Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
J Chin Med Assoc. 2020 Jan;83(1):32-40. doi: 10.1097/JCMA.0000000000000194.
Rapamycin is a type of immunosuppressive agent that acts through inhibition of mammalian target of rapamycin (mTOR). Hepatopulmonary syndrome (HPS) is a lethal complication in cirrhotic patients. It is characterized by hypoxia and increased intrapulmonary shunts, in which pulmonary inflammation and angiogenesis play important roles. The current study aimed to evaluate the effect of rapamycin on HPS using the experimental model of common bile duct ligation (CBDL)-induced cirrhosis in rats.
The rats received low-dose (0.5 mg/kg), high-dose (2 mg/kg) rapamycin, or vehicle from the 15th to the 28th day post CBDL. Then the mortality rate, hemodynamics, biochemistry parameters, arterial blood gas and plasma levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-α were evaluated on the 28th day post CBDL. Pulmonary histopathological stains were performed, and protein expression was examined. In parallel groups, the intrapulmonary shunts of CBDL rats were measured.
Compared with the control, a high-dose rapamycin treatment decreased portal pressure and improved hypoxia in CBDL rats. It also reduced the plasma level of VEGF and TNF-α and decreased intrapulmonary shunts. Meanwhile, it ameliorated pulmonary inflammation and angiogenesis and downregulated the protein expression of mTOR, P70S6K, nuclear factor kappa B (NFκB), VEGF, and VEGF receptor 2. In contrast, low-dose rapamycin did not attenuate intrapulmonary shunts despite ameliorating portal hypertension.
High-dose rapamycin ameliorates HPS in cirrhotic rats as evidenced by the alleviated hypoxia and decreased intrapulmonary shunts. Downregulation of the mTOR/P70S6K, NFκB, and VEGF signaling pathways might play a key role.
雷帕霉素是一种免疫抑制剂，通过抑制哺乳动物雷帕霉素靶蛋白（mTOR）发挥作用。肝肺综合征（HPS）是肝硬化患者的一种致命并发症。其特征为缺氧和肺内分流增加，其中肺炎症和血管生成起着重要作用。本研究旨在使用胆总管结扎（CBDL）诱导的大鼠肝硬化实验模型评估雷帕霉素对 HPS 的作用。
大鼠在 CBDL 后第 15 至 28 天接受低剂量（0.5mg/kg）、高剂量（2mg/kg）雷帕霉素或载体治疗。然后在 CBDL 后第 28 天评估死亡率、血液动力学、生化参数、动脉血气和血管内皮生长因子（VEGF）和肿瘤坏死因子（TNF）-α的血浆水平。进行肺组织学染色，并检查蛋白表达。在平行组中，测量 CBDL 大鼠的肺内分流。
与对照组相比，高剂量雷帕霉素治疗降低了门静脉压力并改善了 CBDL 大鼠的缺氧。它还降低了 VEGF 和 TNF-α的血浆水平，并减少了肺内分流。同时，它改善了肺炎症和血管生成，并下调了 mTOR、P70S6K、核因子 kappa B（NFκB）、VEGF 和 VEGF 受体 2 的蛋白表达。相比之下，尽管改善了门静脉高压，但低剂量雷帕霉素并未减轻肺内分流。
高剂量雷帕霉素可改善肝硬化大鼠的 HPS，表现为缺氧减轻和肺内分流减少。mTOR/P70S6K、NFκB 和 VEGF 信号通路的下调可能起关键作用。
