Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.

Pathogenesis of liver cirrhosis.

The perfusion of the liver microcirculation is often analyzed in terms of idealized functional units (hexagonal liver lobules) based on a porous medium approach. More elaborate research is essential to assess the validity of this approach and to provide a more adequate and quantitative characterization of the liver microcirculation. To this end, we modeled the perfusion of the liver microcirculation using an image-based three-dimensional (3D) reconstruction of human liver sinusoids and computational fluid dynamics techniques. After vascular corrosion casting, a microvascular sample (+/-0.134 mm(3)) representing three liver lobules, was dissected from a human liver vascular replica and scanned using a high resolution (2.6 mu m) micro-CT scanner. Following image processing, a cube (0.15 x 0.15 x 0.15 mm(3)) representing a sample of intertwined and interconnected sinusoids, was isolated from the 3D reconstructed dataset to define the fluid domain. Three models were studied to simulate flow along three orthogonal directions (i.e., parallel to the central vein and in the radial and circumferential directions of the lobule). Inflow and outflow guidances were added to facilitate solution convergence, and good quality volume meshes were obtained using approximately 9 x 10(6) tetrahedral cells. Subsequently, three computational fluid dynamics models were generated and solved assuming Newtonian liquid properties (viscosity 3.5 mPa s). Post-processing allowed to visualize and quantify the microvascular flow characteristics, to calculate the permeability tensor and corresponding principal permeability axes, as well as the 3D porosity. The computational fluid dynamics simulations provided data on pressure differences, preferential flow pathways and wall shear stresses. Notably, the pressure difference resulting from the flow simulation parallel to the central vein (0-100 Pa) was clearly smaller than the difference from the radial (0-170 Pa) and circumferential (0-180 Pa) flow directions. This resulted in a higher permeability along the central vein direction (k(d,33) = 3.64 x 10(-14) m(2)) in comparison with the radial (k(d),(11) = 1.56 x 10(-14) m(2)) and circumferential (k(d,22) = 1.75 x 10(-14) m(2)) permeabilities which were approximately equal. The mean 3D porosity was 14.3. Our data indicate that the human hepatic microcirculation is characterized by a higher permeability along the central vein direction, and an about two times lower permeability along the radial and circumferential directions of a lobule. Since the permeability coefficients depend on the flow direction, (porous medium) liver microcirculation models should take into account sinusoidal anisotropy.

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Perfusion characteristics of the human hepatic microcirculation based on three-dimensional reconstructions and computational fluid dynamic analysis

Introduction: Chronic liver diseases represent a high unmet medical need and are characterized by persistent inflammation, parenchymal damage and fibrotic remodeling, leading eventually to cirrhosis and hepatic failure. Besides the persisting high prevalence of chronic viral hepatitis B and C, the dramatic increase in nonalcoholic steatohepatitis is now considered to be a major pathophysiologic driver for fibrosis development and subsequently cirrhosis. Increasing evidence suggests that also liver cirrhosis can regress when treated adequately.Areas covered: Herein, the authors review the underlying pathophysiologic mechanisms leading to fibrotic remodeling in the liver. They also highlight the options for novel treatment strategies by using molecular targeted agents.Expert opinion: New in vitro and preclinical animal models, and the careful selection of patients with high disease dynamics for clinical studies, provide a sound basis for the clinical development of antifibrotic agents in humans. Surrogate p...

Early to Phase II drugs currently under investigation for the treatment of liver fibrosis.

Purpose

To determine whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) could monitor progression of liver fibrosis in a piglet model, and which DCE-MRI parameter is most accurate for staging this disease.



Materials and Methods

Sixteen piglets were prospectively used to model liver fibrosis and underwent liver DCE-MRI followed by biopsy on the 0, 5th, 9th, 16th, and 21st weekends after modeling of fibrosis. Time of peak (TOP), time to peak (TTP), positive enhancement integral (PEI), maximum slope of increase (MSI), and maximum slope of decrease (MSD) were measured and statistically analyzed for the monitoring and staging.



Results

As fibrosis progresses, TOP and TTP tended to increase, whereas MSI, MSD, and PEI tended to decrease (all P < 0.05). TOP, TTP, and MSI could discriminate fibrosis stage 0 from 1–4, 0–1 from 2–4, 0–2 from 3–4, and 0–3 from 4; PEI could distinguish the above-mentioned stages except 0–3 from 4; and MSD could distinguish stage 0–3 from 4, and 0 from 1–4 (all P < 0.05). For predicting stage ≥1, ≥2, and ≥3, the area under receiver operating characteristic curve (AUC) of MSI was largest among all parameters; for stage 4 AUC of TTP was largest.



Conclusion

DCE-MRI has the potential to dynamically stage progression of liver fibrosis. J. Magn. Reson. Imaging 2014;39:872–878. © 2013 Wiley Periodicals, Inc.

Liver dynamic contrast-enhanced MRI for staging liver fibrosis in a piglet model.

Epidermal growth factor (EGF) and its signaling molecules, EGFreceptor (EGFR) and signal transducer and activator of transcription factor 3 (STAT3), have been considered to play a role in liver fibrosis and cirrhosis. Plumbagin (PL) is an extracted component from the plant and has been used to treat different kinds of cancer. However, its role in regulation of EGFR and STAT3 during liver fibrosis has not been investigated. In this study, the effects of PL on the regulation of EGFR and STAT3 were investigated in carbon tetrachloride (CCl4) induced liver fibrosis and hepatic stellate cells (HSC-T6). PL significantly attenuated liver injury and fibrosis in CCl4 treated rats. At concentrations of 2 to 6 μM, PL did not induce significant cytotoxicity of HSC-T6 cells. Moreover, PL reduced phosphorylation of EGFR and STAT3 in both fibrotic liver and heparin-binding EGF-like growth factor (HB-EGF) treated HSC-T6 cells. Furthermore, PL reduced the expression of α-SMA, EGFR, and STAT3 in both fibrotic liver and HB-EGF treated HSC-T6 cells. In conclusion, plumbagin could ameliorate the development of hepatic fibrosis through its downregulation of EGFR and STAT3 in the liver, especially in hepatic stellate cells.

/pdf/plumbagin-ameliorates-ccl4-induced-hepatic-fibrosis-in-rats-4x8h72zhad.pdf

Plumbagin Ameliorates CCl4-Induced Hepatic Fibrosis in Rats via the Epidermal Growth Factor Receptor Signaling Pathway

This study aimed to develop a new experimental model of liver cirrhosis in swine by using carbon tetrachloride (CCl4) and ethanol. Liver cirrhosis was induced by intraperitoneal injection of CCl4 twice a week for 9 weeks. Maize flour was the only food provided and the animals drunk a 5% alcohol-water mixture. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, bilirubin and portal venous pressure (PVP) levels were determined throughout CCl4 treatment. The animals were sacrificed under general anesthesia at week 9 and liver samples were collected for histological analysis. 83.3% of the swine had liver cirrhosis and 33.3% had died. There was no change of body weight during the course of the experiment (p > 0.05). The AST and ALT levels increased significantly in the early stage of the study but had a trend to decrease during the late phase. The level of bilirubin increased greatly and albumin decreased during the whole experiment (p 4-treated swine, but increased significantly at the late phase. In conclusion, this study was successful in producing liver cirrhosis and offers an ideal experimental model for observing surgical therapeutic efficacy.

G.-Q. Yue

Papers

Development of a new animal model of liver cirrhosis in swine.