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
Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
PLoS One. 2015 May 1;10(5):e0124654. doi: 10.1371/journal.pone.0124654. eCollection 2015.
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 P2X7 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 P2X7 antagonist and food additive) or vehicle from the 15th to 28th 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 P2X7 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. P2X7 antagonism alleviates splanchnic hyperemia, severity of portal-systemic shunting, mesenteric angiogenesis, liver fibrosis, and enhances portal-systemic collateral vasoresponsiveness in cirrhotic rats. P2X7 blockade may be a feasible strategy to control cirrhosis and complications.
肝硬化时内脏血管生成常导致诸如胃食管静脉曲张出血等并发症，而与一氧化氮（NO）相关的门体侧支血管反应性差会对治疗效果产生不利影响。嘌呤能受体亚型P2X7参与炎症、血管生成、纤维生成和血管反应性的调节，但在肝硬化中的相关影响尚不清楚。将胆总管结扎（CBDL）或假手术的Sprague-Dawley大鼠在术后第15天至28天给予亮蓝G（BBG，一种P2X7拮抗剂和食品添加剂）或赋形剂，然后评估血流动力学、肠系膜血管生成、门体分流、肝纤维化以及血管生成和纤维生成因子的蛋白表达。还研究了氧化ATP（oATP，另一种P2X7受体拮抗剂）对精氨酸加压素（AVP）侧支血管反应性的影响。BBG降低了CBDL大鼠的肠系膜上动脉（SMA）血流、门体分流、肠系膜血管密度以及肠系膜中血管内皮生长因子（VEGF）、VEGF受体2（VEGFR2）、磷酸化（p）-VEGFR2、血小板衍生生长因子（PDGF）、PDGF受体β（PDGFRβ）、环氧化酶（COX）-1、COX-2和内皮型一氧化氮合酶（eNOS）的蛋白表达。BBG还改善了肝纤维化，并下调了CBDL大鼠肝脏中白细胞介素-6（IL-6）、肿瘤坏死因子-α（TNF-α）、PDGF、IL-1β、转化生长因子-β（TGF-β）、磷酸化细胞外信号调节激酶（ERK）和α-平滑肌肌动蛋白（α-SMA）的表达。oATP增强了对AVP的侧支血管收缩性。oATP下调了脾肾分流（啮齿动物腹腔内最主要的侧支血管）中eNOS、诱导型一氧化氮合酶（iNOS）、VEGF、Akt、磷酸化Akt和核因子-κB（NF-κB）的表达。P2X7拮抗作用可减轻肝硬化大鼠的内脏充血、门体分流严重程度、肠系膜血管生成、肝纤维化，并增强门体侧支血管反应性。阻断P2X7可能是控制肝硬化及其并发症的一种可行策略。
