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:
- 金额:$ 42.64万
- 依托单位:
- 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:
- 关键词:
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,影响到全球10%的重症监护病房患者,最严重的患者死亡率高达48%,令人无法接受。这是一种复杂且知之甚少的综合征,导致肺部进行性衰竭。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,因此患者的肺部充满液体-“从内部溺水”。随着病情的进展,患者通常需要增加氧气量,并最终需要呼吸机的支持。到目前为止,还没有有效的治疗方法可以限制,停止或修复这一过程。这项研究的目的是研究血管产生的一种天然物质,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进行的各种研究,这些研究已经确定了CNP在维持血管细胞中的广泛作用,并在肺屏障功能中发挥重要作用:内皮细胞。为了确定这是否是真的,我将研究体外培养的内皮细胞,以确定CNP对该层泄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代CNP来挽救这种情况。最重要的是,有一种现有的安全药物已被用于治疗腹泻数十年,其部分工作原理是限制CNP的分解。如果CNP确实增强了肺的内皮屏障,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,这些模型模拟患者的ARDS,以寻找在他们的肺部发现的泄漏程度的改善。我还将在健康志愿者研究中,在一个成熟的、安全的炎症诱导的皮肤水疱模型中测试这种药物的效果,以初步确定这种药物治疗是否减少了这些水疱中的液体积聚,即渗漏。如果我的假设被证明是正确的,那么有可能在ARDS患者中快速廉价地进行新的治疗试验。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Encyclopedia of Respiratory Medicine
呼吸系统医学百科全书
- DOI:10.1016/b978-0-08-102723-3.00232-8
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Proudfoot A
- 通讯作者:Proudfoot A
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