Defining the anti-fibrotic mechanisms of prostacyclin drugs in pulmonary fibrosis

特发性肺纤维化(IPF)是一种由瘢痕组织取代健康肺组织的侵袭性疾病。肺部变得僵硬，失去了将氧气从大气转移到血液的能力。由于病因不明，这种疾病被称为“特发性”。在英国，IPF是呼吸系统疾病的第四大死因。这种情况在男性中更常见，特别是对70岁以上的人。根据2012年记录的最新数据，有3.25万人患有这种疾病。这一数字正在上升，预计还会继续上升。平均存活率很低，从确诊之日起的预期寿命只有三年。这与最严重的癌症不相上下。IPF的症状包括进行性呼吸急促和干咳。在后期，肺动脉的血压也会升高，对心脏和循环造成压力(称为肺动脉高压)，导致心力衰竭和液体滞留。目前对IPF微观水平上发生的事情的理解如下：肺内呼吸道的细胞受损(例如，吸入烟雾或病毒)，伴随这种损伤的正常修复过程以不受控制的方式进行，并产生大量疤痕组织。这可能是因为一个人携带了一组基因，使他们更容易受到影响。不幸的是，这种情况缺乏有效的治疗方法。有两种药物在英国获得批准--Pirfenidone和Nintdanib--但这两种药物都只被证明可以减缓疤痕形成的过程，并伴随着一些副作用。目前还没有可以阻止或逆转疤痕形成的治疗方法。在最近的一项临床试验中，一种名为Treprostinil的药物被证明既能改善肺部的高血压，又能减轻肺疤痕患者的肺组织僵硬。曲普替尼属于一类被称为前列环素的药物，这种药物自然存在于体内，在维持血压和凝血方面具有重要功能。长期以来，它们一直被用来治疗肺动脉高压。Treprostinil和其他可用的前列环素药物如何改善肺瘢痕形成的确切原因尚不清楚，可能是一种令人兴奋的新疗法。了解前列环素药物在IPF中的作用将有助于更好地确定如何最好地使用这些药物来治疗这种疾病。我的研究建议是更好地定义前列环素药物在肺中发现的参与纤维化的单个细胞内如何发挥作用。我的三个目标如下：1)确认前列环素药物如何与相关细胞相互作用--例如，通过确定这些药物与哪些受体结合，以及这对细胞内的机制有什么影响。我将在从人类和老鼠身上获得的细胞中测试这一点。2)确定前列环素药物对瘢痕组织的生成有什么影响--例如，前列环素药物是否减少了纤维组织的生成，这种影响在特定的细胞中是否最明显？3)测试不同的前列环素药物和其他在细胞内作用的药物是否可以最大限度地发挥任何有益作用。从这些实验中获得的信息将有助于解释这些药物是如何工作的，以及重要的是它们如何潜在地使IPF患者受益。

Idiopathic pulmonary fibrosis (IPF) is an aggressive disease in which healthy lung tissue is replaced by scar tissue. The lungs become stiff and lose their ability to transfer oxygen from the atmosphere to the blood. The disease is termed "idiopathic" as the cause is unknown. IPF is the fourth leading cause of death from a respiratory illness in the UK. The condition is more common in men, particularly affecting those over the age of 70. 32,500 people were living with the condition as per the last available data recorded in 2012. This number is rising and is predicted to continue to do so. The average survival is poor with a life expectancy of only three years from the time of diagnosis. This is comparable to the worst cancers. Symptoms of IPF include progressive shortness of breath and dry cough. In the later stages, the blood pressure in the arteries of the lungs can also rise, putting strain on the heart and circulation (termed pulmonary hypertension) leading to heart failure and fluid retention.The current understanding of what happens on a microscopic level in IPF is as follows: cells which line the airways in the lungs are damaged (by, for example, smoke inhalation or a virus) and the normal repair process that would follow this damage does so in an uncontrolled manner and produces large amounts of scar tissue. This may happen because an individual carries a set of genes making them more susceptible. Unfortunately, there is a lack of effective treatments for the condition. Two drugs are approved in the UK - Pirfenidone and Nintedanib - but both have only been proven to slow the scarring process down and come with a number of side effects. No treatments are available which can stop or reverse the scarring. In a recent clinical trial, a drug called Treprostinil was shown to improve both the high blood pressure in the lungs but also reduce the stiffness of the lung tissue in patients with lung scarring. Treprostinil belongs to a class of drugs known as prostacyclins which naturally occur in the body and have important functions in maintaining blood pressure and also blood clotting. They have long been used to treat pulmonary hypertension. Precisely how Treprostinil and other available prostacyclin drugs improve lung scarring is less well understood and possibly represent an exciting new treatment for IPF.Understanding how prostacyclin drugs work in IPF will help to better establish how these agents can be best used to treat the condition. My research proposal is to better define how prostacyclin drugs act within individual cells found in the lungs which are involved in fibrosis. My three aims are as follows: 1) Confirm how prostacyclin drugs interact with relevant cells - for example by establishing which receptors these agents combine with and what effect this has on the machinery inside the cells. I will test this in cells obtained from humans and mice. 2) Establish what effect prostacyclin drugs have on the generation of scar tissue - for example, do prostacyclin drugs reduce the amount of fibrotic tissue generated and is this effect most pronounced in a specific cell? 3) Test whether combining different prostacyclin drugs and other agents which act within the cells can be used to maximize any beneficial effect seen.The information gained from these experiments will have helped explain how these drugs work and importantly how they can potentially benefit patients with IPF.