The role of elastin degradation in the pathogenesis of liver fibrosis

长期或慢性肝病，无论原因如何，都会导致肝脏瘢痕形成(称为纤维化和肝硬变)。这种疤痕会导致肝脏衰竭，并与严重的疾病和死亡有关。在英国，肝硬变的负担已被首席医疗官确定为下一个十年的主要挑战。目前还没有有效的治疗肝脏疤痕的方法。我们有一个研究计划，研究调节疤痕恢复的因素，以提供和开发抗瘢痕(所谓的抗纤维化)疗法。我们最近证明，如果允许的话，肝脏有显著的能力打破疤痕组织，恢复更正常的结构和功能。然而，在晚期肝病中，疤痕组织持续存在，似乎对分解具有抵抗力。一种名为弹性蛋白的蛋白质的存在似乎对防止疤痕组织的有效分解至关重要。此外，我们有初步证据表明，一种特殊形式的炎症细胞--巨噬细胞--会产生一种特定的蛋白质(酶)来分解弹性蛋白。综上所述，这些结果表明，弹性蛋白是不可逆的瘢痕形成(肝硬变)的特征，它是由于正常的分解过程的失败而积累的。我们正在进行的工作将确定弹性蛋白的细胞来源和弹性蛋白降解蛋白及其在肝瘢痕形成的不同阶段(可逆和不可逆)的相对水平。此外，我们将使用实验模型来确定使瘢痕形成抵抗破坏的机制，并使用纯化的炎性细胞和特定数量的干细胞来促进瘢痕的破坏。最终，通过了解调节弹性蛋白在肝瘢痕形成中周转的机制，我们将能够更好地设计适用于临床的有效的抗瘢痕治疗方法。

Long term or chronic liver disease, regardless of cause, results in scarring of the liver (termed fibrosis and cirrhosis). This scarring causes the liver to fail and is associated with significant illness and death. In the UK, the burden of cirrhosis has been identified by the Chief Medical Officer as a major challenge of the next decade. Currently there are no effective treatments for liver scarring. We have a programme of research investigating the factors which regulate recovery from scarring to inform and develop anti-scarring (so called anti-fibrotic) therapies.We have recently demonstrated that if it is allowed to, the liver has a significant ability to break the scar tissue with a return towards more normal structure and function. In advanced liver disease though, the scar tissue persists and appears to be resistant to break-down. The presence of a protein called elastin seems to be critical to preventing effective breakdown of the scar tissue. In addition, we have preliminary evidence to suggest that a specialised form of inflammatory cell, the macrophage, produces a specific protein (enzyme) which breaks down elastin. Taken together these results suggest that elastin characterises irreversible scarring (cirrhosis) and that it accumulates as a result of a failure of the normal processes of breakdown.Work we are undertaking will determine the cell source of elastin and the elastin degrading proteins and their relative levels at different stages of liver scarring (reversible and irreversible).In addition, we will use experimental models to determine the mechanisms that make scarring resistant to breakdown and use infusions of purified inflammatory cells and specific population of stem cells to enhance scar breakdown.Ultimately, by understanding the mechanisms regulating the turnover of elastin in liver scarring we will be better able to design effective anti-scarring therapies applicable in the clinic.