Bioactive fragments of the extracellular matrix orchestrate lung epithelial cell repair.

细胞外基质的生物活性片段协调肺上皮细胞修复。

• 批准号: BB/Y004183/1
• 负责人: Robert Snelgrove
• 金额: $ 82.8万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY004183%2F1
• 关键词: Bioactive; fragments; extracellular; matrix; orchestrate

On a daily basis, our lungs are exposed to an array of environmental insults including viruses, bacteria and toxic particles. Specialised 'epithelial' cells run from our nose all the way down to the depths of our lungs, forming a barrier to the external environment and protecting us from these insults. However, these epithelial cells are frequently and sometimes severely damaged by these exposures. It is critical that after injury, the epithelial cells are quickly repaired to restore this barrier. If epithelial cells are not efficiently repaired then we are more prone to infection, and our ability to breathe is compromised. The lungs are able to repair themselves when damaged but this ability deteriorates as we get older and in some people the repair process doesn't work properly, leading to disease. Currently, there are no treatments able to restore damaged lung tissue, and this is clearly an urgent clinical need. A greater understanding of how the lungs repair themselves is required to promote long term lung health and to identify new treatments that can promote lung repair. The extracellular matrix (ECM) is a three-dimensional meshwork of proteins and other factors that supports the structure of the lungs and acts as a scaffold for cells that populate the lungs. We are interested in a small fragment of this ECM called Pro-Gly-Pro (PGP), which is normally hidden but becomes released from the ECM in response to infection or injury. We have exciting data that demonstrates that PGP is potent at promoting repair responses in lung epithelial cells. Furthermore, PGP can also operate to drive the influx of cells called neutrophils into the lungs. Neutrophils are essentially the soldiers of our immune system that can kill any invading organisms that have entered the lung as a result of injury. Therefore, we believe that PGP is a fragment of the lung tissue that is released in response to injury and then subsequently acts to direct localised epithelial repair to seal the breach to the external environment, whilst simultaneously causing the influx of neutrophils to sterilise the lung tissue. We also believe that pathways governing the levels of PGP may be disrupted in disease settings. Consequently, understanding how PGP promotes repair responses could yield novel treatments to counteract lung injury. Because the ECM is a critical component of all tissues, our data is highly likely to also be relevant for repair of other organs in the body. In this proposal, we want to understand more about how PGP drives repair in epithelial cells and ascertain the relative importance of PGP as a mediator of repair following lung injury. We will use epithelial cells isolated from the lungs of healthy individuals to probe how exactly PGP is able to drive repair responses, thus revealing potential strategies for therapeutic intervention. Subsequently, we will induce micro-injuries in slices of human and mouse lung tissue that are essentially 'mini lungs' and assess how manipulation of PGP in this more complex 3D setting modulates subsequent repair responses. The use of human lung cells and tissue is critical if we are to understand the importance of PGP to human lung injury and repair. However, to truly demonstrate the capacity of PGP to instigate lung repair and minimize pathology over a prolonged period of time, it is also necessary to assess the role of PGP in a mouse model of lung epithelial cell injury. We will determine the importance of naturally generated PGP in supporting epithelial repair and also ascertain to what extent supplementation of PGP can enhance repair. The results of this proposal could lead in future to new treatments that can promote lung repair via modulation of PGP.

每天，我们的肺部都暴露在一系列的环境侮辱中，包括病毒、细菌和有毒颗粒。特殊的“上皮”细胞从我们的鼻子一直延伸到我们的肺部深处，形成了对外部环境的屏障，保护我们免受这些侮辱。然而，这些上皮细胞经常甚至有时会因这些暴露而严重受损。关键是在损伤后，上皮细胞被迅速修复，以恢复这种屏障。如果上皮细胞得不到有效的修复，我们就更容易受到感染，我们的呼吸能力也会受到影响。肺部受损时能够自我修复，但随着年龄的增长，这种能力会恶化，对一些人来说，修复过程不能正常工作，从而导致疾病。目前，还没有能够修复受损肺组织的治疗方法，这显然是临床上的迫切需要。需要更多地了解肺是如何自我修复的，以促进长期的肺健康，并找到能够促进肺修复的新疗法。细胞外基质(ECM)是由蛋白质和其他因素组成的三维网络，支持肺的结构，并充当填充肺的细胞的支架。我们感兴趣的是这种ECM的一小段叫做Pro-Gly-Pro(PGP)，它通常是隐藏的，但在感染或损伤时会从ECM中释放出来。我们有令人兴奋的数据表明PGP在促进肺上皮细胞修复反应方面是有效的。此外，PGP还可以推动称为中性粒细胞的细胞流入肺部。中性粒细胞本质上是我们免疫系统的战士，可以杀死任何因受伤而进入肺部的入侵微生物。因此，我们认为PGP是肺组织的一部分，它在损伤后被释放，然后指导局部的上皮修复，以封闭与外部环境的裂口，同时导致中性粒细胞的涌入，以杀菌肺组织。我们还认为，在疾病环境中，控制Pgp水平的途径可能会被扰乱。因此，了解PGP是如何促进修复反应的可以产生新的治疗方法来对抗肺损伤。由于细胞外基质是所有组织的关键组成部分，我们的数据很可能也与人体其他器官的修复有关。在这项提案中，我们希望更多地了解PGP如何驱动上皮细胞的修复，并确定PGP作为肺损伤后修复的介体的相对重要性。我们将使用从健康人的肺部分离的上皮细胞来探索PGP到底如何能够驱动修复反应，从而揭示潜在的治疗干预策略。随后，我们将在人和小鼠的肺组织切片中诱导微损伤，本质上是“迷你肺”，并评估在这种更复杂的3D环境中操作PGP如何调节后续的修复反应。如果我们要了解PGP对人类肺损伤和修复的重要性，那么使用人类肺细胞和组织是至关重要的。然而，为了真正证明PGP在较长时间内促进肺修复和最大限度减少病理变化的能力，还有必要评估PGP在小鼠肺上皮细胞损伤模型中的作用。我们将确定自然生成的PGP在支持上皮修复中的重要性，并确定补充PGP在多大程度上可以促进修复。这一建议的结果可能会导致未来的新治疗方法，可以通过调节Pgp来促进肺修复。