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

每天，我们的肺部都暴露在一系列的环境污染中，包括病毒、细菌和有毒颗粒。专门的“上皮”细胞从我们的鼻子一直延伸到肺部深处，形成了一个外部环境的屏障，保护我们免受这些伤害。然而，这些上皮细胞经常并且有时会受到这些暴露的严重损害。损伤后，上皮细胞迅速修复以恢复这一屏障是至关重要的。如果上皮细胞不能有效地修复，那么我们就更容易受到感染，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，这种能力会退化，有些人的修复过程不能正常工作，从而导致疾病。目前，还没有能够恢复受损肺组织的治疗方法，这显然是迫切的临床需求。为了促进肺部的长期健康和确定能够促进肺部修复的新疗法，需要对肺部如何自我修复有更深入的了解。细胞外基质（ECM）是一种由蛋白质和其他因子组成的三维网状结构，它支持肺部的结构，并作为肺部细胞的支架。我们感兴趣的是这个ECM的一个小片段，叫做Pro-Gly-Pro (PGP)，它通常是隐藏的，但在感染或损伤时从ECM中释放出来。我们有令人兴奋的数据表明PGP在促进肺上皮细胞的修复反应方面是有效的。此外，PGP还可以驱使中性粒细胞进入肺部。中性粒细胞本质上是我们免疫系统的士兵，它可以杀死任何由于受伤而进入肺部的入侵生物。因此，我们认为PGP是肺组织的一个片段，在受到损伤后释放出来，随后指导局部上皮修复，以封闭外部环境的缺口，同时引起中性粒细胞的涌入，对肺组织进行消毒。我们还认为，控制PGP水平的途径可能在疾病环境中被破坏。因此，了解PGP如何促进修复反应可能会产生新的治疗方法来对抗肺损伤。因为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身体其他器官的修复有关。在这项提议中，我们想要更多地了解PGP如何驱动上皮细胞的修复，并确定PGP作为肺损伤后修复介质的相对重要性。我们将使用从健康个体的肺中分离的上皮细胞来探测PGP究竟是如何驱动修复反应的，从而揭示治疗干预的潜在策略。随后，我们将在人类和小鼠肺组织切片中诱导微损伤，这些肺组织本质上是“迷你肺”，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，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在长时间内促进肺修复和减少病理的能力，还需要评估PGP在肺上皮细胞损伤小鼠模型中的作用。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可以在多大程度上增强修复。这一建议的结果可能会导致未来通过调节PGP来促进肺修复的新疗法。

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.