Liver deformation in Ahr-null mice:: Evidence for aberrant hepatic perfusion in early development
Liver deformation in Ahr-null mice:: Evidence for aberrant hepatic perfusion in early development
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DOI：
10.1124/mol.105.020107
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发表时间：
2006-05-01
影响因子：
3.6
通讯作者：
Bradfield, CA
中科院分区：
文献类型：
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作者：
Harstad, EB;Guite, CA;Bradfield, CA
携带Ahr位点突变的小鼠在一生中表现出静脉导管未闭和较小的肝脏。我们通过对野生型和Ahr（-/-）小鼠的肝脏发育进行详细分析，验证了这些肝脏畸变是继发于肝血管血流发育缺陷的假设。本研究显示，早在胚胎15.5天，Ahr（-/-）胎儿肝脏周围就出现了坏死性病变，其发生率在出生后第1天增加，并在产后2周消退。为了观察胎儿肝脏的灌注情况，我们将异硫氰酸荧光素标记的葡聚糖注射到颅动脉中，并在显微镜下监测肝脏荧光。中叶和左叶周围在发育后期出现坏死的相应区域显示灌注减少。对成年Ahr（-/-）动物的检查显示，肝脏变小主要是由于左右叶大小减小，与胎儿肝脏中观察到的灌注减少和肝坏死区域相对应。门静脉的组织学异常也支持Ahr（-/-）肝脏灌注受损的模型。综上所述，这些结果表明，Ahr位点是发育中的肝脏正常灌注所必需的，Ahr信号通路的破坏会导致胎儿肝坏死和随后的肝脏变形，这种变形会持续到成年。
Mice harboring mutations in the Ahr locus display a patent ductus venosus and smaller livers throughout life. We tested the hypothesis that these hepatic aberrations are secondary to a developmental defect in hepatovascular blood flow by performing a detailed analysis of hepatic development in wild-type and Ahr(-/-) mice. This study revealed necrotic lesions in the peripheries of Ahr(-/-) fetal livers as early as embryonic day 15.5, with an increasing incidence up to postnatal day 1 and resolution by 2 weeks post partum. To visualize perfusion of fetal livers, we injected fluorescein isothiocyanate-labeled dextran into the cranial artery and monitored hepatic fluorescence by microscopy. The peripheries of the median and left lobes displayed decreased perfusion in regions corresponding to those regions that displayed necrosis at later developmental times. An examination of adult Ahr(-/-) animals revealed that smaller livers are predominantly due to decreased sizes of the left and right lobes, corresponding to regions of decreased perfusion and hepatic necrosis observed in fetal livers. Histological aberrations in the portal vein also support a model in which perfusion is compromised in the Ahr(-/-) liver. Taken in sum, these results indicate that the Ahr locus is required for normal perfusion of the developing liver and that disruption of the AHR signaling pathway gives rise to fetal hepatic necrosis and consequent liver deformation which persists through adulthood.