特发性肺纤维化（Idiopathic pulmonary fibrosis，IPF）是一种慢性、进行性、纤维化性的间质性肺疾病，病变局限在肺脏，好发于中老年人群，是一种不可治愈的肺病，其治疗选择有限。研究表明，信号分子WNT5A在IPF致病过程中起关键作用。近日，来自慕尼黑亥姆霍兹中心的一组科学家与丹佛大学的研究者合作，进一步发现了导致肺纤维化发展的机制：IPF与细胞外囊泡的增加有关，这些囊泡将WNT5A信号传递给肺细胞。该研究发表在美国呼吸与危重症医学杂志（American Journal of Respiratory and Critical Care Medicine, IF=15.239）上，提出了另一种新的药理学生物标志物和可能的治疗方法。
肺纤维化与肺中结缔组织的形成增加有关，导致功能性肺组织的瘢痕形成（纤维化）。这导致极薄的肺泡的内表面以及肺的张力的降低，这样会阻碍了氧的摄入和二氧化碳的释放，结果导致肺功能受损。 IPF是一种具有侵袭性的肺部疾病，目前其发生仍不能归因于特定原因。IPF的症状恶化速度极快，现有药物可以减缓疾病的进展，但目前还无法永久阻止疾病进展。
因此，研究关注与IPF相关的病理组织变化的潜在机制非常重要。目前在慕尼黑亥姆霍兹中心的肺修复和再生（LRR）和肺部生物学和疾病研究所（ILBD）已经深入研究的一种方法旨在调节WNT信号传导途径。因为已知信号分子WNT5A参与了刺激肺中结缔组织细胞的增殖。
细胞外囊泡运输IPF形成的信号
由Melanie Königshoff博士领导的LRR研究小组发现，细胞外囊泡很可能也与IPF有关。“简而言之，细胞外囊泡是由细胞释放的微囊泡，可以包裹大量的信使物质，如蛋白质和核酸。”该研究的作者之一Mareike Lehmann博士说。“它们是细胞和器官之间交流的重要手段，有助于确保包裹的物质到达新位置。”
直到目前，尚不清楚细胞外囊泡是否以及如何参与IPF的形成。“我们能够在研究中证明，IPF患者细胞外囊泡水平增加，然后成为了WNT5A的携带者。”论文主要作者之一Aina Martin-Medina解释说。“我们还能够在我们的实验模型中证实这些结果。”此外，作者在体外实验中表明，减少囊泡数量可减少肺组织瘢痕形成。
在进一步的临床前研究中，研究人员将继续研究细胞外囊泡作为药理学生物标志物的适用性，以及可能的治疗靶点。
文章摘要：
Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by lung epithelial cell injury, increased (myo)fibroblast activation and extracellular matrix deposition. Extracellular vesicles (EVs) regulate intercellular communication by carrying a variety of signaling mediators, including WNT proteins. The relevance of EVs in pulmonary fibrosis and their potential contribution to disease pathogenesis, however, remains unexplored. Objective: To characterize EVs and study the role of EV-bound WNT signaling in IPF.
Methods: We isolated EVs from bronchoalveolar lavage fluid (BALF) from experimental lung fibrosis as well as samples from IPF, non IPF-ILD, non-ILD and healthy volunteers from two independent cohorts. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis and Western Blotting (WB). Primary human lung fibroblasts (phLFs) were used for EV isolation and analyzed by metabolic activity assays, cell counting, qPCR and WB upon WNT gain- and loss-of-function studies.
Measurements and Main Results: We found increased EVs, particularly exosomes, in BALF from experimental lung fibrosis as well as from IPF patients. WNT-5A was secreted on EVs in lung fibrosis and induced by TGF-β in primary human lung fibroblasts. The phLF-derived EVs induced phLF proliferation, which was attenuated by WNT-5A silencing and antibody-mediated inhibition and required intact EV structure. Similarly, EVs from IPF-BALF induced phLF proliferation, which was mediated by WNT-5A.
Conclusions: Increased EVs function as carriers for signaling mediators, such as WNT-5A, in IPF and thus contribute to disease pathogenesis. Characterization of EV secretion and composition may lead to novel approaches to diagnose and develop treatments for pulmonary fibrosis.
参考文献：
- Martin-Medina A et al. (2018). Increased Extracellular Vesicles Mediate WNT-5A Signaling in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med [Epub ahead of print].
- https://www.helmholtz.de/en/current_topics/news/
外泌体资讯网 Am J Respir Crit Care Med：细胞外囊泡的增加介导特发性肺纤维化中的WNT5A信号转导
