scholarly journals Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Miren Bravo ◽  
Imma Raurell ◽  
Diana Hide ◽  
Anabel Fernández-Iglesias ◽  
Mar Gil ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Endothelial Dysfunction ◽  
Control Diet ◽  
Portal Pressure ◽  
Developed Countries ◽  
Liver Disorder ◽  
Statin Treatment ◽  
Liver Sinusoidal Endothelial Cell ◽  
Sprague Dawley ◽  
Sinusoidal Cell

AbstractNon-alcoholic steatohepatitis (NASH) is a common chronic liver disorder in developed countries, with the associated clinical complications driven by portal hypertension (PH). PH may precede fibrosis development, probably due to endothelial dysfunction at early stages of the disease. Our aim was to characterize liver sinusoidal endothelial cell (LSEC) dedifferentiation/capillarization and its contribution to PH in NASH, together with assessing statins capability to revert endothelial function improving early NASH stages. Sprague-Dawley rats were fed with high fat glucose-fructose diet (HFGFD), or control diet (CD) for 8 weeks and then treated with simvastatin (sim) (10 mg·kg−1·day−1), atorvastatin (ato) (10 mg·kg−1·day−1) or vehicle during 2 weeks. Biochemical, histological and hemodynamic determinations were carried out. Sinusoidal endothelial dysfunction was assessed in individualized sorted LSEC and hepatic stellate cells (HSC) from animal groups and in whole liver samples. HFGFD rats showed full NASH features without fibrosis but with significantly increased portal pressure compared with CD rats (10.47 ± 0.37 mmHg vs 8.30 ± 0.22 mmHg; p < 0.001). Moreover, HFGFD rats showed a higher percentage of capillarized (CD32b−/CD11b−) LSEC (8% vs 1%, p = 0.005) showing a contractile phenotype associated to HSC activation. Statin treatments caused a significant portal pressure reduction (sim: 9.29 ± 0.25 mmHg, p < 0.01; ato: 8.85 ± 0.30 mmHg, p < 0.001), NASH histology reversion, along with significant recovery of LSEC differentiation and a regression of HSC activation to a more quiescent phenotype. In an early NASH model without fibrosis with PH, LSEC transition to capillarization and HSC activation are reverted by statin treatment inducing portal pressure decrease and NASH features improvement.

scholarly journals Insulin resistance in patients with cirrhosis and portal hypertension

2012 ◽  
Vol 302 (12) ◽  
pp. G1458-G1465 ◽  
Author(s):  
Eva Erice ◽  
Elba Llop ◽  
Annalisa Berzigotti ◽  
Juan G. Abraldes ◽  
Ignacio Conget ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Portal Hypertension ◽  
Endothelial Dysfunction ◽  
Intracellular Signaling ◽  
Venous Pressure ◽  
Portal Pressure ◽  
Model Assessment ◽  
Hepatic Hemodynamics ◽  
Clinically Significant ◽  
The Relationship

Insulin resistance (IR) is involved in the pathogenesis of endothelial dysfunction and is also present in patients with cirrhosis. Intrahepatic endothelial dysfunction plays a major role, increasing hepatic vascular resistance and promoting portal hypertension (PH). In addition, β-adrenergic agonists and insulin share several intracellular signaling pathways. Thus IR may influence the response to β-blockers. This study aimed at evaluating the relationship between IR and hepatic hemodynamics in patients with cirrhosis and with the portal pressure response to acute β-blockade. Forty-nine patients with cirrhosis and PH were included. Hepatic and systemic hemodynamics were measured, and IR was estimated by using the updated homeostasis model assessment (HOMA)-2 index. Patients with HOMA-2 > 2.4 were considered IR. In patients with hepatic venous pressure gradient (HVPG) ≥ 10 mmHg) [clinically significant PH (CSPH)], hemodynamic measurements were performed again 20 min after intravenous propranolol. Mean HOMA-2 index was 3 ± 1.4. Fifty-seven percent of patients had IR. A weak correlation between HOMA-2 index and HVPG was observed. Eighty-six percent of patients had CSPH. HOMA-2 index was an independent predictor of CSPH. However, in patients with CSPH, the correlation between HOMA-2 index and HVPG was lost. HVPG, but not IR, predicted the presence of esophageal varices. Response to propranolol was not different between patients with or without IR. In nondiabetic patients with cirrhosis, HOMA-2 index is directly associated with the presence of CSPH and indirectly with varices, but does not allow either grading HVPG or predicting its response to propranolol.

