导语：慢阻肺作为一种慢性气道炎症性疾病，其发病机制尚未完全明了，吸入有害颗粒或气体可引起肺部炎症反应。了解疾病发病机制是做好慢阻肺防治的首要任务。丁香园非常荣幸邀请到上海瑞金医院感染病和呼吸病研究所名誉所长黄绍光教授和德克萨斯大学圣安东尼奥健康科学中心内科教授、GOLD指南科学委员会成员Antonio R. Anzueto教授一同谈谈慢阻肺发病机制，并由此选择合适治疗方案对慢阻肺进行早治早防。
丁香园：气流受限是慢阻肺的主要疾病特征，请您谈谈气流受限的发病机制以及支气管扩张剂的作用？
DXY: The airflow limitation is the major symptom of COPD, Would you please talk about the pathogenesis of airflow limitation and the role of bronchodilators with these two factors above?
黄绍光教授：慢阻肺最主要的病理生理变化是过度充气，而过度充气原因是气道阻塞之后呼吸气流受限。气流受限以后，很多气体在呼气末尾的时候储存到肺部，这时候就表现出过度充气的现象。
慢阻肺病人在静止状态下表现出过度充气造成的气流受限，而在运动过程中，这个现象更加明显。所以慢阻肺病人还有一个特征，就是动则气促。这种情况下，就出现了一个动态的充气周期。
这种病理生理变化造成了病人呼吸困难和活动能力受到限制。在这种情况下，要解决这些症状就要减低气道阻力。
支气管扩张剂的应用对这些病人十分重要，尤其是可以缓解病人在活动时造成的动态活动充气。应用了支气管扩张剂的病人在症状上缓解很明显，所以支气管扩张剂对这一类病人来说，是很有利的临床治疗。
Prof. Anzueto: As you say, the airflow limitation is the primary symptom of COPD. The consequence of that used to be the changes in the airway, the air cannot exhale with each breath. So patients could develop hyperinflation.
Hyperinflation means that our airway muscles are not efficient to work. You were hyper inflated with the airway that is flat, is not contracting in a proper way. That’s going to produce dyspnea and give short of breath when we try to do any kind of exertion, and that’s going to limit all activities.
The pharmacal therapy is to try to relive bronchial constriction. We didn’t understand that during 1990s to early 2013 until we have long acting bronchodilators available. We started with long active beta2-agonists (LABA)first and then long active anti-cholinergics (LAMA) and once-a-day anti-cholinergics.
With tiotropium, we see that air restriction can be reversed and reduced, the hyperinflation can also be reduced, and this translate in increasing exercise capacity.
Anzueto教授：就像你所说的一样，慢阻肺最主要的症状是气流受限。而气流受限的结果就是气道的改变，病人呼吸时气体不能完全呼出。这就导致了过度通气。
过度通气意味着呼吸肌不能有效地做功。呼吸肌不能正常收缩，就会导致病人在运动时出现气短和呼吸困难，这将会限制病人进行各种活动。
慢阻肺药物治疗目的就是减轻支气管收缩。上世纪九十年代，我们还不清楚这一点。直到2013年初，临床上开始使用长效支气管扩张剂，最初是长效β2受体激动剂，然后是长效抗胆碱能药物，现在已经发展到一天只需要用一次的长效抗胆碱能药物了。
比如噻托溴铵，一种抗胆碱能药物，病人使用后，我们观察到气道受限和过度充气有所减轻和逆转，运动后肺容积也有所提升。
丁香园：慢阻肺发病机制尚未完全明了，但目前已经知道，自主神经系统功能紊乱（如胆碱能神经受体分布异常）在慢阻肺的发病中起重要作用。那么从治疗角度考虑，您认为胆碱能通路对慢阻肺上起到什么作用？
DXY: The mechanism of COPD is still unknown, but it is know that the autonomic nervous system disorders such as abnormal distribution of cholinergic nerve receptors has played an important role in the pathogenesis of COPD, what do you think about the role of the cholinergic pathways play in treating COPD?
黄绍光教授：虽然现在慢阻肺的发病机制还不是很清楚，但是至少我们知道，按照GLOD指南的说法，慢阻肺是一种气道炎症性疾病。
气道炎症反应是一个很关键的病理变化，在气道炎症反应过程中神经调节机制也起到很重要的作用。由于神经调节机制的参与可以使炎症反应扩大,所以如果能从这个方面对应治疗会有很好的效果。
慢阻肺病人表现出的胆碱能神经兴奋性增高，增加了气道张力，造成了气道阻力的增大。在治疗过程中，如果要减轻气道张力增加，那么对于病人来说，胆碱能通路是慢阻肺稳定期唯一一个能干预治疗的因素。
如果在急性加重期有支气管痉挛，可以使用支气管扩张剂解决，也包括抗胆碱能药物。但在稳定期，支气管主要问题就是张力增加，张力增加用一般支气管扩张剂的帮助不大，而用抗胆碱能药物可以更有效缓解张力增加。所以对于稳定期病人，这一点更加突出。
Prof. Anzueto: Our bodies have different pathways to maintain the airway and prevent airway constriction, one of those I used to say is the cholinergic system.
