Cellular localization of endothelin-1 and increased production in liver injury in the rat: Potential for autocrine and paracrine effects on stellate cells

Rockey, Don C.; Fouassier, Laura; Chung, John J.; Carayon, A.; Vallee, P. A. La; Rey, Colette; Housset, Chantal

doi:10.1002/hep.510270222

Cited by 229 publications

(179 citation statements)

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“…One possible explanation would be that HSC were not accessible to optimal doses of STI571 in vivo. Another possibility is that the induction of HSC proliferation in liver injury depends upon additional growth factors such as endothelin-1, insulin-like growth factor 1, and transforming growth factor ␣, which stimulate the proliferation of HSC in early culture (Bachem et al, 1993;Rockey et al, 1998).…”

Section: Kinnman Et Almentioning

confidence: 99%

Hepatic Stellate Cell Proliferation is an Early Platelet-Derived Growth Factor-Mediated Cellular Event in Rat Cholestatic Liver Injury

Kinnman

Goria

Wendum

et al. 2001

Laboratory Investigation

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SUMMARY:After liver injury, hepatic stellate cells (HSC) undergo a pleiotropic response termed "activation" that also occurs in culture models and ultimately leads to the conversion of HSC into myofibroblasts expressing smooth muscle ␣-actin (␣-SMA). The onset of HSC proliferation in primary culture coincides with the induction of platelet-derived growth factor receptor-␤ (PDGFR-␤) expression, while platelet-derived growth factor (PDGF) is the most potent mitogen for culture-activated HSC. Yet, the mechanisms and the stage of activation required for HSC proliferation in the intact liver are still uncertain. In the present study, we analyzed the proliferative response of HSC to rat cholestatic liver injury and the role of PDGF in this response. After in vivo incorporation of bromodeoxyuridine (BrdU), pure vitamin A-containing HSC were isolated at different time points after bile duct ligation (BDL) or sham operation and were analyzed by means of flow cytometry. The induction of HSC proliferation, as ascertained by BrdU incorporation, occurred between 24 and 48 hours and reached a plateau as soon as 48 hours after BDL. Flow cytometry and immunoblot analyses of HSC indicated that the induction of proliferation in HSC coincided with the up-regulation of PDGFR-␤ protein on their surface but preceded that of ␣-SMA. A dose-dependent inhibition of PDGF-BBinduced HSC proliferation by STI571, a PDGF receptor tyrosine kinase inhibitor, was documented in vitro. Daily intraperitoneal injections of STI571 (20 mg/kg) caused a 60% reduction in BrdU positive isolated HSC and in the amount of desminimmunoreactive sinusoidal cells on liver tissue sections in 48-hour bile duct-ligated rats. These results indicate that cholestatic liver injury elicits an early proliferative response in HSC that is mainly mediated by PDGF, and which precedes HSC phenotypic conversion into myofibroblasts. (Lab Invest 2001, 81:1709 -1716.

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Section: Kinnman Et Almentioning

confidence: 99%

Hepatic Stellate Cell Proliferation is an Early Platelet-Derived Growth Factor-Mediated Cellular Event in Rat Cholestatic Liver Injury

Kinnman

Goria

Wendum

et al. 2001

Laboratory Investigation

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“…22 In cirrhosis, the total amount of ETs produced was greater in SECs than in hepatic stellate cells, although the relative increase in ET-1 expression was higher in hepatic stellate cells than in SECs. 23 In liver injury, fibrogenesis occurs after activation of hepatic stellate cells, and the activation cascade includes features of proliferation, fibrogenesis, up-regulation of smooth muscle actin, and enhanced contractility. 24 However, the effects of ETs on SECs has not yet been characterized.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 Suppresses Plasma Membrane Ca++-ATPase, Concomitant with Contraction of Hepatic Sinusoidal Endothelial Fenestrae

