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类型，影响了全球重症监护病房的10％的患者，在患病最严重的情况下，高死亡率高达48％。这是一个复杂且知之甚少的综合征，导致肺进行性衰竭。至关重要的是，发炎的肺使液体从循环中泄漏到空域，从而使患者的肺充满液体 - “从内部溺水”。随着这种情况的发展，患者通常需要增加氧气量，最终需要呼吸机的支撑。迄今为止，尚无对ARDS的有效治疗方法可以限制，停止或修复此过程。这项研究的目的是研究由血管，C型纳地酸肽（CNP）产生的天然物质。我们有证据表明，CNP在维持血管提供的屏障中起作用，从而阻止流体泄漏到组织中。这是基于我们的研究小组对CNP进行的各种研究，该研究在维持血管排列血管并在肺部屏障功能中起着至关重要的作用而建立了广泛的作用：内皮。为了确定是否确实是这种情况，我将研究在体外层中生长的内皮细胞，以确定CNP对层泄漏的影响及其通常如何影响炎症。此外，我将评估无法使CNP在其内皮中无法使肺部衰竭的遗传修饰的小鼠以及是否可以通过更换CNP来挽救这一点。最重要的是，有一种现有的安全药物数十年来用于治疗腹泻，可以通过部分限制CNP的分解来治疗腹泻。如果CNP实际上确实加强了肺部内皮屏障，则该药物可能使ARDS患者受益。因此，我将研究这种药物对模仿患者的急性肺损伤小鼠模型的影响，以寻求改善其肺部泄漏程度。在一项健康的人类志愿者研究中，我还将在炎症引起的皮肤水泡的良好安全模型中测试该药物的作用，以确定主要的液体积累，即泄漏，通过使用这种药物的治疗来降低这些水泡。如果我的假设被证明是正确的，那么有可能在Ards和Indspsimends和Indss的患者中进行新的治疗方法，可以进行试验。