No abstract

Nogo-B, also known as Reticulon 4B, plays important roles in vascular injuries. Its function in the liver is not understood. The aim of this study was to characterize Nogo-B in liver fibrosis and cirrhosis. Nogo-B distribution was assessed in normal and cirrhotic human liver sections. We also determined the levels of liver fibrosis in wild-type (WT) and Nogo-A/B knockout (NGB KO) mice after sham operation or bile duct ligation (BDL). To investigate the mechanisms of Nogo-B’s involvement in fibrosis, hepatic stellate cells were isolated from WT and NGB KO mice and transformed into myofibroblasts. Portal pressure was measured to test whether Nogo-B gene deletion could ameliorate portal hypertension. In normal livers, Nogo-B expression was found in nonparenchymal cells, whereas its expression in hepatocytes was minimal. Nogo-B staining was significantly elevated in cirrhotic livers. Fibrosis was significantly increased in WT mice 4 weeks after BDL compared with NGB KO mice. The absence of Nogo-B significantly reduced phosphorylation of Smad2 levels upon transforming growth factor β (TGF-β) stimulation. Reconstitution of the Nogo-B gene into NGB KO fibroblasts restored Smad2 phosphorylation. Four weeks after BDL, portal pressure was significantly increased in WT mice by 47%, compared with sham-operated controls (P = 0.03), whereas such an increase in portal pressure was not observed in NGB KO mice (P = NS). Conclusion Nogo-B regulates liver fibrosis, at least in part, by facilitating the TGFβ/Smad2 signaling pathway in myofibroblasts. Because absence of Nogo-B ameliorates liver fibrosis and portal hypertension, Nogo-B blockade may be a potential therapeutic target in fibrosis/cirrhosis.

Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque-Dawley rats with common bile duct ligation-induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6-cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice-weekly for 8 weeks)-induced cirrhotic rats. Caffeine down-regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho-VEGFR2, and phospho-Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. Conclusions: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH-related complications in cirrhosis. (HEPATOLOGY 2015;61:1672-1684

Endoscopic variceal ligation (EVL) is a new techniquedesigned to manage esophageal varices. The effect of sclerotherapy following repeated banding ligation remains unknown. Seventy-two patients with a history of esophageal variceal bleeding received regular EVL until variceal disappearance or until left with residual small varices. Subsequently, patients were randomized to receive sclerotherapy (Group 1, 37 patients) or serve as a control (Group 2, 35 patients). Group 1 received one to two sessions of low-dose sclerotherapy to achieve complete variceal disappearance. After a mean follow-up of 2 years, 4 months, recurrent esophageal varices developed in 14% of Group 1 and 43% of Group 2 (P F .02). Rebleeding was encountered in 8% of Group 1 versus 31% of Group 2 (P ‫؍‬ .01). One case of esophageal stricture (2.7%) was encountered in Group 1. Endoscopic injection sclerotherapy (EIS) has been well documented as a valuable tool to help control acute variceal bleeding, to prevent recurrent bleeding, and perhaps to improve survival. [1][2][3][4] However, it may be associated with substantial complications. 5 Endoscopic variceal ligation (EVL) has emerged in recent years as a new tool in the management of bleeding esophageal varices. 6 Controlled studies have demonstrated that EVL is superior to EIS in terms of obliterating esophageal varices, i.e., fewer treatment sessions are required with EVL than that with EIS. 7-11 On the other hand, varices, when reduced to minimal size by EVL, become inaccessible to EVL. Whether the addition of EIS may be of benefit to those patients remains unknown. This study was undertaken to investigate this issue. PATIENTS AND METHODSBetween July 1991 and July 1993, patients with a history of esophageal variceal bleeding admitted to Veterans General HospitalKaohsiung were considered for enrollment. Patients admitted with acute esophageal variceal bleeding between January 1992 and July 1993 were included in a trial comparing EIS and EVL, which has been published elsewhere. 10 During the overlapping period, only patients who were admitted to prevent variceal rebleeding but not eligible for prior study were enrolled in the current study. In this study, all the patients were treated with repeated EVL, and then randomized to receive additional EIS or not. The patient population was different from the previous study. The aims of the current study were to observe whether recurrent varices and rebleeding could be reduced in patients receiving EIS following repeated EVL. The inclusion criteria of this study were: 1) patients were cirrhotic and had a history of esophageal variceal bleeding; and 2) patients received repeated EVL until variceal disappearance or until left with residual small varices (defined below). The exclusion criteria were: 1) association with gastric variceal bleeding; 2) association with malignancy, uremia, or other debilitating disease; and 3) history of sclerotherapy or shunt operation. ␤-Blocker was not administered during the study. An informed consent was obtained from all o...