Kristensen Jacob Hull, Karsdal Morten Asser, Genovese Federica, Johnson Simon, Svensson Birte, Jacobsen Susanne, Hägglund Per, Leeming Diana Julie
Nordic Bioscience, Herlev, Denmark.
Respiration. 2014;88(6):487-99. doi: 10.1159/000368163. Epub 2014 Oct 29.
This review discusses the role of extracellular matrix (ECM) quality in the pathogenesis of pulmonary fibrosis (PF). In PF, the highly ordered structure of collagens and elastin within the ECM of the lung is severely disrupted and lacks its original tissue quality. Discussions about the ECM have focused on the role of protein quantity in relation to the progression of PF, while the importance of lung ECM quality, defined by the levels of ECM protein modifications and by the protein distribution in lung tissue, has not been properly addressed. The quality and function of proteins may be altered by different post-translational modifications (PTMs), such as cross-linking, proteolytic cleavage, citrullination, misfolding and glycosylation. This paper is the first to review key data from the literature related to the lung ECM at the molecular level, relate these to changes observed at a macroscopic level and evaluate which PTMs most likely contribute to PF. This paper also reviews the role of novel neo-epitope-specific biomarkers in the early diagnosis and prognosis of fibrotic disorders. We discuss and argue that the altered quality of the individual ECM proteins contributes to the progression of PF and may also lead to the increased quantity of lung proteins. Thus, both quantity and quality appear to be of utmost importance.
本综述讨论了细胞外基质（ECM）质量在肺纤维化（PF）发病机制中的作用。在PF中，肺ECM内胶原蛋白和弹性蛋白的高度有序结构受到严重破坏，失去了其原有的组织质量。关于ECM的讨论主要集中在蛋白质数量与PF进展的关系上，而由ECM蛋白质修饰水平和肺组织中蛋白质分布所定义的肺ECM质量的重要性尚未得到充分探讨。蛋白质的质量和功能可能会因不同的翻译后修饰（PTM）而改变，如交联、蛋白水解切割、瓜氨酸化、错误折叠和糖基化。本文首次在分子水平上综述了与肺ECM相关的文献中的关键数据，将这些数据与宏观水平上观察到的变化联系起来，并评估哪些PTM最有可能导致PF。本文还综述了新型新表位特异性生物标志物在纤维化疾病早期诊断和预后中的作用。我们讨论并认为，单个ECM蛋白质质量的改变会导致PF的进展，也可能导致肺蛋白质数量的增加。因此，数量和质量似乎都至关重要。
