Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 188, Issue 7, Pages 1608-1624Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2018.03.018
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Funding
- Molecular and Genetic Imaging Core/National Research Program for Genomic Medicine at National Yang-Ming University
- National Science Council [MOST-105-2314-B-010-024-MY3]
- Taipei Veterans General Hospital [V105C-010, V106C-007]
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Recent studies have reported that peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist decreases intrahepatic resistance, whereas PPAR gamma agonist reduces portosystemic shunts (PSSs) and splanchnic angiogenesis in cirrhotic rats. The present study investigated the effects of a 21-day treatment with the dual PPAR alpha/gamma agonist aleglitazar (Ale) on progressive abnormalities in bile-duct-ligated and thioacetamide-induced cirrhotic rats with portal hypertension (PH). In vivo and in vitro effects were evaluated. Chronic Ale treatment significantly up-regulated PPAR alpha/PPAR gamma receptors and down-regulated tumor necrosis factor-alpha (TNF-alpha) and NF-kappa B expression in the liver, splanchnic tissues, collateral vessels, and intestines of cirrhotic rats with PH. Notably, Ale improved PH by the suppression of systemic/tissue inflammation, hepatic fibrosis, hepatic Rho-kinase-mediated endothelin-1 hyperresponsiveness, intrahepatic/mesenteric angiogenesis, vascular endothelial growth factor expression, PSS, intestinal mucosal injury, and hyperpermeability in cirrhotic rats. Acute Ale treatment-inhibited TNF-alpha-enhanced endothelin-1-induced contraction of primary hepatic stellate cells, vascular endothelial growth factor-induced migration/angiogenesis of liver sinusoidal endothelial cells, and TNF-alpha-induced disruption of Caco-2 cell monolayer-epithelial barrier. The present study suggested that Ale can potentially treat relevant abnormalities through the inhibition of inflammatory, vasoconstrictive, angiogenic, and mucosal-disrupted pathogenic markers in cirrhosis. Overall, chronic Ale treatment ameliorated PH syndrome by the suppression of hepatic fibrogenesis, neoangiogenesis, vasoconstrictor hyperresponsiveness, splanchnic vasodilatation, and PSS; and decreased intestinal mucosal injury and hyperpermeability in cirrhotic rats.
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