HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects

Klein, Sabine; Beuge, Marike Marjolijn van; Granzow, M; Beljaars, Leonie; Schierwagen, Robert; Kilic, Sibel; Heidari, Iren; Huss, Sebastian; Sauerbruch, Tilman; Poelstra, Klaas; Trebicka, Jonel

doi:10.1016/j.jhep.2012.07.033

Cited by 89 publications

(80 citation statements)

References 28 publications

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“…Specific integrin inhibitors have been developed for cancer therapy, but need better validation for treatment of fibrosis (37,38). Myofibroblast stress relaxation and resultant amelioration of both fibrogenesis and portal hypertension has been shown in rats by inhibition of Rho kinase, which is downstream of integrin signaling (39).…”

Section: Figurementioning

confidence: 99%

Evolving therapies for liver fibrosis

Schuppan

Kim²

2013

J. Clin. Invest.

542

529

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Fibrosis is an intrinsic response to chronic injury, maintaining organ integrity when extensive necrosis or apoptosis occurs. With protracted damage, fibrosis can progress toward excessive scarring and organ failure, as in liver cirrhosis. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development, with enormous potential but also high risks. Preclinical research has yielded numerous targets for antifibrotic agents, some of which have entered early-phase clinical studies, but progress has been hampered due to the relative lack of sensitive and specific biomarkers to measure fibrosis progression or reversal. Here we focus on antifibrotic approaches for liver that address specific cell types and functional units that orchestrate fibrotic wound healing responses and have a sound preclinical database or antifibrotic activity in early clinical trials. We also touch upon relevant clinical study endpoints, optimal study design, and developments in fibrosis imaging and biomarkers.

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Section: Figurementioning

confidence: 99%

Evolving therapies for liver fibrosis

Schuppan

Kim²

2013

J. Clin. Invest.

542

529

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“…The effector cells of intrahepatic contraction are presumably the HSCs. Relevant mechanisms of intrahepatic contraction Rho kinases have been evaluated [13,14,21,22,23,24,25]. The importance of Rho kinase for HSC contraction was first described by studies with isolated cultured HSCs.…”

Section: Kc Activation In Cirrhotic Rat Liversmentioning

confidence: 99%

“…HSC activation is associated with excessive proliferation and transformation to the contractile phenotype [28], which confers hypercontractility to the intrahepatic vasculature resulting in increased intrahepatic vascular resistance [21]. HSC-specific blockade of Rho kinases might therefore be another promising therapeutic strategy in TLR-dependent portal hypertension [24]. …”

Section: Kc Activation In Cirrhotic Rat Liversmentioning

confidence: 99%

Infection as a Trigger for Portal Hypertension

Steib¹,

Schewe²,

Gerbes³

2015

Dig Dis

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Background: Microbial infections are a relevant problem for patients with liver cirrhosis. Different types of bacteria are responsible for different kinds of infections: Escherichia coli and Klebsiella pneumoniae are frequently observed in spontaneous bacterial peritonitis or urinary tract infections, and Streptococcus pneumoniae and Mycoplasma pneumoniae in pulmonary infections. Mortality is up to 4-fold higher in infected patients with liver cirrhosis than in patients without infections. Key Messages: Infections in patients with liver cirrhosis are due to three major reasons: bacterial translocation, immune deficiency and an increased incidence of systemic infections. Nonparenchymal liver cells like Kupffer cells, sinusoidal endothelial cells and hepatic stellate cells are the first liver cells to come into contact with microbial products when systemic infection or bacterial translocation occurs. Kupffer cell (KC) activation by Toll-like receptor (TLR) agonists and endothelial sinusoidal dysfunction have been shown to be important mechanisms increasing portal pressure following intraperitoneal lipopolysaccharide pretreatment in cirrhotic rat livers. Reduced intrahepatic vasodilation and increased intrahepatic vasoconstriction are the relevant pathophysiological pathways. Thromboxane A₂ and leukotriene (LT) C₄/D₄ have been identified as important vasoconstrictors. Accordingly, treatment with montelukast to inhibit the cysteinyl-LT₁ receptor reduced portal pressure in cirrhotic rat livers. Clinical studies have demonstrated that activation of KCs, estimated by the amount of soluble CD163 in the blood, correlates with the risk for variceal bleeding. Additionally, intestinal decontamination with rifaximin in patients with alcohol-associated liver cirrhosis reduced the portal pressure and the risk for variceal bleeding. Conclusions: TLR activation of nonparenchymal liver cells by pathogens results in portal hypertension. This might explain the pathophysiologic correlation between microbial infections and portal hypertension in patients with liver cirrhosis. These findings are the basis for both better risk stratifying and new treatment options, such as specific inhibition of TLR for patients with liver cirrhosis and portal hypertension.

