Sorafenib treatment improves hepatopulmonary: Syndrome in rats with biliary cirrhosis

Ching Chih Chang, Chiao Lin Chuang, Fa Yauh Lee*, Sun Sang Wang, Han Chieh Lin, Hui Chun Huang, Tzu Hua Teng, Shao Jung Hsu, Hsian Guey Hsieh, Shou Dong Lee

*此作品的通信作者

研究成果: Article同行評審

45 引文 斯高帕斯(Scopus)

摘要

HPS (hepatopulmonary syndrome) is characterized by oxygen desaturation in patients with chronic liver disease. The initiation of HPS comes from abnormal pulmonary vasodilatation and/or angiogenesis. In the present study, we evaluated anti-angiogenesis therapy using sorafenib in experimental HPS animals. HPS was induced by CBDL (common bile duct ligation) in rats. A 2-week 10 mg·(kg of body weight)-1·day-1 treatment regimen of sorafenib or distilled water (control) was initiated 2 weeks after the surgical procedure. Haemodynamics, liver biochemistry, plasma VEGF (vascular endothelial growth factor) measurements and blood gas analysis of the CBDL rats were performed. The livers of the CBDL rats were dissected for histopathology examination, and the lungs were examined by immunohistochemical staining, real-time PCR and Western blot analysis. In another two parallel groups, intrapulmonary shunts were determined. The AaPO2 (alveolar-arterial O2 gradient) and plasma VEGF levels were reduced after sorafenib treatment [AaPO2, 7.2 ± 3.4 mmHg in sorafenib-treated rats compared with 15.3 ± 4.2 mmHg in controls (P=0.004); VEGF, 45.3 ± 2.7 pg/ml in sorafenib-treated rats compared with 54.4 ± 7.7 pg/ml in controls (P=0.021)]. Sorafenib attenuated pulmonary VEGF mRNA and VEGF, VEGFR-2 (VEGF receptor 2), phospho-VEGFR-2 and Akt protein expression. In addition, sorafenib significantly attenuated intrapulmonary angiogenesis and decreased the degree of intrapulmonary shunting by 33.7% (11.2± 5.7% in sorafenib-treated rats compared with 16.9 ± 5.9% in controls; P=0.003). Our findings suggest that sorafenib attenuates intrapulmonary shunting and decreases the AaPO2 in CBDL rats, implicating the improvement of HPS in this experimental animal model. The beneficial effect may be attributed to the reduction in intrapulmonary angiogenesis through inhibition of the VEGF/VEGFR-2/Akt pathway.

原文English
頁(從 - 到)457-466
頁數10
期刊Clinical Science
124
發行號7
DOIs
出版狀態Published - 4月 2013

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