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.

我们的肺部每天都会受到一系列环境侵害，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肺部深处，形成对外部环境的屏障，保护我们免受这些侵害。然而，这些上皮细胞经常且有时因这些暴露而严重受损。受伤后，上皮细胞迅速修复以恢复这一屏障至关重要。如果上皮细胞没有得到有效修复，那么我们就更容易受到感染，并且我们的呼吸能力也会受到损害。肺部在受损时能够自我修复，但随着年龄的增长，这种能力会减弱，对于某些人来说，修复过程无法正常进行，从而导致疾病。目前，尚无能够恢复受损肺组织的治疗方法，这显然是临床的迫切需求。需要更好地了解肺部如何自我修复，以促进长期肺部健康并确定可以促进肺部修复的新疗法。细胞外基质 (ECM) 是蛋白质和其他因子的三维网络，支持肺部结构并充当肺部细胞的支架。我们对这种 ECM 的一个小片段感兴趣，称为 Pro-Gly-Pro (PGP)，它通常是隐藏的，但会在感染或受伤时从 ECM 中释放出来。我们有令人兴奋的数据表明 PGP 能够有效促进肺上皮细胞的修复反应。此外，PGP 还可以驱动中性粒细胞流入肺部。中性粒细胞本质上是我们免疫系统的士兵，可以杀死任何因受伤而进入肺部的入侵生物体。因此，我们认为 PGP 是肺组织的一个碎片，它因损伤而释放，然后随后发挥作用，指导局部上皮修复，以密封与外部环境的缺口，同时引起中性粒细胞的流入，对肺组织进行消毒。我们还认为，在疾病环境中，控制 PGP 水平的途径可能会被破坏。因此，了解 PGP 如何促进修复反应可能会产生对抗肺损伤的新疗法。由于 ECM 是所有组织的重要组成部分，因此我们的数据很可能也与体内其他器官的修复相关。在本提案中，我们希望更多地了解 PGP 如何驱动上皮细胞修复，并确定 PGP 作为肺损伤后修复介质的相对重要性。我们将使用从健康个体肺部分离的上皮细胞来探究 PGP 究竟如何能够驱动修复反应，从而揭示治疗干预的潜在策略。随后，我们将在本质上是“迷你肺”的人类和小鼠肺组织切片中诱导微损伤，并评估在这种更复杂的 3D 环境中操纵 PGP 如何调节随后的修复反应。如果我们要了解 PGP 对人类肺损伤和修复的重要性，人类肺细胞和组织的使用至关重要。然而，为了真正证明 PGP 在较长时间内促进肺修复和最小化病理的能力，还需要评估 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 在支持上皮修复方面的重要性，并确定补充 PGP 可以在多大程度上增强修复。该提案的结果可能会在未来带来新的治疗方法，通过调节 PGP 来促进肺部修复。