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

定义前列环素药物在肺纤维化中的抗纤维化机制

• 批准号: MR/X001814/1
• 负责人: James May
• 金额: $ 36.91万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FX001814%2F1
• 关键词: Defining; anti; fibrotic; mechanisms; prostacyclin

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.

特发性肺纤维化（IPF）是一种侵袭性疾病，健康的肺组织被疤痕组织取代。肺部变得僵硬，失去将氧气从大气转移到血液的能力。由于病因不明，该疾病被称为“特发性”。 IPF 是英国呼吸系统疾病的第四大死因。这种疾病在男性中更为常见，特别是影响 70 岁以上的人。根据 2012 年记录的最新可用数据，有 32,500 人患有这种疾病。这个数字正在上升，并且预计将继续增加。平均生存率很差，从诊断之日起预期寿命仅为三年。这与最严重的癌症相当。 IPF 的症状包括进行性呼吸短促和干咳。在后期，肺动脉血压也会升高，对心脏和循环系统造成压力（称为肺动脉高压），导致心力衰竭和体液潴留。目前对 IPF 微观层面发生情况的了解如下：肺部气道内的细胞受到损害（例如，由于吸入烟雾或病毒），而这种损害后的正常修复过程会以不受控制的方式进行，并产生大量疤痕组织。发生这种情况可能是因为一个人携带一组基因，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。英国批准了两种药物——吡非尼酮和尼达尼布——但这两种药物仅被证明可以减缓疤痕形成过程，并伴有许多副作用。没有任何治疗方法可以阻止或逆转疤痕。在最近的一项临床试验中，一种名为曲前列环素的药物被证明可以改善肺部高血压，还可以降低肺部疤痕患者的肺组织硬度。曲前列环素属于一类被称为前列环素的药物，它天然存在于体内，在维持血压和凝血方面具有重要功能。它们长期以来被用于治疗肺动脉高压。曲前列环素和其他可用的前列环素药物到底如何改善肺部疤痕尚不清楚，但它可能代表了一种令人兴奋的 IPF 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。我的研究计划是更好地定义前列环素药物如何在肺部参与纤维化的单个细胞中发挥作用。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何影响。我将在从人类和小鼠身上获得的细胞中对此进行测试。 2) 确定前列环素药物对疤痕组织的生成有何影响 - 例如，前列环素药物是否会减少纤维化组织的产生量？这种作用在特定细胞中是否最明显？ 3) 测试是否可以将不同的前列环素药物和其他在细胞内作用的药物组合起来，以最大限度地发挥所见的有益效果。从这些实验中获得的信息将有助于解释这些药物如何发挥作用，更重要的是它们如何可能使 IPF 患者受益。

项目成果

Beyond epithelial damage: vascular and endothelial contributions to idiopathic pulmonary fibrosis.

• DOI: 10.1172/jci172058
• 发表时间: 2023-09-15
• 期刊: JOURNAL OF CLINICAL INVESTIGATION
• 影响因子: 15.9
• 作者: May, James;Mitchell, Jane A.;Jenkins, R. Gisli
• 通讯作者: Jenkins, R. Gisli