Li Tzu-Hao, Huang Chia-Chang, Yang Ying-Ying, Lee Kuei-Chuan, Hsieh Shie-Liang, Hsieh Yun-Cheng, Alan Lin, Lin Han-Chieh, Lee Shou-Dong, Tsai Chang-Youh
Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
PLoS One. 2016 Jan 28;11(1):e0147212. doi: 10.1371/journal.pone.0147212. eCollection 2016.
By blocking TNFα-related effects, thalidomide not only inhibits hepatic fibrogenesis but improves peripheral vasodilatation and portal hypertension in cirrhotic rats. Nonetheless, the investigation of thalidomide's effects on splanchnic and collateral microcirculation has been limited. Our study explored the roles of intestinal and mesenteric TNFα along with inflammasome-related pathway in relation to cirrhosis and the splanchnic/collateral microcirculation.
Using in vivo and in vitro approaches, mechanisms of the effects of thalidomide on intestinal and mesenteric inflammatory, vasodilatory and angiogenic cascades-related abnormalities were explored in cirrhotic rats that had received 1-month thalidomide (C-T) treatment.
In cirrhotic rats, high tumor necrosis factor (TNF)α, vascular endothelial growth factor (VEGF) and nitric oxide (NO)x levels were associated with the NOD-like receptors protein 3 (NLRP3), IL-1β and caspase-1 inflammasome over-expression in splenorenal shunt and mesenteric tissues. The thalidomide-related inhibition of mesenteric and splenorenal shunt inflammasome expression was accompanied by a significantly decreased intestinal mucosal injury and inflammasome immunohistochemical staining expression. Suppression of various angiogenic cascades, namely VEGF-NOS-NO, was paralleled by a decrease in mesenteric angiogenesis as detected by CD31 immunofluorescence staining and by reduced portosystemic shunting (PSS) in C-T rats. The down-regulation of the mesenteric and collateral vasodilatory VEGF-NOS-NO cascades resulted in a correction of vasoconstrictive hypo-responsiveness and in an attenuation of vasodilatory hyper-responsiveness when analyzed by in situ perfusion of the superior mesenteric arterial (SMA) and portosystemic collaterals. There was also a decrease in SMA blood flow and an increase in SMA resistance in the C-T rats. Additionally, acute incubation with thalidomide abolished TNFα-augmented VEGF-mediated migration of and tube formation of human umbilical vein endothelial cells, which was accompanied by corresponding changes in inflammatory and angiogenic substances release.
The suppression of inflammasome over-expression by chronic thalidomide treatment ameliorates inflammatory, angiogenic and vasodilatory cascades-related pathogenic changes in the splanchnic and collateral microcirculation of cirrhotic rats. Thalidomide seems to be a promising agent that might bring about beneficial changes to the disarrangements of peripheral, hepatic, splanchnic and collateral systems in cirrhosis.
通过阻断肿瘤坏死因子α（TNFα）相关效应，沙利度胺不仅能抑制肝纤维化，还可改善肝硬化大鼠的外周血管舒张及门静脉高压。尽管如此，沙利度胺对内脏和侧支微循环影响的研究仍较为有限。我们的研究探讨了肠道和肠系膜TNFα以及炎性小体相关通路在肝硬化及内脏/侧支微循环中的作用。
采用体内和体外方法，在接受1个月沙利度胺（C-T）治疗的肝硬化大鼠中，探究沙利度胺对肠道和肠系膜炎症、血管舒张及血管生成级联反应相关异常的影响机制。
在肝硬化大鼠中，高肿瘤坏死因子（TNF）α、血管内皮生长因子（VEGF）和一氧化氮（NO）x水平与脾肾分流和肠系膜组织中NOD样受体蛋白3（NLRP3）、白细胞介素-1β（IL-1β）和半胱天冬酶-1炎性小体的过度表达有关。沙利度胺对肠系膜和脾肾分流炎性小体表达的抑制作用，伴随着肠黏膜损伤和炎性小体免疫组化染色表达的显著降低。通过CD31免疫荧光染色检测发现，沙利度胺对各种血管生成级联反应（即VEGF-NOS-NO）的抑制作用，与肠系膜血管生成减少以及C-T大鼠门体分流（PSS）减少相平行。当通过肠系膜上动脉（SMA）和门体侧支原位灌注分析时，肠系膜和侧支血管舒张性VEGF-NOS-NO级联反应的下调导致血管收缩性低反应性的纠正以及血管舒张性高反应性的减弱。C-T大鼠的SMA血流量也减少，SMA阻力增加。此外，沙利度胺急性孵育可消除TNFα增强的VEGF介导的人脐静脉内皮细胞迁移和管腔形成，同时伴有炎症和血管生成物质释放的相应变化。
慢性沙利度胺治疗对炎性小体过度表达的抑制作用，改善了肝硬化大鼠内脏和侧支微循环中与炎症、血管生成和血管舒张级联反应相关的病理变化。沙利度胺似乎是一种有前景的药物，可能会给肝硬化患者外周、肝脏、内脏和侧支系统的紊乱带来有益的改变。
