Jing-Yi Lee

Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats.

Angiogenesis in liver cirrhosis leads to splanchnic hyperemia, increased portal inflow, and portosystemic collaterals formation, which may induce lethal complications, such as gastroesophageal variceal hemorrhage and hepatic encephalopathy. Cannabinoids (CBs) inhibit angiogenesis, but the relevant influences in cirrhosis are unknown. In this study, Spraque‐Dawley rats received common bile duct ligation (BDL) to induce cirrhosis. BDL rats received vehicle, arachidonyl‐2‐chloroethylamide (cannabinoid receptor type 1 [CB1] agonist), JWH‐015 (cannabinoid receptor type 2 [CB2] agonist), and AM630 (CB2 antagonist) from days 35 to 42 days after BDL. On the 43rd day, hemodynamics, presence of CB receptors, severity of portosystemic shunting, mesenteric vascular density, vascular endothelial growth factor (VEGF), VEGFR‐1, VEGFR‐2, phospho‐VEGFR‐2, cyclooxygenase (COX)‐1, COX‐2, and endothelial nitric oxide synthase (eNOS) expressions as well as plasma VEGF levels were evaluated. Results showed that CB1 and CB2 receptors were present in left adrenal veins of sham rats, splenorenal shunts (the most prominent intra‐abdominal shunts) of BDL rats, and mesentery of sham and BDL rats. CB2 receptor was up‐regulated in splenorenal shunts of BDL rats. Both acute and chronic JWH‐015 treatment reduced portal pressure and superior mesenteric arterial blood flow. Compared with vehicle, JWH‐015 significantly alleviated portosystemic shunting and mesenteric vascular density in BDL rats, but not in sham rats. The concomitant use of JWH‐015 and AM630 abolished JWH‐015 effects. JWH‐133, another CB2 agonist, mimicked the JWH‐015 effects. JWH‐015 decreased mesenteric COX‐1, COX‐2 messenger RNA expressions, and COX‐1, COX‐2, eNOS protein expressions. Furthermore, JWH‐015 decreased intrahepatic angiogenesis and fibrosis. Conclusions: CB2 agonist alleviates portal hypertension (PH), severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. The mechanism is, at least partly, through COX and NOS down‐regulation. CBs may be targeted in the control of PH and portosystemic collaterals. (HEPATOLOGY 2012;56:248–258)

Comparison of the model for end-stage liver disease (MELD), MELD-Na and MELDNa for outcome prediction in patients with acute decompensated hepatitis

BACKGROUND AND AIM The model for end-stage liver disease (MELD) is used to predict the outcome of patients with cirrhosis. Incorporation of serum sodium (Na) into MELD may further increase its prognostic ability. Two Na-containing MELD models, MELD-Na and MELDNa, were proposed to enhance the prognostic ability. This study compared the predictive accuracy of these models for acute decompensated hepatitis. METHODS We investigated the outcome of 182 patients with acute decompensated hepatitis. RESULTS Twenty (11%) patients died at 3 months. The MELD-Na and MELDNa both had significantly higher area under the receiver operating characteristic curve (AUC) in comparison to MELD (MELD-Na: 0.908, MELDNa: 0.895, MELD: 0.823, p=0.004 and 0.001, respectively). Among 96 patients without specific antiviral treatment, the MELD-Na and MELDNa consistently had significantly higher AUC than the MELD (MELD-Na: 0.901, MELDNa: 0.882, MELD: 0.810, p=0.008 and 0.004, respectively). Three independent indicators, pre-existing cirrhosis (odds ratio [OR]: 5.67, 95% confidence interval [CI]: 1.72-18.7), serum albumin<3.7 g/dL (OR: 5.68, 95% CI: 1.18-27.03) and serum sodium (Na)<138 mequiv./L (OR: 10.0, 95% CI: 2.08-47.62), were associated with 3-month mortality. CONCLUSION MELD-Na and MELDNa provide better prognostic accuracy than the MELD for patients with acute decompensated hepatitis. The adequacy of liver reserve determines the outcome of these patients.

The Beneficial Effects of P2X7 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 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.

Simvastatin effects on portal‐systemic collaterals of portal hypertensive rats

Background and Aim:  Portal‐systemic collateral vascular resistance and vasoconstrictor responsiveness are crucial in portal hypertension and variceal bleeding control. Statins enhance vasodilators production, but their influence on collaterals is unknown. This study aimed to survey the effect of simvastatin on collaterals.

Kinetics of cytokine expression in cirrhotic rats

Background: Cytokines are involved in liver injury and cirrhosis and systemic and hepatic cytokine levels may help predict cirrhosis evolution. However, the relevant survey has not been performed. Methods: Male Sprague‐Dawley rats (240–270 g) received either common bile duct ligation (BDL, animal model of cholestatic liver injury) or sham operation (control). Five rats were sacrificed and liver and serum were collected from each in weeks 1, 2, 4, 6, 8 and 10 after surgery. Hepatic expression of interferon‐γ (IFN‐γ), tumor necrosis factor‐α (TNF‐α), interleukin‐10 (IL‐10) and transforming growth factor‐β (TGF‐β) were analyzed by immunohistochemial staining. The corresponding serum levels were measured by ELISA. Results: Compared to the corresponding sham groups, hepatic expression of these cytokines in BDL rats was significantly and progressively enhanced during cirrhosis development. However, serum IFN‐γ levels of BDL rats did not change significantly. Serum TNF‐α of BDL rats increased gradually and reached a peak in week 6. Serum TGF‐β level was elevated up to week 8, whereas IL‐10 level decreased progressively until week 6. Conclusion: Cirrhosis development in BDL rats is associated with progressively enhanced expression of hepatic pro‐inflammatory and anti‐inflammatory cytokines, which is not in accord with the corresponding serum concentration. The circulating cytokine concentration may not totally reflect the hepatic expression level throughout the development of cirrhosis.

Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats

Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin‐1 (ET‐1), an endothelium‐derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension.

The Roles of Angiotensin II Receptors in the Portosystemic Collaterals of Portal Hypertensive and Cirrhotic Rats

Background/Aims:In liver cirrhosis/portal hypertension, collaterals as varices may bleed and are influenced by vasoresponsiveness. An angiotensin blockade ameliorates portal hypertension but the influence on collaterals is unknown. Methods:Portal hypertension and cirrhosis were induced by portal vein (PVL) and common bile duct ligation (BDL). Hemodynamics, real-time PCR of angiotensin II receptors (AT1R, AT2R) in the left adrenal vein (LAV, sham) and splenorenal shunt derived from LAV (PVL, BDL) were performed. With an in situcollateral perfusion model, angiotensin II vasoresponsiveness with different preincubations was evaluated: (1) vehicle; (2) AT1R blocker losartan; (3) losartan plus nonselective nitric oxide synthase (NOS) inhibitor (Nω-nitro-L-arginine); (4) AT2R blocker PD123319; (5) PD123319 plus Nω-nitro-L-arginine; (6) Nω-nitro-L-arginine, and (7) losartan plus inducible NOS inhibitor aminoguanidine. Results: LAV AT1R and AT2R expression decreased in PVL and BDL rats. Losartan attenuated angiotensin II-elicited vasoconstriction but PD123319 had no effect. Nω-nitro-L-arginine but not aminoguanidine reversed the losartan effect. Conclusions:Angiotensin receptors are downregulated in the collateral vessel of portal hypertensive and cirrhotic rats. The AT1R blockade attenuates the angiotensin II vasoconstrictive effect, suggesting AT1R mediates collateral vasoconstriction and the influence of AT2R is negligible. The lack of aminoguanidine influence indicates that endothelial NOS participates in the losartan effect.

Lipopolysaccharide enhanced renal vascular response to endothelin‐1 through ETA overexpression in portal hypertensive rats

Hypo‐perfusion resulting from intense renal vasoconstriction is traditionally contributed to renal dysfunction in advanced liver disease, although cumulative studies demonstrated renal vasodilatation with impaired vascular contractility to endogenous vasoconstrictors in portal hypertension and compensated liver cirrhosis. The pathophysiology of altered renal hemodynamics remains unclear. This study, using a rat model of portal hypertension with superimposed endotoxemia, was designed to delineate the evolution of renal vascular reactivity and vaso‐regulatory gene expression during liver disease progression.

Effects of simvastatin on the portal-systemic collateral vascular response to endothelin-1 and shunting degree in portal hypertensive rats

Abstract Objective. Endothelin-1 (ET-1) exerts vasoconstrictive effect on portal-systemic collateral vascular bed of portal hypertensive rats. Statins are lipid-lowering agents with nitric oxide (NO)-related vasodilatory effects. Considering NO-associated vascular hyporesponsiveness to vasoconstrictors and shunting formation in portal hypertension, this study investigated the effects of simvastatin on 1) the portal-systemic collateral vascular responsiveness to ET-1 and 2) the portal-systemic shunting degree. Materials/methods. Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Simvastatin (20 mg/kg/day) or distilled water (control) was randomly administered by oral gavage since 2 days prior to until 7 days after PVL. Systemic and portal hemodynamics were measured on the 8th day. In another series, collateral perfusion with Krebs solution at different flow rates was performed to get flow–pressure curves which serve as an index of shunting degree. To survey the direct vascular effect, PVL rats randomly underwent preincubation with 1) Krebs solution, that is, the control group; or Krebs solution plus 2) simvastatin; 3) simvastatin + N ω-nitro-l-arginine (NNA, a NO synthase inhibitor); 4) simvastatin + indomethacin (a cyclooxygenase inhibitor), followed by ET-1 to evaluate the collateral vascular responsiveness. Results. Chronic simvastatin treatment significantly reduced portal pressure. The flow–pressure curves were similar between two groups. Simvastatin preincubation reduced collateral perfusion pressure changes to ET-1 (p < 0.05), which were partially reversed by NNA (p < 0.05), but not by indomethacin. Conclusions. Chronic simvastatin treatment significantly improved portal hypertension. The effect was at least partially exerted by decreased portal-systemic collateral vascular resistance through NO-mediated vascular hyporesponsiveness. The severity of portal-systemic collaterals was not influenced by simvastatin.

Selecting an optimal cutoff value for creatinine in the model for end-stage liver disease equation

Huo T‐I, Hsu C‐Y, Lin H‐C, Lee P‐C, Lee J‐Y, Lee F‐Y, Hou M‐C, Lee S‐D. Selecting an optimal cutoff value for creatinine in the model for end‐stage liver disease equation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01099.x.
© 2009 John Wiley & Sons A/S.