Hepatocyte growth factor ameliorates dermal sclerosis in the tight-skin mouse model of scleroderma
Hepatocyte growth factor ameliorates dermal sclerosis in the tight-skin mouse model of scleroderma
复制标题
DOI：
10.1186/ar2068
复制
发表时间：
2006-01-01
影响因子：
4.9
通讯作者：
Sano, Hajime
中科院分区：
文献类型：
--
作者：
Iwasaki, Tsuyoshi;Imado, Takehito;Sano, Hajime
紧皮（TSK/+）小鼠，系统性硬化症（SSc）的遗传模型，发展皮肤纤维化和肺结构缺陷。由于肝细胞生长因子（HGF）是一种重要的有丝分裂原和形态，有助于组织损伤后的修复过程，我们研究了肝细胞生长因子在皮肤纤维化和肺结构缺陷的SSc使用TSK/+小鼠的作用。用含有8 μ g人HGF表达载体的日本血凝病毒（HVJ）脂质体（HGF-HVJ脂质体）或模拟载体（未处理的对照）注射TSK/+小鼠的臀肌。每周重复一次基因转移，持续8周。观察肝细胞生长因子基因转染对TSK/+小鼠肿瘤组织病理学及肿瘤生长因子（TGF）-β和白细胞介素4（IL-4）mRNA表达的影响。体外观察重组HGF对同种异体树突状细胞（DCs）刺激TSK/+ CD 4（+）T细胞产生IL-4的影响。组织学分析显示，TSK/+小鼠中的HGF基因转染导致皮下厚度（包括皮下结缔组织层）显著减少。与未治疗的TSK/+小鼠相比，HGF治疗的TSK/+小鼠的皮下厚度降低了2倍至3倍。然而，TSK/+相关的肺结构缺陷不受HGF基因转染的影响。肝细胞生长因子基因转染可显著抑制脾和皮肤中IL-4和TGF-β 1 mRNA的表达，但对肺中IL-4和TGF-β 1 mRNA的表达无影响。我们还进行了混合淋巴细胞培养，并检查了重组HGF对IL-4产生的影响。重组HGF可显著抑制同种异体DC刺激的TSK/+ CD 4（+）T细胞产生IL-4。HGF基因转染抑制IL-4和TGF-β 1 mRNA表达，这被认为在纤维蛋白生成和减少皮下厚度（包括TSK/+小鼠的皮下结缔组织层）中具有主要作用。肝细胞生长因子可能是一种新的战略，为治疗SSc。
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 mu g 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)-beta 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-beta 1 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-beta 1 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.