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

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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.