Vatalanib, a tyrosine kinase inhibitor, decreases hepatic fibrosis and sinusoidal capillarization in CCl4-induced fibrotic mice

Abstract

Among the various consequence arising from lung injury, hepatic fibrosis is the most severe. Decreasing the effects of hepatic fibrosis remains one of the primary therapeutic challenges in hepatology. Dysfunction of hepatic sinusoidal endothelial cells is considered to be one of the initial events that occur in liver injury. Vascular endothelial growth factor signaling is involved in the progression of genotype changes. The aim of the present study was to determine the effect of the tyrosine kinase inhibitor, vatalanib, on hepatic fibrosis and hepatic sinusoidal capillarization in a carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis. Liver fibrosis was induced in BALB/c mice using CCl4 by intraperitoneal injection for 6 weeks. The four experimental groups included a control, and three experimental groups involving administration of CCl4, vatalanib and a combination of the two. Histopathological staining and measuring live hydroxyproline content evaluated the extent of liver fibrosis. The expression of α-smooth muscle actin (SMA) and cluster of differentiation (CD) 34 was detected by immunohistochemistry. Collagen type I, α-SMA, transforming growth factor (TGF)-β1 and vascular endothelial growth factor receptor (VEGFR) expression levels were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The average number of fenestrae per hepatic sinusoid was determined using transmission electron microscopy. Liver fibrosis scores and hydroxyproline content were decreased in both vatalanib groups. In addition, both doses of vatalanib decreased mRNA expression levels of hepatic α-SMA, TGF-β1, collagen-1, VEGFR1, and VEGFR2. Levels of α-SMA and CD34 protein were decreased in the vatalanib group compared with the CCl4 group. There were significant differences in the number of fenestrae per sinusoid between the groups. The present study identified that administration of vatalanib was associated with decreased liver fibrosis and hepatic sinusoidal capillarization in CCl4-induced mouse models, and is a potential compound for counteracting liver fibrosis.

<p>Carvedilol attenuates carbon tetrachloride-induced liver fibrosis and hepatic sinusoidal capillarization in mice</p>

“…Moreover, previous studies have revealed that the relationship between liver fibrosis and endothelial-mediated angiogenesis seriously impedes the reversal and remission of liver fibrosis 13,14. Antiangiogenic therapy might be a strategy for the treatment of hepatic fibrosis and portal hypertension 8,15,16…”

Actin Depolymerization in Dedifferentiated Liver Sinusoidal Endothelial Cells Promotes Fenestrae Re‐Formation

“…These observations emphasize the importance of identifying the exact composition of the cytoskeleton ring and molecules involved in membrane fusion. Identification of such a mechanism will also help us to understand how to control fenestrae opening and to design drugs that could slow down the fibrosis progression or promote fibrosis reversion . Indeed, after chronic injury, such as viral hepatitis or alcoholic disorder and nonalcoholic steatohepatitis, the liver develops fibrosis.…”

“…Identification of such a mechanism will also help us to understand how to control fenestrae opening and to design drugs that could slow down the fibrosis progression or promote fibrosis reversion. (20) Indeed, after chronic injury, such as viral hepatitis or alcoholic disorder and nonalcoholic steatohepatitis, the liver develops fibrosis. Fibrosis is a slow process promoting an extracellular matrix accumulation, resulting in a general increase in organ stiffness.…”

Effect of Curcumol on the Fenestrae of Liver Sinusoidal Endothelial Cells Based on NF‐κB Signaling Pathway

“…LSECs can synthesize and secrete NO and ET, thereby regulating intrahepatic vasodilation and contraction, and play an important role in regulating hepatic sinus blood flow. NO has a powerful vasodilator effect, which directly stimulates soluble guanylate cyclase in a paracrine form, which increases cyclic guanylate, which causes Ca 2+ reduction and vasodilation [25,26]. Under physiological conditions, LSECs can express endothelial nitric oxide synthase (eNOS) and synthesize NO through eNOS, but the level of NO is low.…”