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

急性呼吸窘迫综合症是一种严重的肺损伤，影响全球10%的重症监护病房患者，在那些病情最严重的患者中，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，导致肺功能进行性衰竭。至关重要的是，发炎的肺部允许液体从循环中泄漏到空气中，从而使患者的肺部充满液体--“从内部溺水”。随着病情的发展，患者通常需要越来越多的氧气，最终需要呼吸机的支持。到目前为止，还没有有效的治疗ARDS的方法来限制、停止或修复这一过程。这项研究旨在观察一种由血管产生的自然物质--C型利钠肽(CNP)。我们有证据表明，CNP在维持血管提供的屏障方面发挥作用，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，这些研究确定了CNP在维持排列血管的细胞以及在肺屏障功能中发挥关键作用的广泛作用：内皮。为了确定是否真的是这样，我将研究生长在体外一层的内皮细胞，以确定CNP对这一层的渗漏的影响，以及它一般是如何影响炎症的。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，以及是否可以通过取代CNP来挽救这一问题。最重要的是，现有的一种安全药物已经用于治疗腹泻数十年，这种药物在一定程度上通过限制CNP的分解发挥作用。如果CNP确实增强了肺部的内皮屏障，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，以期改善他们肺部的渗漏程度。我还将在一项健康的志愿者研究中，在一个成熟的、安全的炎症诱导皮肤水泡模型中测试这种药物的效果，以初步确定使用这种药物治疗是否减少了这些水泡中的液体积累，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有可能迅速和廉价地进入ARDS患者的试验。

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.