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The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis

Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X(7) participates in the...

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Autores principales: Tung, Hung-Chun, Lee, Fa-Yauh, Wang, Sun-Sang, Tsai, Ming-Hung, Lee, Jing-Yi, Huo, Teh-Ia, Huang, Hui-Chun, Chuang, Chiao-Lin, Lin, Han-Chieh, Lee, Shou-Dong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416718/
https://www.ncbi.nlm.nih.gov/pubmed/25933224
http://dx.doi.org/10.1371/journal.pone.0124654
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author Tung, Hung-Chun
Lee, Fa-Yauh
Wang, Sun-Sang
Tsai, Ming-Hung
Lee, Jing-Yi
Huo, Teh-Ia
Huang, Hui-Chun
Chuang, Chiao-Lin
Lin, Han-Chieh
Lee, Shou-Dong
author_facet Tung, Hung-Chun
Lee, Fa-Yauh
Wang, Sun-Sang
Tsai, Ming-Hung
Lee, Jing-Yi
Huo, Teh-Ia
Huang, Hui-Chun
Chuang, Chiao-Lin
Lin, Han-Chieh
Lee, Shou-Dong
author_sort Tung, Hung-Chun
collection PubMed
description Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X(7) participates in the modulation of inflammation, angiogenesis, fibrogenesis and vasoresponsiveness, but the relevant influence in cirrhosis is unknown. Common bile duct-ligated (CBDL) or sham-operated Spraque-Dawley rats received brilliant blue G (BBG, a P2X(7) antagonist and food additive) or vehicle from the 15(th) to 28(th) day after operations, then hemodynamics, mesenteric angiogenesis, portal-systemic shunting, liver fibrosis, and protein expressions of angiogenic and fibrogenic factors were evaluated. The influence of oxidized ATP (oATP, another P2X(7) receptor antagonist) on the collateral vasoresponsiveness to arginine vasopressin (AVP) was also surveyed. BBG decreased superior mesenteric artery (SMA) flow, portal-systemic shunting, mesenteric vascular density, and mesenteric protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), phospho (p)-VEGFR2, platelet-derived growth factor (PDGF), PDGF receptor beta (PDGFRβ), cyclooxygenase (COX)-1, COX-2, and endothelial NO synthase (eNOS) in CBDL rats. BBG also ameliorated liver fibrosis and down-regulated hepatic interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), PDGF, IL-1β, transforming growth factor-beta (TGF-β), p-extracellular-signal-regulated kinases (ERK), and alpha-smooth muscle actin (α-SMA) expressions in CBDL rats. The collateral vasocontractility to AVP was enhanced by oATP. oATP down-regulated eNOS, inducible NOS (iNOS), VEGF, Akt, p-Akt, and nuclear factor-kappa B (NF-κB) expressions in splenorenal shunt, the most prominent intra-abdominal collateral vessel in rodents. P2X(7) antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X(7) blockade may be a feasible strategy to control cirrhosis and complications.
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spelling pubmed-44167182015-05-07 The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis Tung, Hung-Chun Lee, Fa-Yauh Wang, Sun-Sang Tsai, Ming-Hung Lee, Jing-Yi Huo, Teh-Ia Huang, Hui-Chun Chuang, Chiao-Lin Lin, Han-Chieh Lee, Shou-Dong PLoS One Research Article Splanchnic angiogenesis in liver cirrhosis often leads to complications as gastroesophageal variceal hemorrhage and the treatment efficacy is adversely affected by poor portal-systemic collateral vasoresponsiveness related to nitric oxide (NO). Purinergic receptor subtype P2X(7) participates in the modulation of inflammation, angiogenesis, fibrogenesis and vasoresponsiveness, but the relevant influence in cirrhosis is unknown. Common bile duct-ligated (CBDL) or sham-operated Spraque-Dawley rats received brilliant blue G (BBG, a P2X(7) antagonist and food additive) or vehicle from the 15(th) to 28(th) day after operations, then hemodynamics, mesenteric angiogenesis, portal-systemic shunting, liver fibrosis, and protein expressions of angiogenic and fibrogenic factors were evaluated. The influence of oxidized ATP (oATP, another P2X(7) receptor antagonist) on the collateral vasoresponsiveness to arginine vasopressin (AVP) was also surveyed. BBG decreased superior mesenteric artery (SMA) flow, portal-systemic shunting, mesenteric vascular density, and mesenteric protein expressions of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), phospho (p)-VEGFR2, platelet-derived growth factor (PDGF), PDGF receptor beta (PDGFRβ), cyclooxygenase (COX)-1, COX-2, and endothelial NO synthase (eNOS) in CBDL rats. BBG also ameliorated liver fibrosis and down-regulated hepatic interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), PDGF, IL-1β, transforming growth factor-beta (TGF-β), p-extracellular-signal-regulated kinases (ERK), and alpha-smooth muscle actin (α-SMA) expressions in CBDL rats. The collateral vasocontractility to AVP was enhanced by oATP. oATP down-regulated eNOS, inducible NOS (iNOS), VEGF, Akt, p-Akt, and nuclear factor-kappa B (NF-κB) expressions in splenorenal shunt, the most prominent intra-abdominal collateral vessel in rodents. P2X(7) antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X(7) blockade may be a feasible strategy to control cirrhosis and complications. Public Library of Science 2015-05-01 /pmc/articles/PMC4416718/ /pubmed/25933224 http://dx.doi.org/10.1371/journal.pone.0124654 Text en © 2015 Tung et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Tung, Hung-Chun
Lee, Fa-Yauh
Wang, Sun-Sang
Tsai, Ming-Hung
Lee, Jing-Yi
Huo, Teh-Ia
Huang, Hui-Chun
Chuang, Chiao-Lin
Lin, Han-Chieh
Lee, Shou-Dong
The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis
title The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis
title_full The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis
title_fullStr The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis
title_full_unstemmed The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis
title_short The Beneficial Effects of P2X(7) Antagonism in Rats with Bile Duct Ligation-induced Cirrhosis
title_sort beneficial effects of p2x(7) antagonism in rats with bile duct ligation-induced cirrhosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416718/
https://www.ncbi.nlm.nih.gov/pubmed/25933224
http://dx.doi.org/10.1371/journal.pone.0124654
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