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

急性呼吸窘迫综合征是一种严重类型的肺损伤，影响着全世界10%的重症监护病房住院患者，最严重形式的患者死亡率高达48%，令人无法接受。这是一种复杂且知之甚少的综合征，可导致肺部进行性衰竭。至关重要的是，发炎的肺部会让液体从循环系统中泄漏到空气中，这样患者的肺部就会充满液体——“从内部淹死”。随着病情的发展，患者通常需要越来越多的氧气，并最终需要呼吸机的支持。迄今为止，还没有有效的治疗方法可以限制、停止或修复这一过程。这项研究旨在研究一种由血管产生的天然物质，c型利钠肽（CNP）。我们有证据表明，CNP在维持血管提供的屏障中起作用，阻止液体泄漏到组织中。这是基于我们的研究小组对CNP所做的各种研究，这些研究已经确定了CNP在维持血管细胞和肺屏障功能（内皮）中发挥重要作用方面的广泛作用。为了确定这是否真的是这样，我将研究生长在体外一层的内皮细胞，以确定CNP对该层渗漏的影响，以及它如何影响炎症。此外，我将评估不能在内皮细胞中产生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，已有一种安全的药物用于治疗腹泻已有几十年的历史，它的部分作用是限制CNP的分解。如果CNP确实增强了肺内皮屏障，那么这种药物可能对ARDS患者有益。因此，我将研究这种药物对急性肺损伤小鼠模型的影响，这些模型模拟ARDS患者，以寻找改善肺部泄漏程度的方法。我还将在一个健康的人类志愿者研究中，在一个完善的、安全的炎症性皮肤水泡模型中测试这种药物的效果，主要是为了确定用这种药物治疗是否会减少这些水泡中的液体积聚，即泄漏。如果我的假设被证明是正确的，那么就有可能有一种新的治疗方法快速而廉价地进入ARDS患者的试验阶段。

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.