Selective cyclooxygenase inhibition by SC-560 improves hepatopulmonary syndrome in cirrhotic rats
by Ching-Chih Chang, Wen-Shin Lee, Hsian-Guey Hsieh, Chiao-Lin Chuang, Hui-Chun Huang, Fa-Yauh Lee, Shou-Dong LeeObjective
Hepatopulmonary syndrome (HPS) is characterized by hypoxia in patients with chronic liver disease. The mechanism of HPS includes pulmonary vasodilatation, inflammation, and angiogenesis. Prostaglandins synthesized by cyclooxygenases (COX) participate in vascular responsiveness, inflammation and angiogenesis, which can be modulated by COX inhibitors. We therefore evaluated the impact of COX inhibition in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS.Methods
Cirrhotic rats were randomly allocated to receive non-selective COX inhibitor (indomethacin), selective COX-1 inhibitor (SC-560), or COX-2 inhibitor (celecoxib) for 14 days. After that, hemodynamic parameters, severity of hypoxia and intrapulmonary shunts, liver and renal biochemistry parameters, histological finding and protein expressions were evaluated.Results
Non-selective COX inhibition by indomethacin improved hepatic fibrosis and pulmonary inflammation in cirrhotic rats with HPS. It also decreased mean arterial blood pressure, portal pressure, and alleviated hypoxia and intrapulmonary shunts. However, indomethacin increased mortality rate. In contrast, selective COX inhibitors neither affected hemodynamics nor increased mortality rate. Hypoxia was improved by SC-560 and celecoxib. In addition, SC-560 decreased intrapulmonary shunts, attenuated pulmonary inflammation and angiogenesis through down-regulating COX-, NFκB- and VEGF-mediated pathways.Conclusion
Selective COX-1 inhibitor ameliorated HPS by mitigating hypoxia and intrapulmonary shunts, which are related to anti-inflammation and anti-angiogenesis.
Publisher URL: http://journals.plos.org/plosone/article
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