Modulation of neutrophil dysfunction in tracheostomised children to prevent respiratory infections

调节气管切开儿童的中性粒细胞功能障碍以预防呼吸道感染

• 批准号: MR/X018237/1
• 负责人: Jason Powell
• 金额: $ 196.97万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX018237%2F1
• 关键词: Modulation; neutrophil; dysfunction; tracheostomised; children

Many young children who have serious medical problems require help with their breathing long-term. In this setting some children need a procedure called a "tracheostomy'', which involves a surgeon making a small hole in the windpipe, and inserting a small tube, allowing them to breathe more easily. The tracheostomy can sometimes be removed at a later date. However, many children have the tracheostomy for a number of years. Living with a tracheostomy carries a significant burden as carers have to ensure the tube does not block, which would result in death. Children with tracheostomies are much more prone to chest infections than other children. These infections can result in multiple admissions to hospital and can themselves be life-threatening. Little is known about why children with tracheostomies get so many chest infections and therefore we do not know how to prevent them. A major problem with research in this area has been getting samples from children undergoing a tracheostomy. My previous research has overcome this by working closely with those involved in the care of these children, including doctors, nurses and parents. This work has shown that children's windpipes "overreact" to the tracheostomy procedure, and that this might actually reduce the body's ability to fight infection. During infection, cells called neutrophils normally recognise, "eat" and kill bacteria and we believe this essential process does not happen properly after a tracheostomy. In children with tracheostomies, neutrophils seem to cause damage to the lining of the windpipe, allowing harmful bacteria to enter and cause chest infections.I plan to use samples of sputum (taken directly from the windpipe) and blood taken from children with and without a tracheostomy to: 1) understand why neutrophils might not be fighting bacteria effectively - this will include using innovative technologies to look at and measure the way neutrophils, taken out of the body, respond to bacteria; 2) assess how this defective function might be causing the lungs to become damaged; and 3) look at ways of "repairing" these neutrophils using drugs that restore their ability to kill bacteria and stop neutrophils from releasing chemicals that harm the windpipe. This, we anticipate, will reduce damage in the airway, allowing neutrophils to kill bacteria in the way they are intended to. By using live cells taken out of the body (from children's sputum or blood samples) and testing them in the laboratory I can check if these drugs work, without any risk of harm to the child, and without using animal testing. The drugs that I identify to be most efficient at restoring neutrophil function can subsequently be tested on children in a clinical trial. The ultimate aim of the work is to find new drugs to reduce the number of chest infections that children with tracheostomies children have to endure, and the associated complications of these infections.Findings of the study will be shared with other researchers, and much of this work will help researchers studying other lung conditions in which neutrophils play a damaging role.I will collaborate with researchers in other centres, including Durham, Belfast, Berlin and Vancouver. As part of my vision for this project I have assembled a team of people with relevant experiences and skills from different backgrounds, such as clinicians, physicists and laboratory scientists all bringing specific skills together to solve an important problem. The research will provide me with a unique skillset to become a world-leading researcher seeking new solutions to improve the quality of life and survival of children requiring tracheostomies.

许多有严重医疗问题的幼儿需要长期的呼吸帮助。在这种情况下，一些儿童需要一种称为“气管造口术”的手术，这涉及外科医生在气管上打一个小孔，插入一根小管，让他们更容易呼吸。气管切开术有时可以在稍后的日期删除。然而，许多儿童进行气管切开术多年。气管造口术带来了巨大的负担，因为护理人员必须确保管道不会堵塞，这将导致死亡。气管造口术的儿童比其他儿童更容易发生胸部感染。这些感染可能导致多次入院，本身也可能危及生命。对于为什么气管切开的儿童会有如此多的胸部感染，我们知之甚少，因此我们不知道如何预防它们。这一领域研究的一个主要问题是从接受气管切开术的儿童中获取样本。我以前的研究已经克服了这一点，与那些参与照顾这些儿童，包括医生，护士和父母密切合作。这项研究表明，儿童的气管对气管切开术“反应过度”，这实际上可能会降低身体抵抗感染的能力。在感染期间，称为中性粒细胞的细胞通常会识别、“吃掉”并杀死细菌，我们相信这一重要过程在气管切开术后不会正确发生。在气管切开的儿童中，中性粒细胞似乎会对气管内壁造成损伤，让有害细菌进入并引起胸部感染。我计划使用痰液样本（直接从气管中抽取）和从有和没有气管造口术的儿童中抽取的血液：1）了解为什么中性粒细胞可能无法有效地对抗细菌-这将包括使用创新技术来观察和测量从体内取出的中性粒细胞对细菌的反应方式; 2）评估这种有缺陷的功能如何导致肺部受损; 3）寻找“修复”这些中性粒细胞的方法，使用药物恢复它们杀死细菌的能力，并阻止中性粒细胞释放损害气管的化学物质。我们预计，这将减少气道损伤，使中性粒细胞以预期的方式杀死细菌。通过使用从体内取出的活细胞（从儿童的痰液或血液样本中）并在实验室中进行测试，我可以检查这些药物是否有效，而不会对儿童造成任何伤害，也不会使用动物测试。我确定的恢复中性粒细胞功能最有效的药物随后可以在临床试验中对儿童进行测试。这项工作的最终目的是找到新的药物来减少气管切开儿童必须忍受的胸部感染的数量，以及这些感染的相关并发症。这项研究的结果将与其他研究人员分享，这项工作的大部分将有助于研究中性粒细胞发挥破坏性作用的其他肺部疾病的研究人员。我将与其他中心的研究人员合作，包括达勒姆，贝尔法斯特，柏林和温哥华。作为我这个项目愿景的一部分，我组建了一个由来自不同背景的相关经验和技能的人员组成的团队，例如临床医生、物理学家和实验室科学家，他们都将特定技能结合在一起来解决一个重要问题。这项研究将为我提供一个独特的技能，成为一个世界领先的研究人员寻求新的解决方案，以提高生活质量和需要气管切开术的儿童的生存。