Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats

Yasuda, Hiroshi; Imai, Eiichi; Shiota, Akira; Fujise, Nobuaki; Morinaga, Tsutomu; Higashio, Kanji

doi:10.1053/jhep.1996.v24.pm0008781336

Cited by 82 publications

(58 citation statements)

References 35 publications

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“…HGF is known to have beneficial effects in an experimental fibrotic disease model [17]. Our results suggested that HGF corrected the imbalance between MMP-3 and TIMP-3 mRNA induced by TGF-β1.…”

Section: Discussionsupporting

confidence: 51%

Fibrogenic and Inflammatory Cytokines Modulate mRNA Expressions of Matrix Metalloproteinase-3 and Tissue Inhibitor of Metalloproteinase-3 in Type II Pneumocytes

Hoshino

Mio²,

Nagai³

et al. 2001

Respiration

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Background: Imbalance between proteinases and their inhibitors released from alveolar type II pneumocytes may cause development of inflammatory lung diseases. Objectives and Methods: We examined mRNA expressions of matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in a cell line (A549) and in primary culture of normal adult human type II pneumocytes using reverse transcription-competitive polymerase chain reaction. Results: Interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) increased MMP-3 and TIMP-3 expressions in A549 cells in a time- and concentration-dependent manner. IL-1β mainly augmented MMP-3 expression, while TGF-β1 mainly augmented TIMP-3 expression. Dexamethasone attenuated both IL-1β- and TGF-β1-stimulated expressions of MMP-3 and TIMP-3. Interleukin-10 had no significant effect. Hepatocyte growth factor alone had no effect on constitutive MMP-3 expression or TIMP-3 expression, but it augmented TGF-β1-stimulated MMP-3 expression. The constitutive expressions were higher in normal type II pneumocytes than in A549 cells, but the regulations were similar. Conclusions: These data indicated that the matrix degradation is enhanced by IL-1β and suppressed by TGF-β1 via regulations in the balance between MMP-3 and TIMP-3. Further, these regulations were shown to be modulated by glucocorticoids and growth factors.

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Section: Discussionsupporting

confidence: 51%

Fibrogenic and Inflammatory Cytokines Modulate mRNA Expressions of Matrix Metalloproteinase-3 and Tissue Inhibitor of Metalloproteinase-3 in Type II Pneumocytes

Hoshino

Mio²,

Nagai³

et al. 2001

Respiration

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“…Furthermore, HGF is shown to have therapeutic roles in preventing tissue fibrosis and dysfunctions in a variety of organs. [25][26][27][28] The progression of these chronic tissue fibrosis diseases is a slow process that often progresses over long periods ranging from years to decades in human. [29][30][31][32] Given that long-term therapy may be necessary, repeated injection of recombinant HGF is not only inconvenient, but also extremely costly.…”

Section: Discussionmentioning

confidence: 99%

Sustained expression of naked plasmid DNA encoding hepatocyte growth factor in mice promotes liver and overall body growth

Yang

2001

Hepatology

103

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To understand the physiological functions of exogenous hepatocyte growth factor (HGF) on normal adult animals, we delivered human HGF gene into mice by a hydrodynamics-based in vivo gene transfection approach using a naked plasmid vector. Systemic administration of naked plasmid containing HGF cDNA driven under cytomegalovirus promoter (pCMV-HGF) by rapid injection via the tail vein produced a remarkable level of human HGF protein in the circulation, beginning to appear at 4 hours and peaking at 12 hours following injection. Tissue distribution studies identified the liver as the organ with the highest level of transgene expression. Through weekly repeated injections of plasmid vector, we achieved sustained, long-term, high levels of exogenous HGF expression in mice for 8 weeks. Increases of more than 31% and 16% in liver and body weights were found, respectively, in the mice that received pCMV-HGF plasmid compared with that given the control vector for 8 weeks. Expression of exogenous HGF in vivo activated mitogen-activated protein kinases and induced proliferating cell nuclear antigen expression in normal adult liver and kidneys. These data suggest that systemic administration of naked plasmid vector is a convenient, safe, and highly efficient approach to introduce and maintain exogenous HGF gene expression in vivo in a controllable fashion. Our results also indicate that long-term expression of human HGF in mice markedly activates growth-related signal transduction events, promotes cell proliferation, and leads to liver and overall body growth in whole adult animals. (HEPATOLOGY 2001;33:848-859.)

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“…Partial hepatectomy, acute liver failure, and acute lung injury are also common pathologies where the use of HGF as a mitogenic tool to repopulate damaged tissues can be potentially applied (138)(139)(140)(141)(142)(143)(144)(145)(146). As far as chronic diseases are concerned, HGF has been demonstrated recently to be effective in retarding progression of liver cirrhosis (147)(148)(149) or pulmonary fibrosis (150).…”

Section: Scatter Factors As Therapeutic Tools For Organ Failure and Cmentioning

confidence: 99%

Interactions between scatter factors and their receptors: hints for therapeutic applications

1998

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The scatter factors, which include hepatocyte growth factor and macrophage stimulating protein, stand out from other cytokines because of their uncommon biological properties. In addition to promoting cell growth and protection from apoptosis, they are involved in the control of cell dissociation, migration into extracellular matrices, and a unique process of differentiation called 'branching morphogenesis'. Through the concerted regulation of these complex phenomena, scatter factors promote development, regeneration, and reconstruction of normal organ architecture. In transformed epithelia, scatter factors can mediate tumor invasive growth, a harmful feature of neoplastic progression in which cancer cells invade surrounding tissues, penetrate across the vascular walls, and eventually disseminate throughout the body, giving rise to systemic metastases. A much-debated issue in basic biology, which has strong implications for experimental medicine, is how to dissociate the favorable effects of growth factors from their adverse ones. Accordingly, to find agonists or antagonists with potential therapeutic applications is a crucial undertaking for current research. Domain-mapping analyses of growth factor molecules can help to isolate specific structural requirements for the induction of selective biological effects. Based on the observation that certain growth factors must undergo posttranslational modifications to exert a full response, it is possible to interfere with their activation mechanisms to modulate their functions. Finally, the identification of cell type-specific coreceptors able to potentiate their activity allows drawing of a functional body map, where some organs or tissues may be more responsive than others to growth factors. This review is focused on how, and to what extent, scatter factors can behave 'well' or 'badly' according to their molecular structure, the way they are activated, and the way they interact with cell surface receptors and coreceptors.

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Antifibrogenic effect of a deletion variant of hepatocyte growth factor on liver fibrosis in rats

Cited by 82 publications

References 35 publications

Fibrogenic and Inflammatory Cytokines Modulate mRNA Expressions of Matrix Metalloproteinase-3 and Tissue Inhibitor of Metalloproteinase-3 in Type II Pneumocytes

Fibrogenic and Inflammatory Cytokines Modulate mRNA Expressions of Matrix Metalloproteinase-3 and Tissue Inhibitor of Metalloproteinase-3 in Type II Pneumocytes

Sustained expression of naked plasmid DNA encoding hepatocyte growth factor in mice promotes liver and overall body growth

Interactions between scatter factors and their receptors: hints for therapeutic applications

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