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“…Arachidonic acid-derived vasoconstriction can be blunted by administering the TXA 2 receptor blocker terutroban [25], or the cysteinyl leukotriene antagonist montelukast [49]. HSC hypercontractility can be normalized using a Rho-kinase inhibitor [50] or the peptide hormone relaxin [51]. Sinusoidal NO bioavailability can be improved by administering antioxidants, which reduce the elevated levels of oxidative stress of the cirrhotic liver and concomitantly reduce NO scavenging by the superoxide radical [52,53,54].…”

Section: Rational Basis Of Therapymentioning

confidence: 99%

Pathophysiology and a Rational Basis of Therapy

Gracia‐Sancho

Maeso‐Díaz

Bosch

2015

Dig Dis

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Portal hypertension is a common complication of chronic liver disease. Its relevance comes from the fact that it determines most complications leading to death or liver transplantation in patients with cirrhosis of the liver: bleeding from esophageal or gastric varices, ascites and renal dysfunction, sepsis and hepatic encephalopathy. Portal hypertension results from increased resistance to portal blood flow through the cirrhotic liver. This is caused by two mechanisms: (1) distortion of the liver vascular architecture due to the liver disease causing structural abnormalities (nodule formation, remodeling of liver sinusoids, fibrosis, angiogenesis and vascular occlusion), and (2) increased hepatic vascular tone due to sinusoidal endothelial dysfunction, which results in a defective production of endogenous vasodilators, mainly nitric oxide (NO), and increased production of vasoconstrictors (thromboxane A₂, cysteinyl leukotrienes, angiotensin II, endothelins and an activated adrenergic system). Hepatic endothelial dysfunction occurs early in the course of chronic liver disease as a consequence of inflammation and oxidative stress, and determines loss of the normal phenotype of liver sinusoidal endothelial cells (LSECs) that become proliferative, prothrombotic, proinflammatory and vasoconstrictor. The cross-talk between LSECs and hepatic stellate cells (HSCs) induces activation of the latter, which in turn proliferate, migrate and increase collagen deposition around the sinusoids, contributing to fibrogenesis, architectural disruption and angiogenesis, which further increase the hepatic vascular resistance and worsen liver failure by interfering with the blood perfusion of the liver parenchyma. An additional factor further worsening portal hypertension is an increased blood flow through the portal system due to splanchnic vasodilatation. This is an adaptive response to decreased effective hepatocyte perfusion, and is maximal once portal pressure has increased sufficiently to promote the development of intrahepatic shunts and portal-systemic collaterals, including varices, through which portal blood flow bypasses the liver. In human portal hypertension collateralization and hyperdynamic circulation start at a portal pressure gradient >10 mm Hg. Rational therapy for portal hypertension aims at correcting these pathophysiological abnormalities: liver injury, fibrogenesis, increased hepatic vascular tone and splanchnic vasodilatation. Continuing liver injury may be counteracted specifically by etiological treatments (the best example being the direct-acting antivirals for hepatitis C viral infection), while architectural disruption and fibrosis can be ameliorated by a variety of antifibrotic drugs and antiangiogenic strategies. Several drugs in this category are currently under investigation in phase II-III randomized controlled trials. Sinusoidal endothelial dysfunction is ameliorated by statins as well as by other drugs increasing NO availability. It is of note that simvastatin has already been proven to b...

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HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects

Cited by 89 publications

References 28 publications

Evolving therapies for liver fibrosis

Evolving therapies for liver fibrosis

Infection as a Trigger for Portal Hypertension

Pathophysiology and a Rational Basis of Therapy

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