The non-steroidal FXR agonists PX20606 and GS-9674 improve liver fibrosis and portal hypertension in rodent models of cholestatic, metabolic and toxic liver cirrhosis

2016 ◽  
Vol 54 (05) ◽  
Author(s):  
T Reiberger ◽  
P Schwabl ◽  
P Supper ◽  
D Bauer ◽  
BA Payer ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Rodent Models

scholarly journals COX-2/sEH Dual Inhibitor PTUPB Alleviates CCl4-Induced Liver Fibrosis and Portal Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhifeng Zhao ◽  
Chihao Zhang ◽  
Jiayun Lin ◽  
Lei Zheng ◽  
Hongjie Li ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Growth Factor ◽  
Liver Fibrosis ◽  
Vascular Remodeling ◽  
Mesenteric Arteries ◽  
Cytokeratin 19 ◽  
Dual Inhibitor ◽  
Bile Duct Proliferation ◽  
Cox 2

Background: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl) -benzenesulfonamide (PTUPB), a dual cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) inhibitor, was found to alleviate renal, pulmonary fibrosis and liver injury. However, few is known about the effect of PTUPB on liver cirrhosis. In this study, we aimed to explore the role of PTUPB in liver cirrhosis and portal hypertension (PHT).Method: Rat liver cirrhosis model was established via subcutaneous injection of carbon tetrachloride (CCl4) for 16 weeks. The experimental group received oral administration of PTUPB (10 mg/kg) for 4 weeks. We subsequently analyzed portal pressure (PP), liver fibrosis, inflammation, angiogenesis, and intra- or extrahepatic vascular remodeling. Additionally, network pharmacology was used to investigate the possible mechanisms of PTUPB in live fibrosis.Results: CCl4 exposure induced liver fibrosis, inflammation, angiogenesis, vascular remodeling and PHT, and PTUPB alleviated these changes. PTUPB decreased PP from 17.50 ± 4.65 to 6.37 ± 1.40 mmHg, reduced collagen deposition and profibrotic factor. PTUPB alleviated the inflammation and bile duct proliferation, as indicated by decrease in serum interleukin-6 (IL-6), liver cytokeratin 19 (CK-19), transaminase, and macrophage infiltration. PTUPB also restored vessel wall thickness of superior mesenteric arteries (SMA) and inhibited intra- or extrahepatic angiogenesis and vascular remodeling via vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), etc. Moreover, PTUPB induced sinusoidal vasodilation by upregulating endothelial nitric oxide synthase (eNOS) and GTP-cyclohydrolase 1 (GCH1). In enrichment analysis, PTUPB engaged in multiple biological functions related to cirrhosis, including blood pressure, tissue remodeling, immunological inflammation, macrophage activation, and fibroblast proliferation. Additionally, PTUPB suppressed hepatic expression of sEH, COX-2, and transforming growth factor-β (TGF-β).Conclusion: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide ameliorated liver fibrosis and PHT by inhibiting fibrotic deposition, inflammation, angiogenesis, sinusoidal, and SMA remodeling. The molecular mechanism may be mediated via the downregulation of the sEH/COX-2/TGF-β.

scholarly journals Portal hypertension is the main driver of liver stiffness in advanced liver cirrhosis

2021 ◽  
pp. 563-577
Author(s):  
Mariia Lunova ◽  
Sona Frankova ◽  
Halima Gottfriedova ◽  
Renata Senkerikova ◽  
Magdalena Neroldova ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Venous Pressure ◽  
Liver Stiffness ◽  
Collagen Content ◽  
Explanted Liver ◽  
Advanced Liver Cirrhosis ◽  
Cirrhotic Patients ◽  
Liver Collagen

Liver stiffness (LS) is a novel non-invasive parameter widely used in clinical hepatology. LS correlates with liver fibrosis stage in non-cirrhotic patients. In cirrhotic patients it also shows good correlation with Hepatic Venous Pressure Gradient (HVPG). Our aim was to assess the contribution of liver fibrosis and portal hypertension to LS in patients with advanced liver cirrhosis. Eighty-one liver transplant candidates with liver cirrhosis of various aetiologies underwent direct HVPG and LS measurement by 2D shear-wave elastography (Aixplorer Multiwave, Supersonic Imagine, France). Liver collagen content was assessed in the explanted liver as collagen proportionate area (CPA) and hydroxyproline content (HP). The studied cohort included predominantly patients with Child-Pugh class B and C (63/81, 77.8 %), minority of patients were Child-Pugh A (18/81, 22.2 %). LS showed the best correlation with HVPG (r=0.719, p<0.001), correlation of LS with CPA (r=0.441, p<0.001) and HP/Amino Acids (r=0.414, p< 0.001) was weaker. Both variables expressing liver collagen content showed good correlation with each other (r=0.574, p<0.001). Multiple linear regression identified the strongest association between LS and HVPG (p<0.0001) and weaker association of LS with CPA (p = 0.01883). Stepwise modelling showed minimal increase in r2 after addition of CPA to HVPG (0.5073 vs. 0.5513). The derived formula expressing LS value formation is: LS=2.48 + (1.29 x HVPG) + (0.26 x CPA). We conclude that LS is determined predominantly by HVPG in patients with advanced liver cirrhosis whereas contribution of liver collagen content is relatively low.

