production and release of endothelin-1 from the gut and spleen in portal hypertension due to cirrhosis

Abstract

This study was aimed to evaluate the source of endothelin-1 (ET-1) in cirrhotic patients. ET-1 is implicated in the pathogenesis of portal hypertension. However, the mechanism and source for increased plasma ET-1 in cirrhotic patients are still obscure. Plasma ET-1 levels in systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood were measured in 23 patients with cirrhosis and 8 controls with normal liver. Fourteen removed spleens were immunohistochemically studied for ET-1, CD34, CD68, and CD20. In situ hybridization was done to localize ET-1 messenger RNA (mRNA). In cirrhosis, ET-1 levels in both SMV and SPV were higher than in SV. ET-1 in SV and SPV were significantly higher in cirrhotic patients than in control patients. Three groups of cells in the spleen expressed both protein and mRNA of ET-1: endothelial cells in the sinus, which were also stained for CD34; cells in the germinal center; and cells in the marginal zone of lymphoid sheaths and follicles, which were also stained for CD20 but not for CD34 and CD68. Endothelins (ETs) are a group of three related peptides of 21 amino acids (ET-1, ET-2, and ET-3) first described as potent vasoconstrictors. 1,2 At present, it is known that ETs exert a variety of biological, physiological, and metabolic actions through two types of receptors (ET A and ET B ) in humans. [3][4][5] In recent years, much attention has been paid to the role of ET-1 in hepatic circulation, particularly in relation to portal hypertension. [6][7][8] Since 1992, more than 10 investigative groups have shown the increased level of plasma ET-1 in patients with cirrhosis. [9][10][11][12][13][14][15][16][17][18][19] The grade of the ET-1 elevation seems to be related to the severity of cirrhosis 13,16 and the presence or absence of ascites. 10,11,19 The highest levels were observed in hepatorenal syndrome. 9 However, the physiological significance of elevated ET-1 levels in cirrhosis is still controversial. The role of endotoxin or plasma volume remains to be elucidated. 10,11,15 Furthermore, the origin and elimination of plasma ET-1 in cirrhosis have not been clarified.Of late, Gerbes et al. 14 and Moller et al. 17 suggested the hepatosplanchnic origin of ET-1 because the highest ET-1 concentrations were found in hepatic venous blood. Martinet et al. 18 showed that high ET-1 levels in the portal blood were reduced after portal decompression by transjugular intrahepatic portosystemic shunt. These studies, however, did not show from which organ or organs of the splanchnic region ET-1 was released in cirrhosis and portal hypertension.The present study was prospectively aimed to clarify this problem. While measuring plasma ET-1 levels in the systemic (SV), superior mesenteric (SMV), and splenic venous (SPV) blood in patients with cirrhosis of different Child-Turcotte classes and control patients with normal liver, we came to know that ET-1 was highest in the SMV in controls but that SPV ET-1 levels were significantly higher in cirrhosis.Therefore, the cellular source of ET-1 in t...

Expression of Cytoplasmic TFF2 Is a Marker of Tumor Metastasis and Negative Prognostic Factor in Gastric Cancer

“…Mouse anti-human TFF2 mAb (GE16C clone; Novocastra Laboratories Ltd., Newcastle, United Kingdom; 1:50 dilution) was used at 4°C for overnight incubation. The streptavidin-biotin peroxidase complex method was used for the immunohistochemical steps and were done with a commercially available kit (Histofine SAB-PO kit; Nichirei, Tokyo, Japan) as we described previously (Nagasue et al, 2000). Color development was done with the peroxidase substrate 3-amino-9-ethylcarbazole.…”

Influence of endothelin-1 on hemodynamics during liver transplantation with and without temporary portocaval shunt: Results of a clinical randomized study

“…15,16 ET-1 is probably the main factor because of its action at two levels: first, at hepatic stellate cells responsible for intrahepatic resistance to flow as a part of portal hypertension, 17 and second, at a systemic level by increasing systemic vascular resistance. 18 Several studies have shown that patients with cirrhosis have greater ET-1 levels than those with normal hepatic function 7,8,19,20 ; this increase in ET-1 levels correlated with the degree of hepatic dysfunction, portal hypertension, and presence of ascites. Our results also showed a threefold increase in ET-1 levels at the beginning of LT. An inverse correlation of systemic ET-1 levels with portal flow also was shown.…”

“…ET-1 levels increase in patients with cirrhosis. [6][7][8] Clinical studies have not elucidated whether ET-1 synthesis during LT occurs mainly in the liver or endothelial cells throughout the vascular systemic bed.…”

Expression of regenerating gene I in gastric adenocarcinomas

“…3 The streptavidin-biotin peroxidase complex method was employed for the immunohistochemical steps, which were performed with a commercially available kit (Histofine SAB-PO kit; Nichirei, Tokyo, Japan) as described previously. 22 Color development was performed with the peroxidase substrate, 3-amino-9-ethylcarbazole. Positive and negative control slides were always included for each immunostaining procedure.…”

“…Hybridization and the immunohistochemical steps were performed as described previously. 22 A pancreatic tumor specimen, previously known as REG positive, was used as a positive control.…”