Vascular NE responsiveness in portal hypertension: role of portal pressure and portosystemic shunting

1994 ◽  
Vol 266 (3) ◽  
pp. H1162-H1168 ◽  
Author(s):  
Z. Y. Wu ◽  
J. N. Benoit
Keyword(s):  
Blood Flow ◽  
Portal Hypertension ◽  
Portal Pressure ◽  
Portacaval Shunt ◽  
Effective Dosage ◽  
Sprague Dawley ◽  
Blood Flow Reduction ◽  
Portosystemic Shunting ◽  
Venous Collaterals ◽  
On Line

Previous studies have suggested that the development of portal venous collaterals and subsequent portosystemic shunting is the key event responsible for the reduced vasoconstrictor effectiveness in chronic portal hypertension. The purpose of the present study was to test this hypothesis. Thirty-nine male Sprague-Dawley rats were divided into four groups: end-to-side portacaval shunt (PCS, n = 11), chronic prehepatic portal hypertension (CPH, n = 10), acute prehepatic portal hypertension (APH, n = 8), and sham-operated controls (Sham, n = 10). The small intestine was prepared for microcirculatory studies. First-order arteriolar diameter and erythrocyte velocity were measured on-line, and blood flow was subsequently calculated. Once steady-state values were obtained the preparation was topically exposed to incremental doses of norepinephrine. The half-maximal effective dosage (ED50) for maximal vasoconstriction (diameter response) was significantly increased in PCS (4.5 microM) and CPH (1.5 microM) compared with Sham (0.8 microM). However, the ED50 was significantly lower in APH (0.17 microM) than in Sham. Similarly the ED50 for maximal blood flow reduction was higher in PCS (2.4 microM) and CPH (1.2 microM) compared with Sham (0.2 microM). The results demonstrate that vascular norepinephrine responsiveness is reduced in both portacaval shunted and chronic portal hypertensive rats, but not in acute portal hypertension. These data indicate that portosystemic shunting, not portal pressure elevation, is the key event leading to the reduced vascular norepinephrine responsiveness observed in CPH conditions.

Role of thromboxane A2 in early BDL-induced portal hypertension

2003 ◽  
Vol 284 (3) ◽  
pp. G453-G460 ◽  
Author(s):  
Yukihiro Yokoyama ◽  
Hongzhi Xu ◽  
Nicole Kresge ◽  
Steve Keller ◽  
Amir H. Sarmadi ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Portal Pressure ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Bicarbonate Buffer ◽  
Constant Flow Rate ◽  
Sprague Dawley Rats ◽  
Duct Ligation ◽  
Cox 2

Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane A2 (TXA2) in the development of portal hypertension has never been explicitly explored. In the present study, we sought to determine the role of TXA2 in bile duct ligation (BDL)-induced portal hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was recirculated in a total volume of 100 ml. The perfusate was sampled for the enzyme immunoassay of thromboxane B2(TXB2), the stable metabolite of TXA2. Although recirculation of the buffer caused no significant change in sham-operated rats, it resulted in a marked increase in portal pressure in BDL rats. The increase in portal pressure was found concomitantly with a significant increase of TXB2 in the perfusate (sham vs. BDL after 30 min of recirculating perfusion: 1,420 ± 803 vs. 10,210 ± 2,950 pg/ml; P < 0.05). Perfusion with a buffer containing indomethacin or gadolinium chloride for inhibition of cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the recirculation-induced increases in both portal pressure and TXB2 release in BDL group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but not COX-1 was upregulated following BDL, and this upregulation was confirmed at the protein level by Western blot analysis. In conclusion, these results clearly demonstrate that increased hepatic TXA2 release into the portal circulation contributes to the increased portal resistance in BDL-induced liver injury, suggesting a role of TXA2 in liver fibrosis-induced portal hypertension. Furthermore, the Kupffer cell is likely the source of increased TXA2, which is associated with upregulation of the COX-2 enzyme.

Pathophysiology and a Rational Basis of Therapy

2015 ◽  
Vol 33 (4) ◽  
pp. 508-514 ◽  
Author(s):  
Jordi Gracia-Sancho ◽  
Raquel Maeso-Díaz ◽  
Jaime Bosch
Keyword(s):  
Blood Flow ◽  
Portal Hypertension ◽  
Liver Disease ◽  
Endothelial Dysfunction ◽  
Vascular Tone ◽  
Portal Pressure ◽  
Portal Blood Flow ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Flow Through

