ENDOTOXIN CAUSES PULMONARY HYPERTENSION BY UPREGULATING SMOOTH MUSCLE ENDOTHELIN TYPE-B RECEPTORS: ROLE OF ALDOSE REDUCTASE
ENDOTOXIN CAUSES PULMONARY HYPERTENSION BY UPREGULATING SMOOTH MUSCLE ENDOTHELIN TYPE-B RECEPTORS: ROLE OF ALDOSE REDUCTASE
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内毒素通过上调平滑肌 B 型内皮素受体引起肺动脉高压：醛糖还原酶的作用
DOI：
10.1097/shk.0b013e318160f03b
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发表时间：
2007
期刊：
影响因子：
3.1
通讯作者：
F. Brunner
中科院分区：
文献类型：
--
作者：
T. Dschietzig;K. Alexiou;C. Richter;Martin Bobzin;G. Baumann;K. Stangl;F. Brunner
内皮素-1（ET-1）是一种强有力的血管收缩剂和促分裂剂，在内毒素血症时肺组织中表达上调，并在内毒素诱导的肺动脉高压中起重要作用。然而，ET受体ETA和ETB是否在内毒素血症肺血管系统中受到差异调节以及这如何影响肺血管张力尚不清楚。为了研究这一主题，我们使用了离体灌注的大鼠肺、肺内皮细胞（EC）和肺血管平滑肌细胞（SMCs）。在6小时的内毒素暴露，离体灌注肺显着肺动脉高压显着衰减拮抗ETA或ET B受体使用亚型选择性或混合ETA/B受体拮抗剂。内毒素刺激后，各组织大ET-1、ET-1肽水平及ET-1前体基因表达均升高。在内毒素血症的离体灌流肺和EC中，在ETB受体或混合拮抗剂完全消失后，对照组中观察到的成熟ET-1显著升高。然而，这种作用在内毒素血症SMC中得以保留。在内皮细胞，内毒素显着下调最大ETB受体位点和ETB mRNA水平，而在SMC，它产生大量的ETB受体上调和中度ETA受体下调。醛糖还原酶抑制剂sorbinil和zopolestat减轻内毒素诱导的肺动脉高压，ET-1刺激和差异ETB受体调节。我们的结论是内毒素诱导的肺动脉高压大鼠的结果从内皮细胞和血管平滑肌ETB受体的同时获得损失。这些变化至少部分由醛糖还原酶介导。
Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, is upregulated in pulmonary tissue during endotoxemia and contributes markedly to endotoxin-induced pulmonary hypertension. It is, however, unknown whether the ET receptors, ETA and ETB, are differentially regulated in endotoxemic pulmonary vasculature and how this may impact on pulmonary vascular tone. To investigate this topic, we used isolated perfused lungs, pulmonary endothelial cells (ECs), and pulmonary vascular smooth muscle cells (SMCs) of the rat. During a 6-h endotoxin exposure, isolated perfused lungs developed significant pulmonary hypertension that was markedly attenuated by antagonizing ETA or ETB receptors using subtype-selective or a mixed ETA/B receptor antagonist. Peptide levels of big ET-1 and ET-1 and gene expression of prepro-ET-1 were increased after endotoxin challenge in all tissues. In endotoxemic isolated perfused lungs and ECs, the significant rise of mature ET-1 seen in controls after ETB receptor or mixed antagonism disappeared completely. However, this effect was preserved in endotoxemic SMCs. In ECs, endotoxin markedly downregulated maximum ETB receptor sites and ETB mRNA levels, whereas in SMCs, it generated substantial ETB receptor upregulation and moderate ETA receptor downregulation. The aldose reductase inhibitors sorbinil and zopolrestat mitigated endotoxin-induced pulmonary hypertension, ET-1 stimulation, and differential ETB receptor regulation. We conclude that endotoxin-induced pulmonary hypertension in the rat results from a loss of endothelial and concomitant gain of vascular smooth muscle ETB receptors. These changes are at least partly mediated by aldose reductase.
DOI：
10.1164/ajrccm.157.1.95-05117
发表时间：
1998-01-01
影响因子：
24.7
作者：
Snapper, JR;Thabes, JS;Lu, WX
通讯作者：
Lu, WX