Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture
Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture
复制标题
DOI：
10.1038/labinvest.2012.103
复制
发表时间：
2012-10-01
影响因子：
5
通讯作者：
Michielsen, Peter
中科院分区：
文献类型：
--
作者：
Francque, Sven;Laleman, Wim;Michielsen, Peter
非酒精性脂肪性肝病可进展为脂肪性肝炎和纤维化，并且还与肝再生受损有关。病理生理学仍然难以捉摸。我们最近发现，严重的脂肪变性与门静脉压力增加有关，提示肝血流受损。本研究的目的是在原位灌注模型中直接评估总肝内阻力及其潜在的功能和结构决定因素。比较了喂食对照（n=30）或蛋氨酸胆碱缺乏（MCD）饲料（n=30）4周的雄性Wistar大鼠。肝组织和血清分析，在体内血流动力学测量，在原位灌注实验和血管腐蚀模型进行。MCD组在组织学上显示重度脂肪变性，无炎症或纤维化。各组之间白细胞介素（IL）-6、肿瘤坏死因子-α、IL-1 β和干扰素-γ的血清水平和肝组织基因表达、肝组织髓过氧化物酶活性以及抗CD 68和抗α平滑肌肌动蛋白的肝脏免疫组织化学相当，不包括明显的炎症。各组之间所有流量的流量-压力曲线均存在显著差异（斜率值：对照组为0.1636 +/- 0.0605 mm Hg/ml/min，而喂食MCD的大鼠为0.7270 +/- 0.0408 mm Hg/ml/min，P
Non-alcoholic fatty liver disease can progress to steatohepatitis and fibrosis, and is also associated with impaired liver regeneration. The pathophysiology remains elusive. We recently showed that severe steatosis is associated with an increase in portal pressure, suggesting liver flow impairment. The objective of this study is to directly assess total intrahepatic resistance and its potential functional and structural determinants in an in situ perfusion model. Male Wistar rats fed a control (n=30) or a methionine choline-deficient (MCD) diet (n=30) for 4 weeks were compared. Liver tissue and serum analysis, in vivo haemodynamic measurements, in situ perfusion experiments and vascular corrosion casts were performed. The MCD group showed severe steatosis without inflammation or fibrosis on histology. Serum levels and liver tissue gene expression of interleukin (IL)-6, tumour necrosis factor-alpha IL-1 beta and interferon-gamma, liver tissue myeloperoxidase activity and liver immunohistochemistry with anti-CD68 and anti-alpha smooth muscle actin were comparable between groups, excluding significant inflammation. Flow-pressure curves were significantly different between groups for all flows (slope values: 0.1636 +/- 0.0605 mm Hg/ml/min in controls vs 0.7270 +/- 0.0408 mm Hg/ml/min in MCD-fed rats, P