Baweja Sukriti, Kumari Anupama, Negi Preeti, Thangariyal Swati, Subudhi P Debishree, Gautam Shivani, Mittal Ashmit, Bihari Chhagan
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi 110070, India.
Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi 110070, India.
Diagnostics (Basel). 2023 Mar 28;13(7):1272. doi: 10.3390/diagnostics13071272.
Hepatopulmonary syndrome (HPS) is a pulmonary vasculature complication in the setting of liver disease that is characterized by pathological vasodilation resulting in arterial oxygenation defects. We investigated the role of extracellular vesicles (EV) in cirrhosis patients with HPS, as well as the functional effect of EV administration in a common bile duct ligation (CBDL) HPS mouse model.
A total of 113 cirrhosis patients were studied: 42 (Gr. A) with HPS and 71 (Gr. B) without HPS, as well as 22 healthy controls. Plasma levels of EV associated with endothelial cells, epithelial cells, and hepatocytes were measured. The cytokine cargoes were estimated using ELISA. The effect of EV administered intranasally in the CBDL mouse model was investigated for its functional effect in vascular remodeling and inflammation.
We found endothelial cells (EC) associated EV (EC-EV) were elevated in cirrhosis patients with and without HPS ( < 0.001) than controls. EC-EV levels were higher in HPS patients ( = 0.004) than in those without HPS. The epithelial cell EVs were significantly high in cirrhosis patients than controls ( < 0.001) but no changes found in patients with HPS than without. There was a progressive increase in EC-EV levels from mild to severe intrapulmonary shunting in HPS patients ( = 0.02 mild vs. severe), and we were able to predict severe HPS with an AUROC of 0.85; < 0.001. An inverse correlation of EC-EVs was found with hemoglobin (r = -0.24; = 0.031) and PaO2 (r = 0.690; = 0.01) and a direct correlation with MELD (r = 0.32; = 0.014). Further, both TNF-α ( = 0.001) and IL-1β ( = 0.021) as cargo levels were significantly elevated inside the EVs of HPS patients than without HPS. Interestingly, upon administration of intranasal EVs, there was a significant decrease in Evans blue accumulation and lung wet-dry ratio ( = 0.042; 0.038). A significant reduction was also noticed in inflammation and cholestasis.
High levels of plasma EC-EV levels were found in patients with HPS with elevated pro-inflammatory cytokine cargoes. EC-EVs were indicative of severe HPS condition. In the CBDL HPS model, we were able to prove the beneficial effects of improving vascular tone, inflammation, and liver pathogenesis.
肝肺综合征（HPS）是一种肝脏疾病背景下的肺血管并发症，其特征是病理性血管扩张导致动脉氧合缺陷。我们研究了细胞外囊泡（EV）在肝硬化合并HPS患者中的作用，以及在胆总管结扎（CBDL）HPS小鼠模型中给予EV的功能效应。
共研究了113例肝硬化患者：42例（A组）合并HPS，71例（B组）未合并HPS，以及22例健康对照。测量了与内皮细胞、上皮细胞和肝细胞相关的血浆EV水平。使用酶联免疫吸附测定法评估细胞因子含量。研究了经鼻给予EV在CBDL小鼠模型中对血管重塑和炎症的功能效应。
我们发现，合并和未合并HPS的肝硬化患者中，与内皮细胞（EC）相关的EV（EC-EV）水平均高于对照组（<0.001）。HPS患者的EC-EV水平高于未合并HPS的患者（=0.004）。肝硬化患者上皮细胞EV水平显著高于对照组（<0.001），但HPS患者与未合并HPS的患者相比无变化。HPS患者中，从轻度到重度肺内分流，EC-EV水平逐渐升高（轻度与重度相比，=0.02），我们能够以0.85的曲线下面积预测重度HPS；<0.001。发现EC-EV与血红蛋白呈负相关（r=-0.24；=0.031），与动脉血氧分压呈负相关（r=-0.690；=0.01），与终末期肝病模型评分呈正相关（r=0.32；=0.014）。此外，HPS患者EV内的肿瘤坏死因子-α（=0.001）和白细胞介素-1β（=0.021）含量均显著高于未合并HPS的患者。有趣的是，经鼻给予EV后，伊文思蓝蓄积和肺干湿比显著降低（=0.042；0.038）。炎症和胆汁淤积也显著减轻。
HPS患者血浆EC-EV水平较高，促炎细胞因子含量升高。EC-EV提示重度HPS状态。在CBDL HPS模型中，我们能够证明其在改善血管张力、炎症和肝脏病变方面的有益作用。
