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

尽管抗生素随处可得，但肺部深处的感染(肺炎)仍然是老年人和重症监护病房危重患者死亡的重要原因。我们的肺部有一群细胞，它们位于肺部的气囊中，可以感知细菌的存在。这些细胞被称为肺泡巨噬细胞(AM)。当AM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，以寻求更多帮助。我们的研究希望找出AM的效果是否随着我们年龄的增长而降低，或者当我们身患重病时，因为这可能解释了为什么我们容易患肺炎。我们知道，体内一种名为粒细胞-巨噬细胞集落刺激因子(GM-CSF)的天然化学物质能维持AM的健康。我们研究的另一个目的是确定将GM-CSF作为吸入性药物直接进入肺内是否可能增强AM的功能。如果是这样的话，这将为进一步的研究提供动力，以确定GM-CSF是否可以用于肺炎风险非常高的人(例如重症监护病房的人)，以预防感染。这可能有很大的好处，因为GM-CSF不是抗生素。重症监护病房中抗生素的大量使用导致了不会被抗生素杀死的“超级细菌”的出现，迫切需要开发安全的治疗方法，可能会增强AM等免疫细胞，而不是完全依赖抗生素。我们关于GM-CSF如何改善AM功能的几乎所有信息都来自对小鼠的研究。我们需要更好地了解人类AM是如何杀死细菌的，我们需要知道随着我们年龄的增长或身体严重不适，这种情况是否会出错，我们需要知道GM-CSF是否可以改善情况。这些问题驱使了我们的研究设计。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)来医院三天。在第一天和第二天，他们会吸入GM-CSF或安慰剂，但他们和研究团队都不知道他们吸入的是哪种。每节课将持续约一小时。在第三天，他们将回来接受肺部的望远镜测试(支气管镜检查)，在那里他们被密切监测，液体被注入肺部的一小块区域，并被轻轻地吸回。被吸回的液体含有数百万支AM。测试持续约20分钟，患者随后在医院休息几个小时后才回家。另外，ICU中的一组危重患者将接受相同的治疗方案，即在第一天和第二天接受GM-CSF或安慰剂治疗，在第三天接受支气管镜检查。最后一种方案是，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GM-CSF治疗，他们将接受第二次安慰剂治疗，反之亦然。我们可以将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功能肯定是重要的。这样，我们将在AM表面(“受体”)或AM内部建立一个关键分子的轮廓一旦我们有了结果，我们就可以“解盲”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AM如何去除细菌？衰老和危重疾病是否会降低AM的功能？如果是，又是如何降低的？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，并增强AM功能，我们将继续研究吸入GM-CSF是否可以有效和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.