Yokomori

Oda

Ogi

et al. 2003

The American Journal of Pathology

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Intracytoplasmic free calcium ions (Ca ؉؉ ) are maintained at a very low concentration in mammalian tissue by extruding Ca ؉؉ from the cytoplasm against a steep extracellular Ca ؉؉ concentration gradient, mainly through the activity of plasma membrane Ca ؉؉ pump-ATPase. The present study aimed to elucidate how endothelin-1 (ET-1) affects the morphology of sinusoidal endothelial fenestrae and ultrastructural distribution of plasma membrane ATPases and intracytoplasmic free Ca ؉؉ in isolated rat hepatic sinusoidal endothelial cells. Sinusoidal endothelial fenestrae were observed by scanning electron microscope. Ando's electron cytochemical method was used for ultrastructural localization of Ca ؉؉ -Mg ؉؉ -ATPase activity, electron immunogold postembedding method for Ca ؉؉ pump-ATPase immunoactivity, and antimonate method for intracytoplasmic free Ca Hepatic sinusoidal endothelial cells (SECs) possess fenestrae mostly arranged in sieve plate-like pores. These fenestrae lack a diaphragm and a basal lamina and therefore are an open connection between the lumen of the sinusoid and the space of Disse. 1 They are not single and independent pores but are interconnected labyrinth-like structures. 2 Actin microfilaments and calmodulin are closely associated with the endothelial plasma membrane, suggesting that in the presence of calcium ions, calmodulin and actin microfilaments may be involved in the contraction and dilatation of endothelial cell fenestrae. [2][3][4] The Ca ϩϩ pump of the plasma membrane extrudes Ca ϩϩ from the cytoplasm against a steep extracellular concentration gradient, and is essential for homeostatic maintenance of a low concentration of intracellular Ca ϩϩ . 5 By immunofluorescence and immunoelectron microscopic study, the Ca ϩϩ pump in capillary endothelial cells and visceral smooth muscle cells is found to be 18-to 25-fold more concentrated in the invaginated caveolar membrane compared with the noncaveolar portion of the plasma membrane. 6,7 Our recently study demonstrated localization of calcium pump-dependent adenosine triphosphatase (Ca ϩϩ pump-ATPase) in hepatic sinusoidal endothelial fenestrae (SEF). 8 Endothelins (ETs) are a family of three potent vasoconstrictor peptides. ET-1 was first identified in the supernatant of cultured endothelial cells. 9 Two other forms of ET have subsequently been characterized and designated ET-2 and ET-3, which differ from ET-1 by two and six amino acids, respectively. 10,11 Recently the authors have reported that ET-1 induces contractions of the SEF not only in vivo 12 but also in vitro. 13 The present study was designed to elucidate the subcellular mechanism of SEF contraction by focusing on the electron cytochemical distribution of plasma membrane Ca ϩϩ -Mg ϩϩ -ATPase, Ca ϩϩ pump-ATPase, and intracytoplasmic free calcium ions in SECs.

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“…18 Recently, Pinzani et al 42 have found that activated stellate cells in human cirrhotic liver are the major site of ET-1 production but that bile duct cells can also produce ET-1. Rockey et al 43 report that ET-1 is synthesized by sinusoidal endothelial cells and stellate cells in rat livers with bile-duct ligation. In the study by Eakes et al, 44 intraportal infusion of endotoxin increased ET-1 mRNA mainly in endothelial cells of normal rat liver.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2000

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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...

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Cellular localization of endothelin-1 and increased production in liver injury in the rat: Potential for autocrine and paracrine effects on stellate cells

Cited by 229 publications

References 41 publications

Hepatic Stellate Cell Proliferation is an Early Platelet-Derived Growth Factor-Mediated Cellular Event in Rat Cholestatic Liver Injury

Hepatic Stellate Cell Proliferation is an Early Platelet-Derived Growth Factor-Mediated Cellular Event in Rat Cholestatic Liver Injury

Endothelin-1 Suppresses Plasma Membrane Ca++-ATPase, Concomitant with Contraction of Hepatic Sinusoidal Endothelial Fenestrae

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

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