Li Yu-Jie, Wu Xian-Feng, Wang Dan-Dan, Li Peng, Liang Hao, Hu Xiao-Yan, Gan Jia-Qi, Sun Yi-Zhu, Li Jun-Hong, Li Jun, Shu Xin, Song Ai-Lin, Yang Chun-Yong, Yang Zhi-Yong, Yu Wei-Feng, Yang Li-Qun, Wang Xiao-Bo, Belguise Karine, Xia Zheng-Yuan, Yi Bin
Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.
J Clin Transl Hepatol. 2023 Oct 28;11(5):1150-1160. doi: 10.14218/JCTH.2022.00421. Epub 2023 Apr 24.
The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies.
Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors.
In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients.
Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.
基础研究结果表明血管内皮生长因子（VEGF）家族可能是肝肺综合征（HPS）的一个潜在靶点。然而，临床研究中抗血管生成治疗的阴性结果凸显了寻找HPS标志物的必要性。因此，我们旨在通过临床和实验研究确定VEGF家族成员及其受体是否可作为HPS的潜在生物标志物。
临床上，招募了来自两个医疗中心的慢性肝病患者并对其进行HPS检查。患者被分为HPS组、肺内血管扩张组[阳性对比增强超声心动图（CEE）且氧合正常]和CEE阴性组。比较HPS患者与非HPS患者的基线信息和围手术期临床数据。检测血清中VEGF家族成员及其受体的水平。同时，通过胆总管结扎建立HPS大鼠模型。收集肝脏、肺和血清样本，以评估病理生理变化以及上述因子的表达水平。
在HPS大鼠中，所有VEGF家族成员及其受体均发生了显著变化；然而，只有可溶性VEGFR1（sFlt-1）和sFlt-1/胎盘生长因子（PLGF）比值的变化方式与HPS患者几乎相同。此外，通过特征选择以及内部和外部验证，sFlt-1和sFlt-1/PLGF比值被确定为区分HPS患者与非HPS患者的最重要变量。
我们在动物和人体研究中的结果表明，血清中的sFlt-1和sFlt-1/PLGF比值是HPS的潜在标志物。
