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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)457-466
Number of pages10
JournalClinical Science
Volume124
Issue number7
DOIs
StatePublished - Apr 2013

Keywords

  • Angiogenesis
  • Hepatopulmonary syndrome
  • Intrapulmonary shunt
  • Liver cirrhosis
  • Sorafenib

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