Portal hypertension is a common complication of chronic liver disease. Its relevance comes from the fact that it determines most complications leading to death or liver transplantation in patients with cirrhosis of the liver: bleeding from esophageal or gastric varices, ascites and renal dysfunction, sepsis and hepatic encephalopathy. Portal hypertension results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (1) distortion of the liver vascular architecture due to the liver disease causing structural abnormalities (nodule formation, remodeling of liver sinusoids, fibrosis, angiogenesis and vascular occlusion), and (2) increased hepatic vascular tone due to sinusoidal endothelial dysfunction, which results in a defective production of endogenous vasodilators, mainly nitric oxide (NO), and increased production of vasoconstrictors (thromboxane A2, cysteinyl leukotrienes, angiotensin II, endothelins and an activated adrenergic system). Hepatic endothelial dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress, and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSECs) that become proliferative, prothrombotic, proinflammatory and vasoconstrictor. The cross-talk between LSECs and hepatic stellate cells (HSCs) induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis, which further increase the hepatic vascular resistance and worsen liver failure by interfering with the blood perfusion of the liver parenchyma. An additional factor further worsening portal hypertension is an increased blood flow through the portal system due to splanchnic vasodilatation. This is an adaptive response to decreased effective hepatocyte perfusion, and is maximal once portal pressure has increased sufficiently to promote the development of intrahepatic shunts and portal-systemic collaterals, including varices, through which portal blood flow bypasses the liver. In human portal hypertension collateralization and hyperdynamic circulation start at a portal pressure gradient >10 mm Hg. Rational therapy for portal hypertension aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments (the best example being the direct-acting antivirals for hepatitis C viral infection), while architectural disruption and fibrosis can be ameliorated by a variety of antifibrotic drugs and antiangiogenic strategies. Several drugs in this category are currently under investigation in phase II-III randomized controlled trials. Sinusoidal endothelial dysfunction is ameliorated by statins as well as by other drugs increasing NO availability. It is of note that simvastatin has already been proven to be clinically effective in two randomized controlled trials. Splanchnic hyperemia can be counteracted by nonselective β-blockers (NSBBs), vasopressin analogs and somatostatin analogs, drugs that until recently were the only available treatments for portal hypertension, but that are not very effective in the initial stages of cirrhosis. There is experimental and clinical evidence indicating that a more effective reduction of portal pressure is obtained by combining agents acting on these different pathways. It is likely that the treatment of portal hypertension will evolve to use etiological treatments together with antifibrotic agents and/or drugs improving sinusoidal endothelial function in the initial stages of cirrhosis (preprimary prophylaxis), while NSBBs will be added in advanced stages of the disease.

Effects of somatostatin on splanchnic hemodynamics and plasma glucagon in portal hypertensive rats

1988 ◽  
Vol 254 (3) ◽  
pp. G322-G328 ◽  
Author(s):  
D. Kravetz ◽  
J. Bosch ◽  
M. T. Arderiu ◽  
M. P. Pizcueta ◽  
R. Casamitjana ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Portal Pressure ◽  
Portal Vein Ligation ◽  
Plasma Glucagon ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Systemic Hemodynamic ◽  
Blood Flows ◽  
Arteriolar Resistance ◽  
Regional Blood Flows

The effects of somatostatin infusion on splanchnic and systemic hemodynamics and plasma glucagon levels were investigated in rats with portal hypertension. Forty-four male Sprague-Dawley rats were studied. Portal hypertension was induced in 26 rats by partial portal vein ligation (PVL). These rats were divided in two experimental groups to receive blindly 1) somatostatin (PVL-SMT, n = 13) at a dose of 25 micrograms/kg body wt during 30 min preceded by a bolus injection of 15 micrograms/kg body wt or 2) placebo (saline) (PVL-P, n = 13) infused at the same rate as in the previous group. The remaining 18 rats were used as normal controls and received somatostatin (n = 9) or saline infusion (n = 9). Regional blood flows and cardiac output were measured using radioactive microspheres. Arterial and portal pressures were also measured. In portal hypertensive rats somatostatin infusion produced significant reductions in the increased portal venous inflow, reductions in portal pressure, and significantly increased portal venous resistance. Reduction of portal venous inflow was due to splanchnic vasoconstriction, evidenced by increased splanchnic arteriolar resistance. No significant differences were observed in systemic hemodynamic parameters between PVL-SMT and PVL-P rats. Plasma glucagon levels were significantly reduced by somatostatin to levels similar to those observed in sham-operated rats. In sham-operated rats, somatostatin also caused significant reduction in portal venous inflow and plasma glucagon concentration, although these changes were of lesser magnitude than in portal hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution

2018 ◽  
Vol 132 (6) ◽  
pp. 669-683 ◽  
Author(s):  
Shao-Jung Hsu ◽  
Ming-Hung Tsai ◽  
Ching-Chih Chang ◽  
Yu-Hsin Hsieh ◽  
Hui-Chun Huang ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Portal Pressure ◽  
Treatment Strategies ◽  
Vascular Complications ◽  
Control Group ◽  
No Production ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Duct Ligation ◽  
Window Area

