Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
J Hepatol. 2023 Jul;79(1):167-180. doi: 10.1016/j.jhep.2023.03.018. Epub 2023 Mar 28.
BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in patients with liver disease. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, suppresses vasodilation by reducing nitric oxide (NO) production. We investigated the role of S1P in patients with HPS and the role of fingolimod as a therapeutic option in an experimental model of HPS.
Patients with cirrhosis with HPS (n = 44) and without HPS (n = 89) and 25 healthy controls were studied. Plasma levels of S1P, NO, and markers of systemic inflammation were studied. In a murine model of common bile duct ligation (CBDL), variations in pulmonary vasculature, arterial oxygenation, liver fibrosis, and inflammation were estimated before and after administration of S1P and fingolimod.
Log of plasma S1P levels was significantly lower in patients with HPS than in those without HPS (3.1 ± 1.4 vs. 4.6 ± 0.2; p <0.001) and more so in severe intrapulmonary shunting than in mild and moderate intrapulmonary shunting (p <0.001). Plasma tumour necrosis factor-α (76.5 [30.3-91.6] vs. 52.9 [25.2-82.8]; p = 0.02) and NO (152.9 ± 41.2 vs. 79.2 ± 29.2; p = 0.001) levels were higher in patients with HPS than in those without HPS. An increase in Th17 (p <0.001) and T regulatory cells (p <0.001) was observed; the latter inversely correlated with plasma S1P levels. In the CBDL HPS model, fingolimod restored pulmonary vascular injury by increasing the arterial blood gas exchange and reducing systemic and pulmonary inflammation, resulting in improved survival (p = 0.02). Compared with vehicle treatment, fingolimod reduced portal pressure (p <0.05) and hepatic fibrosis and improved hepatocyte proliferation. It also induced apoptotic death in hepatic stellate cells and reduced collagen formation.
Plasma S1P levels are low in patients with HPS and even more so in severe cases. Fingolimod, by improving pulmonary vascular tone and oxygenation, improves survival in a murine CBDL HPS model.
A low level of plasma sphingosine-1-phosphate (S1P) is associated with severe pulmonary vascular shunting, and hence, it can serve as a marker of disease severity in patients with hepatopulmonary syndrome (HPS). Fingolimod, a functional agonist of S1P, reduces hepatic inflammation, improves vascular tone, and thus retards the progression of fibrosis in a preclinical animal model of HPS. Fingolimod is being proposed as a potential novel therapy for management of patients with HPS.
肝肺综合征（HPS）的特征是在患有肝脏疾病的患者中，由肺血管扩张引起的动脉血氧合缺陷。 fingolimod 是一种鞘氨醇-1-磷酸（S1P）受体调节剂，通过减少一氧化氮（NO）的产生来抑制血管扩张。我们研究了 S1P 在 HPS 患者中的作用以及 fingolimod 在 HPS 实验模型中作为治疗选择的作用。
研究了 44 例肝硬化伴 HPS （HPS）患者和 89 例无 HPS （无 HPS）患者以及 25 例健康对照者。研究了血浆 S1P、NO 和全身炎症标志物的水平。在胆总管结扎（CBDL）的小鼠模型中，在给予 S1P 和 fingolimod 之前和之后，估计了肺血管，动脉血氧合，肝纤维化和炎症的变化。
与无 HPS 患者相比（3.1±1.4 对 4.6±0.2；p<0.001），HPS 患者的血浆 S1P 水平明显降低，在严重肺内分流中降低更明显（p<0.001）。与无 HPS 患者相比（76.5[30.3-91.6]对 52.9[25.2-82.8]；p=0.02），HPS 患者的肿瘤坏死因子-α（TNF-α）和 NO 水平（152.9±41.2 对 79.2±29.2；p=0.001）更高。观察到 Th17（p<0.001）和 T 调节细胞（p<0.001）的增加；后者与血浆 S1P 水平呈负相关。在 CBDL HPS 模型中，fingolimod 通过增加动脉血气交换和减轻全身和肺炎症来恢复肺血管损伤，从而提高了生存率（p=0.02）。与载体治疗相比，fingolimod 降低了门静脉压（p<0.05）和肝纤维化，并改善了肝细胞增殖。它还诱导肝星状细胞的凋亡死亡并减少胶原蛋白的形成。
HPS 患者的血浆 S1P 水平较低，在严重病例中甚至更低。 fingolimod 通过改善肺血管张力和氧合作用，可提高 CBDL HPS 模型中动物的生存率。
低水平的血浆鞘氨醇-1-磷酸（S1P）与严重的肺血管分流有关，因此可以作为 HPS 患者疾病严重程度的标志物。 fingolimod 是 S1P 的功能激动剂，可降低肝内炎症，改善血管张力，从而延缓 HPS 临床前动物模型中纤维化的进展。 fingolimod 被提议作为治疗 HPS 患者的潜在新型疗法。
