20分钟，然后在医院休息几个小时，然后回家。单独地，ICU中的一组危重患者将具有相同的方案，即第1天和第2天GM-CSF或安慰剂，以及第3天支气管镜检查。在最后一种变化中，年轻的志愿者将在至少一个月后回来，再次进行相同的程序，除了如果他们第一次接受GM-CSF，他们将在第二次接受安慰剂，反之亦然。我们可以把AM带到实验室，研究他们吃虫子的情况。我们可以阻断AM中特定分子的功能，如果这阻止了抗细菌作用，我们可以推断这些分子对AM功能一定很重要。通过这种方式，我们将建立AM表面（“受体”）或AM内部的关键分子的概况。一旦我们有了结果，我们就可以“揭盲”自己，找出谁有GM-CSF，谁有安慰剂。通过这种方式，我们可以拼凑出我们问题的答案-人类AM如何摆脱虫子？衰老和危重疾病是否会降低AM的功能，如果是，是如何降低的？GM-CSF能恢复AM的良好功能吗？这项研究将产生关于人类AM功能的全新信息。如果GM-CSF是安全的，并能增强AM功能，我们将进一步研究吸入GM-CSF是否能有效和安全地预防高危患者的肺炎。