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塞来昔布通过改善内皮氧化应激降低门静脉高压症肝血管阻力。

Celecoxib reduces hepatic vascular resistance in portal hypertension by amelioration of endothelial oxidative stress.

机构信息

Laboratory of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.

出版信息

J Cell Mol Med. 2021 Nov;25(22):10389-10402. doi: 10.1111/jcmm.16968. Epub 2021 Oct 5.

DOI:10.1111/jcmm.16968
PMID:34609050
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8581330/
Abstract

The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase-2 (COX-2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX-2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX-2 overexpression by COX-2-dependent PGE2-EP2-ERK1/2-NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX-2-independent LKB1-AMPK-NRF2-HO-1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX-2-dependent and COX-2-independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.

摘要

内皮型一氧化氮合酶 (eNOS) 的激活和活性氧 (ROS) 的产生之间的平衡对于肝窦内皮细胞 (LSEC) 中 NO 的动态平衡非常重要。在肝硬化的 LSEC 中观察到环氧化酶-2 (COX-2) 的过表达，COX-2 是 ROS 产生的主要血管内来源。然而，LSEC 中低 NO 生物利用度与 COX-2 过表达之间的联系尚不清楚。本研究通过 COX-2 依赖性 PGE2-EP2-ERK1/2-NOX1/NOX4 信号通路在体内和体外证实了 LSEC 中低 NO 生物利用度与 COX-2 过表达之间的联系。此外，还阐明了 COX-2 非依赖性 LKB1-AMPK-NRF2-HO-1 信号通路对 LSEC 中 NO 动态平衡的调节作用。塞来昔布通过 COX-2 依赖性和 COX-2 非依赖性信号通路对 ROS 减少的联合作用大大降低了 NO 的清除。结果，LSEC 的毛细血管化减少，内皮功能障碍得到纠正。此外，肝硬化门脉高压症的肝血管阻力降低和门脉血流量增加得到了显著改善。随着对 LSEC 保护机制的深入了解，塞来昔布可能成为肝硬化门脉高压症患者的潜在治疗候选药物。

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