The treatment of liver fibrosis induced by hepatocyte growth factor-directed, ultrasound-targeted microbubble destruction in rats



      The purpose of this study was to explore the feasibility of using ultrasound-targeted microbubble destruction to treat liver fibrosis induced by hepatocyte growth factor (HGF).


      Forty Wistar rats were divided into five groups after the models of liver fibrosis were prepared: (1) HGF, ultrasound, and microbubbles (HGF+US/MB); (2) HGF and ultrasound (HGF+US); (3) HGF and microbubbles (HGF+MB); (4) HGF (HGF); and (5) model alone (MA). All rats were killed after being transfected for 14 days. Recovery of the liver was detect by diffusion-weighted imaging (DWI) and pathological methods. Collagen I expression was detected by immunohistochemistry. Hepatocyte growth factor expression in the liver was detect by western blotting.


      The results of DWI and pathological examination showed the recovery of liver in HGF+US/MB group were better than those of other groups. In HGF+US/MB group, collagen I expression was less, and HGF protein was the highest among all the groups.


      Ultrasound-targeted microbubble destruction could deliver HGF into the fibrotic liver and produce an antifibrosis effect, which could provide a novel strategy for gene therapy of liver fibrosis.


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        • Friedman SL
        Liver fibrosis—from bench to bedside.
        J Hepatol. 2003; 38: S38-S53
        • Bataller R
        • Brenner DA
        Liver fibrosis.
        J Clin Invest. 2005; 115: 209-218
        • Isner JM
        Myocardial gene therapy.
        Nature. 2002; 415: 234-239
        • Yla-Herttuala S
        • Martin JF
        Cardiovascular gene therapy.
        Lancet. 2000; 355: 213-222
        • Nishino M
        • Iimuro Y
        • Ueki T
        • et al.
        Hepatocyte growth factor improves survival after partial hepatectomy in cirrhotic rats suppressing apoptosis of hepatocytes.
        J Surg. 2008; 144: 374-384
        • Ozawa S
        • Uchiyama K
        • Nakamori M
        • et al.
        Combination gene therapy of HGF and truncated type II TGF-beta receptor for rat liver cirrhosis after partial hepatectomy.
        Surgery. 2006; 139: 563-573
        • Li F
        • Sun JY
        • Wang JY
        • et al.
        Effect of hepatocyte growth factor encapsulated in targeted liposomes on liver cirrhosis.
        J Control Release. 2008; 131: 77-82
        • Taniyama Y
        • Tachibana K
        • Hiraoka K
        • et al.
        Development of safe and efficient novel nonviral gene transfer using ultrasound: enhancement of transfection efficiency of naked plasmid DNA in skeletal muscle.
        Gene Ther. 2002; 9: 372-380
        • Matsumoto K
        • Nakamura T
        Hepatocyte growth factor (HGF) as a tissue organizer for organogenesis and regeneration.
        Biochem Biophys Res Commun. 1997; 239: 639-644
        • Liu Y
        Hepatocyte growth factor and the kidney.
        Curr Opin Nephrol Hypertens. 2002; 11: 23-30
        • Matsumoto K
        • Nakamura T
        Hepatocyte growth factor: renotropic role and potential therapeutics for renal diseases.
        Kidney Int. 2001; 59: 2023-2038
        • Michalopoulos GK
        • DeFrances MC
        Liver regeneration.
        Science. 1997; 276: 60-66
        • Vargas GA
        • Hoeflich A
        • Jehle PM
        Hepatocyte growth factor in renal failure: promise and reality.
        Kidney Int. 2000; 57: 1426-1436
        • Eddy AA
        Molecular basis of renal fibrosis.
        Pediatr Nephrol. 2000; 15: 290-301
        • Klahr S
        • Morrissey J
        Obstructive nephropathy and renal fibrosis.
        Am J Physiol Renal Physiol. 2002; 283: F861-F875
        • Wang Z
        • Wang Z
        • Xu C
        • et al.
        Experimental study on preparation of lipid ultrasound microbubbles loaded gene and polylysine.
        Chinese J Ultrasound Med. 2009; 25: 101-104
        • Abedi-Valugerdi M
        • Aghdami N
        • Khorram Khorshid HR
        • et al.
        Evaluation of long-term effects of herbal drug formulation IMOD™ in laboratory animals.
        Iran J Allergy Asthma Immunol. 2007; 6: S9
        • Taouli B
        • Vilgrain V
        • Dumont E
        • et al.
        Evaluation of liver diffusion isotropy and characterization of focal hepatic lesion with two single-shot echo-planar MR imaging sequences: prospective study in 66 patients.
        Radiology. 2003; : 71-78
        • Kanemura H
        • Iimuro Y
        • Takeuchi M
        • et al.
        Hepatocyte growth factor gene transfer with naked plasmid DNA ameliorates dimethylnitrosamine-induced liver fibrosis in rats.
        J Hepatol Res. 2008; 38: 930-939
        • Kiyama S
        • Yamada T
        • Iwata H
        Reduction of fibrosis in a rat model of non-alcoholic steatohepatitis cirrhosis by human HGF gene transfection using electroporation.
        J Gastroenterol Hepatol. 2008; 23: 471-476
        • Hellgren I
        • Gorman J
        • Sylven C
        Factors controlling the efficiency of Tat-mediated plasmid DNA transfer.
        J Drug Target. 2004; 12: 39-47
        • Grenier N
        Diffusion-weighted MR imaging of the abdomen: a new clinical tool?.
        J Radiol. 2004; 85: 301-306
        • Boulanger Y
        • Amara M
        • Lepanto L
        • et al.
        Diffusion-weighted MR imaging of the liver of hepatitis C patients.
        NMR Biomed. 2003 May; 16: 132-136
        • Khvorostinka VM
        • Il'chenko IA
        • Bobronnikova LR
        Variations of treatment of chronic alcohol diffusion liver disease.
        Lik Sprava. 2001; 3: 154-155
        • Friedman SL
        Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.
        J Biol Chem. 2000; 275: 2247-2250
        • Nieto N
        • Friedman SL
        • Cederbaum AI
        Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome P450 2E1-derived reactive oxygen species.
        Hepatology. 2002; 35: 62-73
        • Zhigang W
        • Zhiyu L
        • Haitao R
        • et al.
        Ultrasound-mediated microbubble destruction enhances VEGF gene delivery to the infarcted myocardium in rats.
        Clin Imaging. 2004; 28: 395-398
        • Price R
        • Skyba D
        • Kaul S
        • Skalak T
        Delivery of colloidal particles and red blood cells to tissue through microvessel ruptures created by targeted microbubble destruction with ultrasound.
        Circulation. 1998; 98: 1264-1267