Modulation of neutrophil dysfunction in tracheostomised children to prevent respiratory infections

许多患有严重疾病的幼儿需要长期的呼吸帮助。在这种情况下，一些孩子需要进行“气管切开术”，即外科医生在气管上开一个小洞，然后插入一根小管子，让他们更容易呼吸。气管切开术有时可以在以后切除。然而，许多儿童做气管切开术已经很多年了。接受气管切开术的患者负担很大，因为护理人员必须确保气管不会堵塞，否则会导致死亡。气管切开术的儿童比其他儿童更容易发生胸部感染。这些感染可导致多次住院，并可能危及生命。为什么气管切开术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。该领域研究的一个主要问题是如何从接受气管切开术的儿童身上获取样本。我之前的研究通过与那些参与照顾这些孩子的人密切合作，包括医生、护士和父母，克服了这一点。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。在感染过程中，中性粒细胞通常会识别、“吃掉”并杀死细菌，我们认为在气管切开术后，这一基本过程不会正常发生。在气管切开术的儿童中，中性粒细胞似乎会对气管内壁造成损害，使有害细菌进入并引起胸部感染。我计划使用从有或没有气管切开术的儿童身上采集的痰（直接取自气管）和血液样本：1)了解中性粒细胞可能无法有效对抗细菌的原因——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)评估这种功能缺陷是如何导致肺部受损的；3)寻找“修复”这些中性粒细胞的方法，使用药物来恢复它们杀死细菌的能力，并阻止中性粒细胞释放伤害气管的化学物质。我们预计，这将减少对气道的损害，使中性粒细胞以其应有的方式杀死细菌。通过使用从身体中取出的活细胞（来自儿童的痰或血液样本）并在实验室进行测试，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，也不会使用动物试验。我认为在恢复中性粒细胞功能方面最有效的药物随后可以在儿童身上进行临床试验。这项工作的最终目的是找到新的药物，以减少气管切开术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，其中大部分工作将帮助研究人员研究中性粒细胞发挥破坏性作用的其他肺部疾病。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。作为我对这个项目愿景的一部分，我组建了一个团队，他们有着不同背景的相关经验和技能，比如临床医生、物理学家和实验室科学家，他们都把特定的技能结合在一起来解决一个重要的问题。这项研究将为我提供独特的技能，使我成为一名世界领先的研究人员，寻求新的解决方案，以改善需要气管切开术的儿童的生活质量和生存率。

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.