Rosuvastatin improves hepatopulmonary syndrome through inhibition of inflammatory angiogenesis of lung.
The hepatopulmonary syndrome (HPS) is characterized by hypoxia and increased intrapulmonary shunts in cirrhotic patients. Emerging evidence showed promising results of treating HPS by abolishment of intrapulmonary inflammation and angiogenesis. Rosuvastatin is a kind of 3-hydroxy-methyl-3-glutamyl coenzyme A reductase inhibitor. In addition to lipid-lowering effects, it has anti-inflammation and anti-angiogenesis properties. We postulated that rosuvastatin treatment can ameliorate HPS. Common bile duct ligation (CBDL) was applied in an experimental HPS animal model. CBDL rats received 2-week rosuvastatin (20 mg/kg/day) treatments from the fifteenth day after operation. The haemodynamic data, blood gas analysis, liver biochemistries, tumour necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) were examined after rosuvastatin treatment. The liver and lung tissues were dissected for histopathological studies and protein analyses. In the parallel groups, intrapulmonary shunts were determined. The haemodynamic and liver biochemistries were not changed after rosuvastatin treatment in CBDL rats, but the alveolar-arterial oxygen pressure gradient was significantly decreased, implying that HPS-induced hypoxia was reversed after rosuvastatin treatment. In addition, rosuvastatin treatment reduced intrapulmonary shunts and plasma levels of VEGF and TNF-α. Besides, the intrapulmonary protein expression of nuclear factor kappa B (NF-κB), VEGF receptor (VEGFR)-1,2 and Rho-associated A kinase were significantly down-regulated and the intrapulmonary angiogenesis was ameliorated. We concluded that rosuvastatin alleviates experimental HPS through blockade of pulmonary inflammatory angiogenesis via TNF-α/NF-κB and VEGF/Rho-associated A kinase pathways down-regulation.
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan.
Ching-Chih
CC
Chang
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan Department of Medical Affair and Planning, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Sun-Sang
SS
Wang
Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Hsian-Guey
HG
Hsieh
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan.
Wen-Shin
WS
Lee
Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan.
Chiao-Lin
CL
Chuang
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Han-Chieh
HC
Lin
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Fa-Yauh
FY
Lee
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan Division of Gastroenterology, Department of Medicine, Cheng-Hsin General Hospital, Taipei 112, Taiwan.
Shou-Dong
SD
Lee
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei 112, Taiwan Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan hchuang2@vghtpe.gov.tw.
Hui-Chun
HC
Huang
D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005464:Fluorobenzenes / Q000378:metabolism / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D020065:Hepatopulmonary Syndrome / Q000188:drug therapy*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D000068718:Rosuvastatin Calcium
hepatopulmonary syndrome; inflammatory angiogenesis; liver cirrhosis; rosuvastatin