Liver cirrhosis is characterized by portal hypertension. However, the alteration of portal hypertension-related derangements during cirrhosis resolution is not well known. The present study aimed to establish animal models with cirrhosis resolution and to investigate the relevant changes during this process. Male Sprague–Dawley rats were applied. In reverse thioacetamide (rTAA) model, rats were randomly allocated into four groups with control, thioacetamide (TAA) cirrhosis and rTAA groups that discontinued TAA for 4 or 8 weeks after cirrhosis induction. In reverse bile duct ligation (rBDL) model, rats received choledochoduodenal shunt surgery upon the establishment of cirrhosis and 4, 8, or 16 weeks were allowed after the surgery. At the end, portal hypertension-related parameters were evaluated. Cirrhosis resolution was observed in rTAA groups. Portal pressure (PP) decreased after cirrhosis resolution but remained higher than control group (control, TAA, rTAA4, rTAA8 (mmHg): 5.4 ± 0.3, 12.9 ± 0.3, 8.6 ± 0.4, 7.6 ± 0.6). Further survey found the increased splanchnic blood flow did not reduce during cirrhosis resolution. The extrahepatic pathological angiogenesis was not ameliorated (% of mesenteric window area: 1.2 ± 0.3, 7.3 ± 1.1, 8.3 ± 1.0, 11.3 ± 2.7). In collateral system, the shunting degree reduced while the vessels structure remained. The vascular contractility of all systems and nitric oxide (NO) production were normalized. In rBDL series, PP decreased in rBDL16 groups but the extrahepatic angiogenesis persisted. In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated.

Propranolol modulates the collateral vascular responsiveness to vasopressin via a Gα-mediated pathway in portal hypertensive rats

2011 ◽  
Vol 121 (12) ◽  
pp. 545-554 ◽  
Author(s):  
Jing-Yi Lee ◽  
Teh-Ia Huo ◽  
Hui-Chun Huang ◽  
Fa-Yauh Lee ◽  
Han-Chieh Lin ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Mrna Expression ◽  
Perfusion Pressure ◽  
Portal Pressure ◽  
Splenorenal Shunt ◽  
Portal Vein Ligation ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Propranolol Treatment ◽  
Pressure Changes

Gastro-oesophageal variceal haemorrhage is one of the most dreadful complications of portal hypertension and can be controlled with vasoconstrictors. Nevertheless, sympathetic tone abnormality and vascular hyporesponsiveness in portal hypertension may impede the haemostatic effects of vasoconstrictors. Propranolol, a β-blocker binding the G-protein-coupled adrenoceptor, is a portal hypotensive agent. However, whether propranolol influences the collateral vasoresponse is unknown. Portal hypertension was induced by PVL (portal vein ligation) in Sprague–Dawley rats. In an acute study with an in situ perfusion model, the collateral responsiveness to AVP (arginine vasopressin) was evaluated with vehicle, propranolol (10 μmol/l), propranolol plus suramin (100 μmol/l, a Gα inhibitor) or suramin pre-incubation. Gα mRNA expression in the splenorenal shunt, the most prominent intra-abdominal collateral vessel, was measured. In the chronic study, rats received DW (distilled water) or propranolol (10 mg·kg−1 of body weight·day−1) for 9 days. Then the concentration–response relationship of AVP and Gα mRNA expression were assessed. Propranolol pre-incubation elevated the perfusion pressure changes of collaterals in response to AVP, which was inhibited by suramin. The splenorenal shunt Gαq and Gα11 mRNA expression were enhanced by propranolol. The group treated with propranolol plus suramin had a down-regulation of Gα11 as compared with the propranolol group. Chronic propranolol treatment reduced mean arterial pressure, PP (portal pressure) and the perfusion pressure changes of collaterals to AVP. Gαs expression was up-regulated. In conclusion, propranolol pre-incubation enhanced the portal-systemic collateral AVP responsiveness in portal hypertensive rats, which was related to Gαq and Gα11 up-regulation. In contrast, the attenuated AVP responsiveness by chronic propranolol treatment was related to Gαs up-regulation. The Gα signalling pathway may be a therapeutic target to control variceal bleeding and PP in portal hypertension.

542 STATIN TREATMENT DECREASE COLLATERAL FLOW AND PORTAL PRESSURE IN CIRRHOSIS, BUT NOT IN PREHEPATIC PORTAL HYPERTENSION

2010 ◽  
Vol 52 ◽  
pp. S217
Author(s):  
J. Trebicka ◽  
S. Klein ◽  
M. Granzow ◽  
G. Ranabhat ◽  
M. Hennenberg ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Portal Pressure ◽  
Statin Treatment ◽  
Collateral Flow

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.

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