The cholinergic system has multiple receptors, contributes to balance between bronchial constriction and bronchial dilatation. The initial anti-cholinergic medication that we have is atropine, lately ipratropium appeared but proved non-specific, so they were not very effective to produce bronchial dilatation. Late on, when tiotropium was developed, this is a specific that can against entry by receptor while it does produce sustaining bronchial dilatation.
So the anti-cholinergic medications will affect the acetylcholine system and in consequence produce sustaining bronchial dilatation. They become the principal therapy in the treatment of our patients with COPD.
Anzueto教授：我们人体中有很多不同的通路来维持呼吸道的顺畅，从而防止气道收缩，其中一种就是胆碱能神经系统。
胆碱能系统有很多不同受体，作用是维持气管收缩与舒张的平衡。最初，我们用的抗胆碱能药是阿托品，后来用异丙托溴铵，但他们都不是特异性的，所以它们对扩张气道作用并不十分有效。直到后来噻托溴铵的出现——它是一种特异性的通过抑制受体通道从而保持气道扩张的药物。
这些抗胆碱能药物作用于乙酰胆碱系统并能够持续扩张气道，因此它们成为慢阻肺患者的主要治疗药物。
丁香园：支气管哮喘和慢阻肺均为慢性气道炎症性疾病，在您看来，慢阻肺和哮喘的气道炎症有何不同？对于慢阻肺和哮喘的不同炎症，在临床表现和治疗上有何不同？
DXY: We know both asthma and COPD are chronic airway inflammatory diseases, in your opinion, what’s the difference on the airway inflammatory symptoms and therapeutic options between asthma and COPD?
黄绍光教授：我们对于疾病的认识在不断发展。过去我们认为哮喘是支气管痉挛，但后来知道它实际上是个慢性炎症过程。慢阻肺也是一样，是一种气道炎症。
这两个炎症都是呼吸道疾病中的主要慢性炎症，但它们是不一样的，因为参与的炎症细胞不一样。
哮喘中参与的主要是嗜酸性细胞以及其他肥大细胞等，针对这些炎症细胞可以采用激素治疗。但慢阻肺的炎症细胞主要是中性粒细胞、巨噬细胞，而目前对于中性粒细胞参与的炎症，激素治疗是无效的。
所以，虽然两者都是炎症，但由于参与炎症的细胞不一样，最后在治疗上也不完全一样。
Prof. Anzueto: Asthma and COPD are two completely different diseases. Clearly, asthma is seen mainly in younger individuals who have very strong exposure to environmental conditions and history of allergen. So the person in 20s that developed this intermittent episode, we called it asthma. While the patients were in their 60s, 70s, who happened to smoke could developed COPD.
Because we have different diseases, our therapies cannot be the same. In asthma, especially younger patients, we know the inhaled corticosteroid (ICS) is efficient and the role of bronchodilator is not clear.
In the other hand, for COPD the bronchodilators had sustaining bronchial dilatation, once-a-day bronchodilators and cholinergic system bronchodilators had maximum effect. This is the difference in the treatment.
GOLD Committee recommends ICS used in COPD in patients are very sick and those have frequent exacerbations, but this is going to be very small number of patients. It has been shown that those patients will decrease the frequency of exacerbation. And this indicates that how to use ICS.
Nowwe are learning more about how long we need to do with ICS, whether we can stop using ICS and if it is safe to stop ICS. Because ICS had side effects that we would like to minimize with our patients.
