Gadi Spira

Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats

BACKGROUND/AIMS Hepatic fibrosis involves excess deposition of extracellular connective tissue of which collagen type I fibers form the predominant component. Left untreated it develops into cirrhosis, often linked with hepatocellular carcinoma. Owing to the fact that cirrhotic liver regeneration is impaired, resection of hepatocellular carcinoma associated with cirrhosis is questionable. The aim of the present study was to determine the potential of halofuginone, a collagen type I inhibitor, in improving liver regeneration in cirrhotic rats. METHODS Partial hepatectomy (70%) was performed in thioacetamide-induced cirrhotic rats fed a halofuginone-containing diet. Liver regeneration was monitored by mass and proliferating cell nuclear antigen. The Ishak staging system and hydroxyproline content were used to evaluate the level of fibrosis. RESULTS Halofuginone administered prior to and following partial hepatectomy did not inhibit normal liver regeneration despite the reduced levels of collagen type I mRNA. When given to rats with established fibrosis, it caused a significant reduction in alpha smooth muscle actin, TIMP-2, collagen type I gene expression and collagen deposition. Such animals demonstrated improved capacity for regeneration. CONCLUSIONS Halofuginone may prove useful in improving survival of patients with hepatocellular carcinoma and cirrhosis undergoing surgical resection.

Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro.

BackgroundShear stress forces acting on liver sinusoidal endothelial cells following resection have been noted as a possible trigger in the early stages of hepatic regeneration. Thus, the morphology and gene expression of endothelial cells following partial hepatectomy or shear stress in vitro was studied.ResultsFollowing partial hepatectomy blood flow-to-liver mass ratio reached maximal values 24 hrs post resection. Concomitantly, large fenestrae (gaps) were noted. Exposure of liver sinusoidal endothelial cells, in vitro, to physiological laminar shear stress forces was associated with translocation of vascular endothelial cell growth factor receptor-2 (VEGFR-2) and neuropilin-1 from perinuclear and faint cytoplasmic distribution to plasma membrane and cytoskeletal localization. Under these conditions, VEGFR-2 co-stains with VE-cadherin. Unlike VEGFR-2, the nuclear localization of VEGFR-1 was not affected by shear stress. Quantification of the above receptors showed a significant increase in VEGFR-1, VEGFR-2 and neuropilin-1 mRNA following shear stress.ConclusionOur data suggest a possible relation between elevated blood flow associated with partial hepatectomy and the early events occurring thereby.

Functional magnetic resonance imaging monitoring of pathological changes in rodent livers during hyperoxia and hypercapnia

Liver diseases and regeneration are associated with hemodynamic changes denoting pathological alterations. Determining and monitoring physiological and pathological liver changes is essential for diagnostic and therapeutic objectives. Our aim was to determine the feasibility of functional magnetic resonance imaging (fMRI) during hypercapnia and hyperoxia for monitoring liver pathology. Liver fMRI images were acquired in rodents following acute bleeding, partial hepatectomy, and fibrosis. Results were quantitated and confirmed by histology. Changes induced by hyperoxia and hypercapnia following hemorrhage significantly correlated with the percentage of blood loss, reflecting lower liver perfusion and diminished vessel responsiveness to gas saturation. Hepatectomy resulted in an early decline in signal intensity changes due to hyperoxia, suggesting a decrease in liver perfusion and blood content. Following hepatectomy, signal intensity changes due to hypercapnia increased, signifying a change in liver perfusion from a mainly portal to a more arterial source. Two weeks after induction of fibrosis, signal intensity changes due to hypercapnia became much lower and those due to hyperoxia were much higher than those in normal livers, reflecting the increased perfusion due to the inflammatory process as confirmed by histologic analysis. With fibrosis progression, signal intensity changes induced by hypercapnia and hyperoxia were gradually attenuated, indicating structural and functional alterations of the liver vasculature during fibrosis. Conclusion: In various liver pathologies, fMRI response to hypercapnia and hyperoxia is sensitive to changes in liver hemodynamic status involved in hepatic damage or recovery; thus, this technique may offer an additional noninvasive diagnostic tool for evaluation and follow‐up of liver diseases by means of examining perfusion‐related alterations. (HEPATOLOGY 2008.)