Abstract
The tight-skin (TSK/+) mouse, a genetic model of systemic sclerosis (SSc), develops cutaneous fibrosis and defects in pulmonary architecture. Because hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after tissue injury, we investigated the role of HGF in cutaneous fibrosis and pulmonary architecture defects in SSc using TSK/+ mice. TSK/+ mice were injected in the gluteal muscle with either hemagglutinating virus of Japan (HVJ) liposomes containing 8 μg of a human HGF expression vector (HGF-HVJ liposomes) or a mock vector (untreated control). Gene transfer was repeated once weekly for 8 weeks. The effects of HGF gene transfection on the histopathology and expression of tumor growth factor (TGF)-β and IL-4 mRNA in TSK/+ mice were examined. The effect of recombinant HGF on IL-4 production by TSK/+ CD4+ T cells stimulated by allogeneic dendritic cells (DCs) in vitro was also examined. Histologic analysis revealed that HGF gene transfection in TSK/+ mice resulted in a marked reduction of hypodermal thickness, including the subcutaneous connective tissue layer. The hypodermal thickness of HGF-treated TSK/+ mice was decreased two-fold to three-fold compared with untreated TSK/+ mice. However, TSK/+ associated defects in pulmonary architecture were unaffected by HGF gene transfection. HGF gene transfection significantly inhibited the expression of IL-4 and TGF-β1 mRNA in the spleen and skin but not in the lung. We also performed a mixed lymphocyte culture and examined the effect of recombinant HGF on the generation of IL-4. Recombinant HGF significantly inhibited IL-4 production in TSK/+ CD4+ T cells stimulated by allogeneic DCs. HGF gene transfection inhibited IL-4 and TGF-β mRNA expression, which has been postulated to have a major role in fibrinogenesis and reduced hypodermal thickness, including the subcutaneous connective tissue layer of TSK/+ mice. HGF might represent a novel strategy for the treatment of SSc.
Highlights
Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology that is characterized by an excessive deposition of extracellular matrix protein in the affected skin, in addition to various internal organs
Because hepatocyte growth factor (HGF) is an important mitogen and morphogen that contributes to the repair process after tissue injury, we investigated the role of HGF in cutaneous fibrosis and pulmonary architecture defects in systemic sclerosis (SSc) using TSK/+ mice
HGF gene transfection significantly inhibited the expression of IL-4 and tumor growth factor (TGF)-β1 mRNA in the spleen and skin but not in the lung
Summary
Systemic sclerosis (SSc) is a connective tissue disorder of unknown etiology that is characterized by an excessive deposition of extracellular matrix protein in the affected skin, in addition to various internal organs. The tight-skin (TSK/+) mouse is a genetic model for human SSc. the phenotypic characteristics of the TSK/+ mouse are not identical to those of human SSc patients, TSK/+ mice produce autoantibodies against SSc-specific autoantigens, including topo-I, fibrillin 1 (fbn-1), collagen type 1, and Fcγ receptors [2,3]. The gene defect responsible for the TSK/+ phenotype in mice is yet to be definitively identified; the fbn-1 gene has been recently proposed as a candidate locus for this disorder [4]. Other abnormalities in TSK/+ mice include increased lung collagen content, enlarged air spaces reminiscent of pulmonary
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