Modulators of the Hypoxia-inducible Factor (HIF) pathway and their impact on the pulmonary vasculature in humans

缺氧诱导因子 (HIF) 途径的调节剂及其对人类肺血管系统的影响

• 批准号: MR/W030020/1
• 负责人: Mary Slingo
• 金额: $ 25.43万
• 依托单位: University of Oxford
• 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%2FW030020%2F1
• 关键词: Modulators; Hypoxia; inducible; Factor; HIF

The blood vessels within the lungs are unique. In other parts of the body, when there is not enough oxygen present, the blood vessels increase in size (dilate) to deliver more blood to the organs. However, in the lungs, they narrow (constrict). This is because continuing to send blood to an area of the lung that does not contain oxygen is inefficient - blood is diverted to parts of the lung that can continue to pass oxygen into the bloodstream.The blood vessels of the lung react very quickly, and we can see this using ultrasound of the heart - as the vessels constrict, the blood pressure in the lung increases. Eventually, this increase can actually affect how the heart functions and how well it pumps. These blood vessels can constrict more effectively under certain circumstances. For example, we know that when a lack of oxygen (termed hypoxia) continues for several hours, the blood vessels are able to react more strongly i.e. they are 'primed'. This means the blood pressure in the lungs increases to a higher level.Why does sustained hypoxia make changes in the body like this? The answer is due to an important 'signaling pathway' - a cascade of steps that results in genes being switched on from our DNA. These genes have many different effects, and one of these is to make the blood vessels in our lungs more sensitive to hypoxia. This signaling pathway is incredibly important - indeed, the scientists who discovered it were awarded the Nobel Prize in 2019. It is present in all of us, and in all animals, and it orchestrates the changes that happen to us when there is not enough oxygen present e.g. at altitude, or due to lung diseases, or locally in different types of cancers.We now understand a great deal about the different components of this signaling pathway - there are several steps that are very important. When these steps go wrong due to genetic diseases, or when they are manipulated by drugs, changes happen in how the body functions. We know, for example, that there are people with genetic conditions that mean that the pathway is always switched on, even when there is plenty of oxygen present. Scientists discovered that the blood vessels in the lungs of these people constrict very strongly in hypoxia. This tells us that this signaling pathway plays an important role in controlling the blood pressure in our lungs.This is significant, because there is a drug that is licensed in many countries, including in the UK, that switches on this hypoxia signaling pathway. This drug is used to treat the anaemia (low haemoglobin and low red blood count) that accompanies long-term kidney disease. By switching on the hypoxia pathway, this drug (called Roxadustat) switches on the gene for EPO (erythropoietin) and tells the body to make more haemoglobin and red blood cells. This is a good thing, and the drug has been shown to be safe.However, we don't know what this drug does to the blood vessels in the lungs. Based on what we know already, we would expect that it would make them react more strongly when there is a lack of oxygen. This is important - many people around the world will be taking this drug for a long time, and if they become unwell then there will be a lack of oxygen and this could cause high blood pressure in the lungs, and even affect the heart. This can even be relevant during air travel, since the air pressure in the cabin of the plane is a bit lower than normal, and so there is less oxygen to breathe. Most people don't notice this, but it could be important for people taking this kind of drug.Therefore, the aim of this research study is to give Roxadustat to healthy volunteers and measure the blood pressure in the lungs when they are breathing normal air, and when they are breathing in less oxygen. This will tell us what effect the drug is having on the blood vessels in the lungs, and help guide scientists and doctors in the future.

肺部的血管是独一无二的。在身体的其他部位，当没有足够的氧气存在时，血管会增大（扩张）以向器官输送更多的血液。然而，在肺中，它们变窄（收缩）。这是因为继续将血液输送到肺部不含氧气的区域是效率低下的-血液被转移到肺部可以继续将氧气输送到血液中的部分。肺部的血管反应非常快，我们可以通过心脏的超声看到这一点-随着血管收缩，肺部的血压升高。最终，这种增加实际上会影响心脏的功能和泵血的效果。这些血管在某些情况下可以更有效地收缩。例如，我们知道，当缺氧（称为缺氧）持续几个小时时，血管能够做出更强烈的反应，即它们是“启动”的。这意味着肺部的血压升高到一个更高的水平。为什么持续的缺氧会使身体发生这样的变化？答案是由于一个重要的“信号通路”-一个级联的步骤，导致基因从我们的DNA被打开。这些基因有许多不同的作用，其中之一就是使我们肺部的血管对缺氧更敏感。这种信号通路非常重要-事实上，发现它的科学家在2019年获得了诺贝尔奖。它存在于我们所有人和所有动物体内，当氧气不足时，例如在高海拔地区，或由于肺部疾病，或局部不同类型的癌症，它会协调发生在我们身上的变化。我们现在对这个信号通路的不同组成部分有了很多了解-有几个步骤非常重要。当这些步骤由于遗传疾病而出错时，或者当它们被药物操纵时，身体功能就会发生变化。例如，我们知道，有些人的遗传条件意味着这条通路总是打开的，即使有足够的氧气存在。科学家们发现，这些人肺部的血管在缺氧时收缩得非常厉害。这告诉我们，这种信号通路在控制我们肺部的血压方面起着重要作用。这很重要，因为有一种药物在包括英国在内的许多国家都获得了许可，可以打开这种缺氧信号通路。这种药物用于治疗伴随长期肾脏疾病的贫血（低血红蛋白和低红细胞计数）。通过打开缺氧通路，这种药物（称为Roxadustat）打开EPO（促红细胞生成素）的基因，并告诉身体制造更多的血红蛋白和红细胞。这是一件好事，而且这种药物已被证明是安全的。然而，我们不知道这种药物对肺部血管有什么影响。根据我们已经知道的情况，我们预计当缺氧时，它会使它们反应更强烈。这一点很重要-世界各地的许多人将长期服用这种药物，如果他们身体不适，就会缺氧，这可能会导致肺部高血压，甚至影响心脏。这甚至可能与空中旅行有关，因为飞机机舱内的气压比正常情况下略低，因此呼吸的氧气较少。大多数人没有注意到这一点，但这对服用这种药物的人来说可能很重要。因此，这项研究的目的是给健康志愿者服用Roxadustat，并测量他们在呼吸正常空气时和呼吸氧气较少时肺部的血压。这将告诉我们药物对肺部血管的影响，并有助于指导未来的科学家和医生。