Therapy for portal hypertension

Shah, Vijay H.

doi:10.1002/hep.22687

Cited by 6 publications

(5 citation statements)

References 74 publications

(95 reference statements)

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“…Although portal hypertension leads to the most lethal complications of liver disease such as gastro‐oesophageal varices and ascites, there are very limited options for its treatment. Facing this serious clinical situation, there is a strong need for further studies of the vascular changes associated with cirrhosis and portal hypertension (131). Studying the roles of miRNAs, EPCs, EndoMT, and inflammation in the vascular changes associated with cirrhosis and portal hypertension advances our understanding of the molecular and cellular mechanisms underlying these changes.…”

Section: Resultsmentioning

confidence: 99%

Endothelial dysfunction in the regulation of cirrhosis and portal hypertension

Iwakiri

2011

Liver International

164

143

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Portal hypertension is caused by an increased intrahepatic resistance, a major consequence of cirrhosis. Endothelial dysfunction in liver sinusoidal endothelial cells (LSECs) decreases the production of vasodilators, such as nitric oxide (NO) and favors vasoconstriction. This contributes to an increased vascular resistance in the intrahepatic/sinusoidal microcirculation. Portal hypertension, once developed, causes endothelial cell (EC) dysfunction in the extrahepatic, i.e. splanchnic and systemic, circulation. Unlike LSEC dysfunction, EC dysfunction in the splanchnic and systemic circulation overproduces vasodilator molecules, leading to arterial vasodilatation. In addition, portal hypertension leads to the formation of portosystemic collateral vessels. Both arterial vasodilatation and portosystemic collateral vessel formation exacerbate portal hypertension by increasing the blood flow through the portal vein. Pathologic consequences, such as esophageal varices and ascites, result. While the sequence of pathological vascular events in cirrhosis and portal hypertension have been elucidated, the underlying cellular and molecular mechanisms causing EC dysfunctions are not yet fully understood. This review article summarizes the current cellular and molecular studies on EC dysfunctions found during the development of cirrhosis and portal hypertension with a focus on intra- and extrahepatic circulation. The article ends by discussing future directions of study for EC dysfunctions.

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Section: Resultsmentioning

confidence: 99%

Endothelial dysfunction in the regulation of cirrhosis and portal hypertension

Iwakiri

2011

Liver International

164

143

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“…Facing this situation, there is a strong need for studies of the vascular abnormalities associated with cirrhosis and portal hypertension (Shah 2009). These studies will have potential to lead us to develop novel targets for the treatment of portal hypertension.…”

Section: Resultsmentioning

confidence: 99%

The Molecules: Abnormal Vasculatures in the Splanchnic and Systemic Circulation in Portal Hypertension"

Iwakiri¹

2012

Portal Hypertension - Causes and Complications

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“…1 However, our present study together with recent clinical observations suggests that its translation to a new therapy and application in cirrhotic patients should be done with particular care. In patients with portal hypertension, the dosage of our study or standard doses may bear the risk of sorafenib-induced liver damage.…”

Section: Discussionmentioning

confidence: 96%

“…1 The increased portal pressure is partially explained by an increased intrahepatic vascular resistance, due to intrahepatic fibrosis and hyperresponsiveness to vasoconstrictors. [2][3][4][5][6] For both, activation of hepatic stellate cells (HSCs) and transdifferentiation to a myofibroblastlike, highly proliferative phenotype has a key role.…”

mentioning

confidence: 99%

Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis

Hennenberg

Trebicka

Kohistani

et al. 2011

Laboratory Investigation

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Portal hypertension in cirrhosis depends on increased intrahepatic vascular resistance, which is explained by fibrosis and intrahepatic hyperresponsiveness to vasoconstrictors. Both are caused by activation and proliferation of hepatic stellate cells (HSCs). Portal hypertension of cirrhotic rats can be reduced by the multikinase inhibitor sorafenib, due to a reduction of intrahepatic vascular resistance. Therefore, the hepatic effects of sorafenib require further understanding. Here, we investigated hepatic and HSC-specific sorafenib effects in cirrhotic rats. Animal models of bile duct ligation-induced secondary biliary cirrhosis in rats were studied. The rats were treated with sorafenib (60 mg/kg/day) for 1 week, starting after established cirrhosis. Histological evaluation was carried out using hemalaun and eosin (HE) staining. Apoptosis was studied by PARP cleavage, colorimetric caspase-3 assay, and electrophoretic DNA detection. HSC activation was studied by hepatic Sirius red and immunohistochemical aSMA (a-smooth muscle actin) staining, and by in vitro experiments with culture-activated primary HSCs. Biochemical serum parameters suggested the occurrence of sorafenib-induced liver damage. HE staining revealed histological changes in livers of sham-operated and bile duct-ligated (BDL) rats in response to sorafenib, which were different in both groups. In BDL rats and isolated HSCs, the treatment with sorafenib reduced hepatic aSMA and procollagen-1a mRNA expression. As shown by immunohistochemical staining, perisinusoidal aSMA expression was reduced by sorafenib in BDL rats. This was associated with reduced perisinusoidal deposition of extracellular matrix, as revealed by Sirius red staining. Although no change in PARP cleavage and only a minor increase in hepatic caspase-3 activity were detected in BDL rats in response to sorafenib, livers of sorafenib-treated BDL rats contained small DNA fragments, which were not observed in untreated BDL rats. In conclusion, sorafenib treatment reduces the number of activated HSCs in cirrhotic livers. This leads to the decrease in intrahepatic vascular resistance, but also to liver damage in the dosage we used. Therefore, any translation to portal hypertensive patients who may profit from sorafenib should be done with particular care.

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Therapy for portal hypertension

Cited by 6 publications

References 74 publications

Endothelial dysfunction in the regulation of cirrhosis and portal hypertension

Endothelial dysfunction in the regulation of cirrhosis and portal hypertension

The Molecules: Abnormal Vasculatures in the Splanchnic and Systemic Circulation in Portal Hypertension"

Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis

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