title: The role of receptor tyrosine kinase activation in cholangiocytes and pulmonary vascular endothelium in experimental hepatopulmonary syndrome.
abstract: Pulmonary vascular dilation and angiogenesis underlie experimental hepatopulmonary syndrome (HPS) induced by common bile duct ligation (CBDL) and may respond to receptor tyrosine kinase (RTK) inhibition. Vascular endothelial growth factor-A (VEGF-A) expression occurs in proliferating cholangiocytes and pulmonary intravascular monocytes after CBDL, the latter contributing to angiogenesis. CBDL cholangiocytes also produce endothelin-1 (ET-1), which triggers lung vascular endothelin B receptor-mediated endothelial nitric oxide synthase (eNOS) activation and pulmonary intravascular monocyte accumulation. However, whether RTK pathway activation directly regulates cholangiocyte and pulmonary microvascular alterations in experimental HPS is not defined. We assessed RTK pathway activation in cholangiocytes and lung after CBDL and the effects of the type II RTK inhibitor sorafenib in experimental HPS. Cholangiocyte VEGF-A expression and ERK activation accompanied proliferation and increased hepatic and circulating ET-1 levels after CBDL. Sorafenib decreased each of these events and led to a reduction in lung eNOS activation and intravascular monocyte accumulation. Lung monocyte VEGF-A expression and microvascular Akt and ERK activation were also found in vivo after CBDL, and VEGF-A activated Akt and ERK and angiogenesis in rat pulmonary microvascular endothelial cells in vitro. Sorafenib inhibited VEGF-A-mediated signaling and angiogenesis in vivo and in vitro and improved arterial gas exchange and intrapulmonary shunting. RTK activation in experimental HPS upregulates cholangiocyte proliferation and ET-1 production, leading to pulmonary microvascular eNOS activation, intravascular monocyte accumulation, and VEGF-A-mediated angiogenic signaling pathways. These findings identify a novel mechanism in cholangiocytes through which RTK inhibition ameliorates experimental HPS.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Dept. of Internal Medicine, The Univ. of Texas Health Science Center at Houston, 6431 Fannin St., MSB 4.234, Houston, TX 77030-1501. michael.b.fallon@uth.tmc.edu.
authors.forename: Wenli
authors.initials: W
authors.lastname: Yang
authors.forename: Junlan
authors.initials: J
authors.lastname: Zhang
authors.forename: Bingqian
authors.initials: B
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Julie
authors.initials: J
authors.lastname: Venter
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fallon
mesh_terms: D000818:Animals; D003135:Common Bile Duct / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D020065:Hepatopulmonary Syndrome / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008026:Ligation; D008168:Lung / Q000098:blood supply; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D052250:Nitric Oxide Synthase Type III; D020794:Receptor Protein-Tyrosine Kinases
keywords: angiogenesis; bile duct proliferation; common bile duct ligation; endothelin-1; receptor tyrosine kinase