Anzueto教授：支气管哮喘和慢阻肺是两种完全不同的疾病。支气管哮喘常见于青年患者，患者通常暴露在很强的环境因素下和有过敏原接触史。因此，20多岁的患者出现支气管炎症性反应我们称之为支气管哮喘。而60－70岁同时有抽烟史的患者，可能会发展成慢阻肺。
由于支气管哮喘和慢阻肺是两种不同疾病，因此治疗方案也会不同。对于哮喘患者，尤其是年轻患者，吸入性激素治疗是有效的，但支气管扩张剂的疗效性和安全性并不十分清楚。
而对于治疗慢阻肺，支气管扩张剂能够有效持续扩张气道。其中，抗胆碱能药物对扩张气道作用更强。这就是两种疾病在治疗上的不同。
针对激素的使用，GOLD指南委员会推荐在极重度患者和频繁发生急性加重的患者种使用吸入性激素治疗，这样能减少急性加重发生的次数，但这毕竟是少数患者。我相信这个推荐建议能够提示我们如何使用吸入性激素治疗。
如今，我们对于使用激素的时长、是否能够停用激素和停用激素的过程是否安全有了越来越多的探讨，因为我们希望最小化激素副作用对患者的影响。
丁香园：过去常有医师随意使用激素治疗慢阻肺，对于这个问题您如何看待？应该如何规范激素类药物的使用？
DXY: In the past days, many non-specialist clinicians prescribed ICS to treat COPD improperly, how do you think about this problem? How to use ICS properly?
黄绍光教授：上世纪，临床上确实用过激素治疗慢阻肺，临床研究证明它对一些急性加重有一定帮助。
近年认识到，长效支气管扩张剂中加入一些激素使用可能有一定效果，但是对于激素本身，GOLD指南也明确指出，对它的随意使用是不合理的。
Prof. Anzueto: Maybe it’s easier to use ICS and LABA on everybody, unfortunately that is not right. Because ICS is not a good bronchodilator, they don’t have sustaining bronchial dilatation and there are side effects.
So we have to take the therapy to what patients need. In patients who have COPD moderate disease, long active bronchodilators can significantly improve lung function,and there is no need to use ICS until late in life.
Anzueto教授：对于医生来说，简单地对每个慢阻肺病人使用激素或长效β2受体激动剂可能很方便，但其实是不正确的。因为吸入性激素并不是一种很有效的支气管扩张剂，不能持续扩张气道，同时有较多副作用。
因此我们应该根据患者的需要来选择药物。其中对于中度慢阻肺患者，长效支气管扩张药就可以明显提高肺功能，没有必要使用激素治疗。
丁香园：慢阻肺的早期诊断一直是临床工作的一个难点，多数患者仅在出现严重的呼吸困难或急性加重后才引起重视，然而往往为时已晚。您认为应如何提高慢阻肺的诊断率，进行早防早治？
DXY: In China, the early diagnosis of COPD has always been a clinical difficulty. And the decision to seek medical help is usually determined by impact of dyspnea and exacerbation, could you share some experience on improving the diagnosis situation and lead patients to early therapy?
黄绍光教授：慢阻肺的临床症状有咳嗽、咳痰，但到患者就诊时都出现了呼吸困难。而呼吸困难是过度充气到十分明显的时候才会出现，所以慢阻肺病人就诊都是偏迟的。
现在诊断慢阻肺主要靠肺功能检查，特别是要靠通气功能的检测。但目前肺功能检查的推广还是不够，因此慢阻肺要单靠肺功能检测诊断有一定困难。
近年提到，诊断慢阻肺并不完全依赖肺功能检查，也可以做一些临床诊断。比如在咳嗽、咳痰的情况下接触过其他危险因素，比如吸烟，那么再结合一些临床症状也可以做出临床诊断。这样就有可能提早诊断慢阻肺，不一定完全要等肺功能检查结果的诊断。
从目前看，我国吸烟人群很大，其中牵涉到，我们如何提高对慢阻肺的认识。有这样的症状和危险因素接触史，要想到有这种疾病的可能性。
随着我们对慢阻肺的不断宣传，现在人们对这个疾病的认识有所提高。国家已经把慢阻肺放到慢性病防治中去了，相信慢阻肺的诊断情况会改善。
另一个问题就是早诊断需要手段。现在国家正在推行戒烟，同时药物治疗也是需要推广的。尤其强调较早使用支气管扩张剂，帮助病人减轻症状，让他认识到疾病治疗前后的对比。
Prof. Anzueto: The assumption was that smokers will develop COPD. Today we know that is not the case. Not every smoker develops COPD, maybe 15%~20% develop lung fibrosis，which is a completely different disease. That needs to be diagnosed.
Also we know now the correlation between how many packs an individual smokes a day and the severity to disease, people can smoke a little bit and have very severe disease, while some smoke a lot but have mild disease. So this urges that we need to diagnose COPD early. The diagnosis is the combination of clinical characteristics as well as the spirometry to confirm COPD.
Patients don’t realize the cough and the shortness to breath they are having is not normal. Many patients’ first diagnoses of COPD was in autumn or winter when they get respiratory problem, then go to the hospital with bronchitis, pneumonia, and as a consequence of that, get the diagnosis of COPD.
We really need to emphasis to educate patients as health care provider, we need to look for COPD and to make diagnoses.
