Kong Ling-Jian, Li Hao, Du Ya-Ju, Pei Feng-Hua, Hu Ying, Zhao Liao-Liao, Chen Jing
Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
Mol Med Rep. 2017 May;15(5):2604-2610. doi: 10.3892/mmr.2017.6325. Epub 2017 Mar 15.
Among the various consequence arising from lung injury, hepatic fibrosis is the most severe. Decreasing the effects of hepatic fibrosis remains one of the primary therapeutic challenges in hepatology. Dysfunction of hepatic sinusoidal endothelial cells is considered to be one of the initial events that occur in liver injury. Vascular endothelial growth factor signaling is involved in the progression of genotype changes. The aim of the present study was to determine the effect of the tyrosine kinase inhibitor, vatalanib, on hepatic fibrosis and hepatic sinusoidal capillarization in a carbon tetrachloride (CCl4)‑induced mouse model of liver fibrosis. Liver fibrosis was induced in BALB/c mice using CCl4 by intraperitoneal injection for 6 weeks. The four experimental groups included a control, and three experimental groups involving administration of CCl4, vatalanib and a combination of the two. Histopathological staining and measuring live hydroxyproline content evaluated the extent of liver fibrosis. The expression of α‑smooth muscle actin (SMA) and cluster of differentiation (CD) 34 was detected by immunohistochemistry. Collagen type I, α‑SMA, transforming growth factor (TGF)‑β1 and vascular endothelial growth factor receptor (VEGFR) expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT‑qPCR). The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Liver fibrosis scores and hydroxyproline content were decreased in both vatalanib groups. In addition, both doses of vatalanib decreased mRNA expression levels of hepatic α-SMA, TGF-β1, collagen‑1, VEGFR1, and VEGFR2. Levels of α‑SMA and CD34 protein were decreased in the vatalanib group compared with the CCl4 group. There were significant differences in the number of fenestrae per sinusoid between the groups. The present study identified that administration of vatalanib was associated with decreased liver fibrosis and hepatic sinusoidal capillarization in CCl4-induced mouse models, and is a potential compound for counteracting liver fibrosis.
在肺损伤引发的各种后果中，肝纤维化最为严重。减轻肝纤维化的影响仍然是肝病学主要的治疗挑战之一。肝窦内皮细胞功能障碍被认为是肝损伤中最初发生的事件之一。血管内皮生长因子信号传导参与基因型变化的进展。本研究的目的是确定酪氨酸激酶抑制剂凡德他尼对四氯化碳（CCl4）诱导的小鼠肝纤维化模型中肝纤维化和肝窦毛细血管化的影响。通过腹腔注射CCl4 6周，在BALB/c小鼠中诱导肝纤维化。四个实验组包括一个对照组，以及三个分别给予CCl4、凡德他尼和两者联合用药的实验组。通过组织病理学染色和测量肝脏羟脯氨酸含量评估肝纤维化程度。通过免疫组织化学检测α平滑肌肌动蛋白（SMA）和分化簇（CD）34的表达。通过逆转录定量聚合酶链反应（RT-qPCR）测量I型胶原蛋白、α-SMA、转化生长因子（TGF）-β1和血管内皮生长因子受体（VEGFR）的表达水平。使用透射电子显微镜确定每个肝窦窗孔的平均数量。两个凡德他尼组的肝纤维化评分和羟脯氨酸含量均降低。此外，两种剂量的凡德他尼均降低了肝脏α-SMA、TGF-β1、胶原蛋白-1、VEGFR1和VEGFR2的mRNA表达水平。与CCl4组相比，凡德他尼组的α-SMA和CD34蛋白水平降低。各组之间每个肝窦窗孔数量存在显著差异。本研究确定，在CCl4诱导的小鼠模型中，给予凡德他尼与肝纤维化和肝窦毛细血管化的减轻有关，是一种对抗肝纤维化的潜在化合物。
