Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic “gain-of-function” inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD-mediated liver disease. EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples. We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs. AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease.

中文翻译：

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Alpha-1 抗胰蛋白酶缺乏的个体具有循环细胞外囊泡和促纤维化货物。

α-1 抗胰蛋白酶缺乏症 (AATD) 介导的肝病是肝脏中的一种毒性“功能获得性”炎症，与突变型 α-1 抗胰蛋白酶的细胞内滞留有关。该疾病的临床表现包括纤维化、肝硬化和肝功能衰竭。然而，AATD 介导的肝病的发病机制尚不清楚。在这里，我们研究了血浆细胞外囊泡 (EV) 在 AATD 介导的肝病进展中的作用。从患有肝病的 AATD 个体和健康对照者的血浆中分离出 EV。它们的细胞因子和 miRNA 含量通过多重分析和小 RNA 测序进行了检查。通过 qPCR 评估 EV 的生物活性，使用从对照或 AATD 血浆样本中分离的 EV 处理的人肝星状细胞 (HSC) 进行蛋白质印迹分析和免疫荧光实验。我们发现 AATD 个体具有独特的 EV 群体，具有病理性细胞因子和 miRNA 含量。当 HSC 与 AATD 血浆衍生的 EV 一起培养时，与用健康对照血浆 EV 处理的基因相比，与纤维化发展相关的基因表达显着增强。AATD 个体具有独特的 EV 群体，具有异常的细胞因子和 miRNA 含量，并且具有激活 HSC 和介导纤维化的能力。更好地了解导致肝脏炎症和纤维化的成分，从而导致进一步的肝损伤，