Translational studies into the role of CNP and NEP inhibition in acute inflammation- a potential novel therapeutic approach to ARDS

CNP 和 NEP 抑制在急性炎症中作用的转化研究——ARDS 的潜在新治疗方法

基本信息

批准号：
MR/T027991/1
负责人：
Aemun Salam
金额：
$ 42.64万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT027991%2F1
关键词：
Translational studies into role CNP

项目摘要

Acute Respiratory Distress Syndrome is a severe type of lung injury that affects 10% of patients admitted to Intensive Care Units worldwide, with an unacceptably high mortality of up to 48% in those with the most severe form of the condition. It is a complex and poorly understood syndrome that results in progressive failure of the lungs. Crucially, the inflamed lungs allow fluid to leak from the circulation into the airspace, so that patients' lungs fill with fluid - "drowning from the inside". As this condition progresses, the patient typically requires increasing amounts of oxygen and eventually, support from a ventilator. To date, there are no effective treatments for ARDS that can limit, stop or repair this process. This research study is aiming to look at a naturally occurring substance produced by blood vessels, C-type natriuretic peptide (CNP). We have evidence suggesting that CNP plays a role in maintaining the barrier provided by blood vessels that stops fluid leaking out into tissues. This is based on various studies done on CNP by our research group that have established its widespread role in maintaining cells that line blood vessels and play a vital role in lungs' barrier function: the endothelium. To establish whether this is truly the case, I will be studying endothelial cells grown in a layer outside the body to determine the effects of CNP on the leakiness of the layer and how it affects inflammation generally. In addition, I will be assessing whether genetically modified mice that cannot make CNP in their endothelium suffer from worse lung failure, and whether this can be rescued by replacing CNP.Most importantly, there is an existing safe drug that has been used for decades to treat diarrhoea, that works in part by limiting the breakdown of CNP. If CNP does in fact strengthen the lungs' endothelial barrier, then this drug may benefit patients with ARDS. Hence, I will be studying the effects of this drug on mouse models of acute lung injury that mimic ARDS in patients to look for an improvement in the degree of leak found in their lungs. I will also test the effect of this drug in a well-established, safe model of inflammation-induced skin blisters in a healthy human volunteer study to determine primarily whether the fluid accumulation i.e. leak, in these blisters is reduced by treatment with this drug.If my hypothesis is proven to be correct, there is potential for a new treatment to go into trials in patients with ARDS quickly and inexpensively.

急性呼吸窘迫综合征是一种严重的肺损伤，影响全球重症监护病房 10% 的患者，最严重的患者死亡率高达 48%，令人难以接受。这是一种复杂且知之甚少的综合征，会导致肺部进行性衰竭。至关重要的是，发炎的肺部使液体从循环系统泄漏到空气空间中，从而使患者的肺部充满液体——“从内部淹没”。随着病情的发展，患者通常需要增加氧气量，最终需要呼吸机的支持。迄今为止，还没有有效的 ARDS 治疗方法可以限制、停止或修复这一过程。这项研究的目的是研究血管产生的一种天然物质，C 型利尿钠肽 (CNP)。我们有证据表明，CNP 在维持血管提供的屏障方面发挥着作用，阻止液体渗漏到组织中。这是基于我们的研究小组对 CNP 进行的各种研究，这些研究已经确定了 CNP 在维持血管内皮细胞和在肺部屏障功能中发挥重要作用的细胞（内皮细胞）方面的广泛作用。为了确定情况是否属实，我将研究在体外生长的内皮细胞，以确定 CNP 对层渗漏的影响以及它如何影响炎症。此外，我将评估不能在内皮中产生CNP的转基因小鼠是否会遭受更严重的肺衰竭，以及是否可以通过替换CNP来挽救这种情况。最重要的是，有一种现有的安全药物已经使用了几十年治疗腹泻，其部分作用是通过限制 CNP 的分解来发挥作用。如果 CNP 确实能增强肺内皮屏障，那么这种药物可能会使 ARDS 患者受益。因此，我将研究这种药物对模拟 ARDS 患者的急性肺损伤小鼠模型的影响，以寻找肺部渗漏程度的改善情况。我还将在一项健康人类志愿者研究中，在一个完善的、安全的炎症引起的皮肤水泡模型中测试这种药物的效果，以主要确定使用这种药物治疗是否可以减少这些水泡中的液体积聚（即渗漏）。如果我的假设被证明是正确的，那么一种新的治疗方法就有可能快速且廉价地在 ARDS 患者中进行试验。