Ohashi Takenobu, Yamamoto Toshiyuki
Department of Dermatology, Fukushima Medical University, Fukushima, Japan.
Exp Dermatol. 2015 Sep;24(9):698-702. doi: 10.1111/exd.12752. Epub 2015 Jul 14.
The study of lysophosphatidic acid (LPA) receptor has recently focused on its involvement in the pathogenesis of systemic sclerosis (SSc). We examined the inhibitory effects of the antagonist for the LPA receptor, a selective LPA1 and LPA3 antagonist (Ki16425), on dermal and lung fibrosis in a mouse model of SSc. Ki16425 was administered intra-dermally after 6 h on the same sites as bleomycin injection. Histopathological examination showed that skin lesions were markedly attenuated by treatment with Ki16425 at doses of 1 and 10 mg/kg, along with reduced dermal thickness. Hydroxyproline contents in the Ki16425-treated skin showed a decrease of 35% (1 mg/kg) and 45% (10 mg/kg) compared with those in the oil-injected skin of the controls. The number of mast cells and phospho-Smad2/3-positive spindle cells of the Ki16425-treated skin was significantly decreased compared with that in the controls. Additionally, RT-PCR analysis showed that the mRNA levels of TGF-β1, CTGF, MIP-1α, IFN-γ and collagen α1(I) were significantly decreased in both the 1-mg/kg and 10-mg/kg groups of the Ki16425-treated mice compared with those in the controls. Furthermore, treatment with bleomycin and Ki16425 showed reduction in lung fibrosis, and the hydroxyproline contents in the lungs of the Ki16425-treated mice showed a decrease of 25% (1 mg/kg) and 32% (10 mg/kg) compared with those in the lungs of the controls. Taken together, Ki16425 was found to improve dermal and lung fibrosis in a mouse model of bleomycin-induced murine scleroderma. These results suggest that Ki16425 has the potential to be an effective new treatment for scleroderma.
溶血磷脂酸（LPA）受体的研究最近聚焦于其在系统性硬化症（SSc）发病机制中的作用。我们在SSc小鼠模型中研究了LPA受体拮抗剂（一种选择性LPA1和LPA3拮抗剂，Ki16425）对皮肤和肺纤维化的抑制作用。在与博来霉素注射相同的部位，于6小时后皮内注射Ki16425。组织病理学检查显示，1和10mg/kg剂量的Ki16425治疗可使皮肤病变明显减轻，同时皮肤厚度降低。与对照组油注射皮肤相比，Ki16425治疗的皮肤中羟脯氨酸含量分别降低了35%（1mg/kg）和45%（10mg/kg）。与对照组相比，Ki16425治疗的皮肤中肥大细胞和磷酸化Smad2/3阳性梭形细胞的数量显著减少。此外，逆转录聚合酶链反应（RT-PCR）分析表明，与对照组相比，Ki16425治疗的小鼠1mg/kg和10mg/kg组中转化生长因子-β1（TGF-β1）、结缔组织生长因子（CTGF）、巨噬细胞炎性蛋白-1α（MIP-1α）、干扰素-γ（IFN-γ）和胶原蛋白α1（I）的mRNA水平显著降低。此外，博来霉素和Ki16425治疗可减轻肺纤维化，与对照组肺相比，Ki16425治疗的小鼠肺中羟脯氨酸含量分别降低了25%（1mg/kg）和32%（10mg/kg）。综上所述，在博来霉素诱导的小鼠硬皮病模型中，Ki16425可改善皮肤和肺纤维化。这些结果表明，Ki16425有可能成为硬皮病的一种有效的新治疗方法。