Anzueto教授：过去，我们认为抽烟的人最终都会发展成慢阻肺。但如今，我们知道并不是所有抽烟的人都会得慢阻肺，其中有15%~20%的人可能患上肺部纤维化，这是另一种完全不同的疾病了，其病情发展比诊断更为迅速。因此这需要被尽快鉴别诊断。
同样地，现在我们也知道了抽烟量与病情严重度之间的联系，有些人抽得不多但可能病情严重，而一些人抽的很多病情却很轻。这个现象也敦促我们需要尽早诊断慢阻肺，而它的诊断需要结合临床特征和肺功能检查来确诊。
另一方面，病人没有意识到平常那些频繁的咳嗽和气短是不正常的。很多患者在秋冬因为支气管炎症和肺炎到医院就诊，最后却被确诊是慢阻肺。
这些现状都提示，我们作为临床医师，需要加强患者对慢阻肺的疾病认识来尽早诊断慢阻肺。
丁香园：肺功能检查是诊断慢阻肺的金标准。根据FEV1标准，对于属于中度或B组患者人群较大。那么对于中度或B类的慢阻肺患者，应评估哪些因素来选择治疗方案？应首选怎样的治疗方案？
DXY: We know that spirometry is required to make the diagnosis. The use of the fixed FEV1/FVC ratio to define airflow limitation will result in more moderate COPD patients. For moderate/ Group B patients, what factors should be evaluated to select therapeutic option? What’s the first choice?
黄绍光教授：按照现在国内外研究，目前一致认为肺功能检查还是一个非常重要的诊断标准，但是作为随访评估有欠缺的地方。
GOLD指南在2011年修订以后，提出一个比较全面的对慢阻肺进行评估的标准，第一是用肺功能检查判断气流受限程度，第二是要评估基本临床症状尤其是活动能力，第三是评估急性加重的风险。
对于急性加重，现在我们认识到，它是一个非常重要的判断病人预后、治疗等的客观标准。所以我们可以将它综合起来做非常全面的评估。评估的目的，一方面是为了让我们了解病人的病情严重程度，另外也可以在病人治疗以后做一个客观全面的评价。
而根据GOLD指南，B组患者首选长效抗胆碱能药物（LAMA）进行治疗。刚刚也提到了，在胆碱能神经参与的过程当中，它是减轻慢阻肺病人症状的主要可逆因素。
所以在这个过程中使用支气管扩张剂，尤其是在病情比较稳定的状态下，要去改变病人的症状，长效抗胆碱能药物（LAMA）有一定优势。
Prof. Anzueto: There are a couple of issues in this question.
To diagnose hypertension you have to make sure the blood pressure, to diagnose diabetes, you have to make sure the sugar and Hb1C. To diagnose COPD is no different, you cannot diagnose only in patients’ history, you need to have spirometry.
Spirometry is needed to identify the patients as soon as possible in the disease for two reasons. We understand now the moderate patients with 60%~70%, they are impaired in the exercise capacity, they are already having significant symptoms. If they are treated, you can decrease the slope with decline in lung function, you actually can sustain them for longer period.
The second point is the patients who have moderate COPD lose more lung function, so they are 70% now, in two years it’s going to be 60%, in five years it’s going to be 50%, if it goes further down it cannot reverse. So the sooner use therapy intervention from smoking cessation to pharmacal therapy, the better for the patients.
As for Group B, long acting bronchodilators such as LABA or LAMA should be the first line of therapy. Because they could improve the symptoms, decrease the bronchial restriction, and increase the work of respiratory muscles by decreasing the hyperinflation, so this is the ideal patient population.
Anzueto教授：这个问题涉及到很多方面。
就像诊断高血压前要测量血压，诊断糖尿病前要测量血糖和糖化血红蛋白一样，要诊断慢阻肺就不能只看患者病史，还要做肺功能检查。
想要尽可能快地诊断慢阻肺，肺功能检查必不可少。这里有两个原因。第一点是我们知道中度／B组慢阻肺患者通常FEV1占预计值的60%~70%，实际上此时他们运动耐量已经下降，并且出现了明显症状。如果这时他们得到治疗，就能减少对肺功能的损害并且长期维持下去。
第二点是中度／B组慢阻肺患者的肺功能往往下降得更快。FEV1/FVC现在可能是70%，两年后可能下降到60%，五年后可能到50%，如果继续下降，那么肺功能下降将不可逆转。因此，越早让患者戒烟和接受药物治疗，对患者治疗越好。
而针对中度／B组患者的治疗，长效支气管扩张剂如LABA和LAMA都应该作为一线药物使用。它们可以有效改善症状、减轻气道受限和过度充气，中度／B组患者是理想的使用人群。
