Kupffer cell activation in normal and fibrotic livers increases portal pressure via thromboxane A₂

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• 作者：Christian J. Steib ; Alex ; er L. Gerbes ; Markus Bystron ; Mark op den Winkel ; Josef Hä ; rtl ; Frigga Roggel ; Thomas Pr&#xfc ; fer ; Burkhard G&#xf6 ; ke ; Manfred Bilzer
• 关键词：Kupffer cells ; Inflammation ; Zymosan ; Portal hypertension ; Thromboxane A2 ; Reactive oxygen species
• 刊名：Journal of Hepatology
• 出版年：2007
• 期刊代码：162_01688278
• 类别：med
• 出版时间：August 2007
• 卷：47
• 期：2
• 页码：228-238
• 文件大小：567 K

摘要

Cyclooxygenase-1 (COX-1) is overexpressed in sinusoidal endothelial cells (SEC) of cirrhotic rat livers, and through an enhanced production of vasoconstrictor prostanoids contributes to increase intrahepatic resistance. Our study was aimed at investigating the role of enhanced AA bioavailability modulating the hepatic vascular tone of cirrhotic livers and identifying which prostanoid is involved.

Methods

<p>SEC isolated from control and cirrhotic rat livers were incubated with AA, methoxamine or vehicle. TXA₂ was quantified. In addition, portal perfusion pressure (PP) response curves to AA were performed in rat livers pre-incubated with vehicle, SC-560 (COX-1 inhibitor), Furegrelate (inhibitor of TXA₂ synthesis) and SQ-29548 (PGH₂/TXA₂ receptor blocker). cPLA2 activity was determined in control and cirrhotic livers.

Results

<p>AA and methoxamine incubation promoted a significant increase in TXA₂ release by Cirrhotic-SEC, but not in Control-SEC. AA produced a dose-dependent increase in the PP, associated with increased TXA₂ release. These responses were significantly greater in cirrhotic livers. COX-1 inhibition and PGH₂/TXA₂ receptor blockade, but not TXA₂ synthase inhibition, markedly attenuated the PP response to AA of cirrhotic livers. Additionally, cirrhotic livers exhibited significantly increased cPLA2 activity.

Conclusions

<p>An enhanced production of vasoconstrictor prostanoids, probably PGH₂, by SEC contributes to increase vascular tone of cirrhotic livers.