Endotoxin unmasks the role of gap junctions in the liver
Endotoxin unmasks the role of gap junctions in the liver
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DOI：
10.1016/j.bbrc.2004.07.192
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发表时间：
2004-09-24
影响因子：
3.1
通讯作者：
Nathanson, MH
中科院分区：
文献类型：
--
作者：
Correa, PRAV;Guerra, MT;Nathanson, MH
缝隙连接被认为是正常组织功能所必需的。然而，在缺乏连接蛋白32（Cx 32）（肝脏中的主要间隙连接）的患者中，尚未描述明确的肝脏表型。为了确定Cx 32在肝脏中的生理作用，我们比较了野生型和Cx 32缺陷型小鼠对内毒素的反应，因为这种应激增加了与不对称分布在肝小叶中的受体结合的激素的血清水平。在从野生型小鼠分离的肝细胞偶联中，即使在用内毒素处理后，大多数肝细胞也可以将显微注射的染料转移到它们的邻居。在Cx 32缺陷偶联中未观察到染料转移。用加压素处理野生型小鼠的肝细胞偶联诱导钙（Ca 2+）波，以浓度依赖性方式穿过偶联，但在所有浓度下，Cx 32缺陷偶联的传输延迟明显延长。加压素受体和肌醇1，4，5-三磷酸受体的表达并没有减少内毒素或在Cx 32缺陷的对联。最后，内毒素引起短暂的低血糖症和胆汁淤积的野生型动物，但低血糖症轻微延长和胆汁淤积更严重的Cx 32缺陷小鼠与内毒素治疗。在Cx 32缺失的情况下，肝脏对内毒素的反应明显受损。因此，间隙连接在肝脏中的重要作用是确保在应激时的整合和均匀的组织反应。(C)2004年爱思唯尔公司All rights reserved.
Gap junctions are thought to be necessary for proper tissue function. However, no clear hepatic phenotype has been described in patients lacking connexin 32 (Cx32), the principal gap junction in liver. To determine the physiological role of Cx32 in liver, we compared the response of wild type and Cx32-deficient mice to endotoxin, since this stress increases serum levels of hormones that bind to receptors that are asymmetrically distributed across the hepatic lobule. In hepatocyte couplets isolated from wild type mice, most hepatocytes could transfer microinjected dye to their neighbor even after treatment with endotoxin. Dye transfer was not observed in Cx32-deficient couplets. Treatment of hepatocyte couplets from wild type mice with vasopressin induced calcium (Ca2+) waves that crossed the couplets in a concentration-dependent fashion, but the delay in transmission was markedly prolonged at all concentrations in Cx32-deficient couplets. Expression of the vasopressin receptor and the inositol 1,4,5-trisphosphate receptor was not decreased by endotoxin or in Cx32-deficient couplets. Finally, endotoxin caused transient hypoglycemia and cholestasis in wild type animals, but hypoglycemia was slightly prolonged and cholestasis was much worse in Cx32-deficient mice treated with endotoxin. The hepatic response to endotoxin is markedly impaired in the absence of Cx32. Thus, an important role of gap junctions in the liver is to assure integrated and uniform tissue response in times of stress. (C) 2004 Elsevier Inc. All rights reserved.