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

尽管抗生素广泛使用，但肺部深部感染（肺炎）仍然是老年人以及重症监护病房危重病人死亡的一个重要原因。我们的肺部含有一群细胞，它们位于肺部的气穴中，可以感知细菌的存在。这些细胞被称为肺泡巨噬细胞（AMs）。当AMs检测到肺部的细菌时，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获得更多帮助。我们的研究希望发现，随着年龄的增长，或者当我们病重时，人工智能是否会变得不那么有效，因为这可能解释了为什么我们容易患肺炎。我们知道，人体内有一种叫做粒细胞-巨噬细胞集落刺激因子（GM-CSF）的天然化学物质，可以维持我们的AMs的健康。我们研究的另一个目的是确定GM-CSF作为一种吸入药物，直接进入肺部，是否可以增强AMs的功能。如果确实如此，这将为进一步的研究提供动力，看看GM-CSF是否可以给肺炎风险很高的人（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。在重症监护室大量使用抗生素导致了抗生素无法杀死的“超级细菌”的出现，迫切需要开发安全的治疗方法，可以增强免疫细胞，而不是完全依赖抗生素。几乎所有关于GM-CSF如何改善AMs功能的信息都来自小鼠研究。我们需要更好地了解人类AMs是如何杀死细菌的，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是否能改善这种情况。这些问题推动了我们研究的设计。我们将要求20名青年志愿者（18-30岁）和20名老年志愿者（60岁或以上）在三天内来医院。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的是哪种。每节课将持续一个小时左右。第三天，他们将回来进行肺部的望远镜检查（支气管镜检查），在那里他们将受到密切监测，并将液体注入肺部的一小块区域，然后轻轻地吸回。被吸回的液体中含有数百万个AMs。测试持续约20分钟，之后患者在医院休息几个小时，然后回家。另外，一组ICU重症患者将采用相同的方案，即第1天和第2天使用GM-CSF或安慰剂，第3天使用支气管镜检查。在最后一个变化中，年轻的志愿者将在至少一个月后回来，并再次进行相同的程序，只是如果他们第一次接受了GM-CSF，他们将接受第二次安慰剂，反之亦然。我们可以把AMs带到实验室，研究它们如何吃虫子。我们可以阻断AM中特定分子的功能，如果这阻止了抗虫作用，我们可以推断这些分子对AM功能很重要。通过这种方式，我们将建立AM表面（“受体”）或AM内部关键分子的概况。一旦我们有了结果，我们就可以“解开”自己，找出谁服用了GM-CSF，谁服用了安慰剂。通过这种方式，我们可以拼凑出我们问题的答案——人类人工智能是如何摆脱细菌的？衰老和危重疾病是否会降低AMs的功能，如果是，是如何降低的？GM-CSF能恢复AMs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，我们将以此信息进一步研究吸入GM-CSF是否能有效、安全地预防高危患者的肺炎。

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.