Anti-fibrogenic analysis of HGF in intractable organ failures: Clinical potential of HGF as regenerative therapy

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(1) Strategies for ameliorating liver cirrhosis using an HGF gene therapyIn Japan, at least two millions of people are now suffering from intractable liver diseases, and especially, twenty thousands patients become lethal a year, because of an end-stage liver cirrhosis. It is therefore important to establish a new therapy for overcoming this disorder. Using an animal model, we demonstrate that HGF cDNA transfection is useful for suppressing liver cirrhosis-related pathological conditions. In rats undergone chronic treatments with DMN (a hepatotoxic drug), liver cirrhosis progresses, accompanied with increases in hepatic collagen and TGF-beta1 levels, leading to be lethal within 6 weeks after onset of the DMN treatments. On the other hand, all of the cirrhotic rats remained "alive" after transfection of human HQF cDNA, even till 6 weeks of the DMN injections. The cirrhotic rats without the HGF gene treatment manifest severe liver failure, accompanied with increased TGF-beta1 and collage … More n levels. In contrast, there were few fibrotic lesions (including matrix over-accumulation, myofibroblast hyperplasia and elevated TGF-beta1 levels) in the HGF cDNA-transfected DMN rats. These findings clearly demonstrate a therapeutic potential of the HGF gene supplement for minimizing liver cirrhosis in humans.(2) Repressive effect of HGF on progression of chronic renal failureChronic renal failure (CRF) is characterized by a progressive loss in parenchymal nephrons and represents renal fibrosis, especially in an end-stage. Using ICGN mice as a spontaneously occurring CRF model, we found that endogenous HGF is critical for suppressing onset and progression of CRF: The ICGN mice manifest renal dysfunction, accompanied with a decrease in renal HGF level, in reciprocal to increases, in TGF-beta1 and collagen levels in the nephritic kidneys. In order to delineate the loss in endogenous HGF levels, we injected an anti-HGF IgG to the nephrotic ICGN mice. Of note, the HGF-neutralizing treatment led to over-expression of TGF-beta1 levels as well as to down-regulation of endogenous HGF expression. Furthermore, HGF-neutralization caused not only suppressed tubular regeneration but also tubular epithelial apoptosis. Consequently, there: was a rapid progression of renal fibrosis and dysfunction in the HGF-neutralized ICGN mice. These findings show that: 1) Endogenous HGF play a key role for lessening CRF-related pathological states; and 2) The loss of HGF production, in reciprocal to increased TGF-beta1 levels, is responsible for manifesting CRF. If so, exogenous HGF supplement should be considered as a new option for cure-oriented therapy of CRF.(3) HGF ameliorated heart fibrosis and dysfunction in a .model of dilative cardiomyopathyIn the hamster model of dilative cardiomyopathy, there was evident cardiac fibrosis and hypertrophy at ages between 26 and 32 weeks after birth, coinciding with increases in heart TGF-beta1 and ANP levels, leading to be lethal When the hamsters were treated with recombinant HGF, cardiac TGF-beta1 and ANP levels were significantly repressed, resulting in improvements in heart dysfunction: and fibrosis. Although there has been no treatment useful for improving end-stage cardiomyopathy, this is the first research demonstrating reversibility of end-stag-related cardiomyopathy. Taken together, HGF was shown to be available for ameliorating pathological states in the cardiomyopathy. Less