scholarly journals Glycyrrhizin Attenuates Portal Hypertension and Collateral Shunting via Inhibition of Extrahepatic Angiogenesis in Cirrhotic Rats

2021 ◽  
Vol 22 (14) ◽  
pp. 7662
Author(s):  
Chon Kit Pun ◽  
Hui-Chun Huang ◽  
Ching-Chih Chang ◽  
Chiao-Lin Chuang ◽  
Chun-Hsien Yen ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Liver Fibrosis ◽  
Statistical Significance ◽  
Portal Pressure ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Beneficial Effects ◽  
Duct Ligation ◽  
The Impact

Portal hypertension develops along with liver cirrhosis then induces the formation of portal-systemic collaterals and lethal complications. Extrahepatic angiogenesis plays an important role. Glycyrrhizin has been found to exhibit anti-angiogenic features, which leads to its extensive use. However, the relevant effects of glycyrrhizin on liver cirrhosis and portal hypertension have not been evaluated. This study thus aimed to investigate the impact of glycyrrhizin on portal hypertension-related derangements in cirrhotic rats. Male Sprague-Dawley rats received bile duct ligation (BDL) to induce cirrhosis or sham operation as control. The rats were subdivided to receive glycyrrhizin (150 mg/kg/day, oral gavage) or vehicle beginning on the 15th day post operation, when BDL-induced liver fibrosis developed. The effects of glycyrrhizin were determined on the 28th day, the typical timing of BDL-induced cirrhosis. Glycyrrhizin significantly reduced portal pressure (p = 0.004). The splanchnic inflow as measured by superior mesenteric arterial flow decreased by 22% (p = 0.029). The portal-systemic collateral shunting degree reduced by 30% (p = 0.024). The mesenteric angiogenesis and phospho-VEGFR2 protein expression were also downregulated (p = 0.038 and 0.031, respectively). Glycyrrhizin did not significantly influence the liver biochemistry data. Although glycyrrhizin tended to reverse liver fibrosis, statistical significance was not reached (p = 0.069). Consistently, hepatic inflow from portal side, hepatic vascular resistance, and liver fibrosis-related protein expressions were not affected. Glycyrrhizin treatment at the stage of hepatic fibrosis still effectively attenuated portal hypertension and portosystemic collateral shunting. These beneficial effects were attributed to, at least in part, the suppression of mesenteric angiogenesis by VEGF signaling pathway downregulation.

Small intestinal motillity disturbances and bacterial overgrowth in patients with liver cirrhosis is associated with portal hypertension

2001 ◽  
Vol 120 (5) ◽  
pp. A224-A224
Author(s):  
A GUNNARSDOTTIR ◽  
E BJOMSSON ◽  
G RINGSTROM ◽  
M SIMREN ◽  
P STOTZER ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Bacterial Overgrowth ◽  
Small Intestinal

An unusual presentation of epigastric pain due to thrombophlebitis of a recanalised umbilical vein – case report

2019 ◽  
Vol 98 (8) ◽  
pp. 326-327 ◽  
Keyword(s):  
Liver Cirrhosis ◽  
Abdominal Pain ◽  
Case Report ◽  
Portal Hypertension ◽  
Liver Disease ◽  
Epigastric Pain ◽  
Umbilical Vein ◽  
History Of ◽  
Clinically Significant ◽  
Inflammatory Changes

Introduction: The umbilical vein can become recanalised due to portal hypertension in patients with liver cirrhosis but the condition is rarely clinically significant. Although bleeding from this enlarged vein is a known complication, the finding of thrombophlebitis has not been previously described. Case report: We report the case of a 62-year-old male with a history of liver cirrhosis due to alcoholic liver disease presenting to hospital with epigastric pain. A CT scan of the patient’s abdomen revealed a thrombus with surrounding inflammatory changes in a recanalised umbilical vein. The patient was managed conservatively and was discharged home the following day. Conclusion: Thrombophlebitis of a recanalised umbilical vein is a rare cause of abdominal pain in patients with liver cirrhosis.

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