Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan.
Int J Mol Sci. 2018 Feb 6;19(2):474. doi: 10.3390/ijms19020474.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in -deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in -deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by -deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF.
特发性肺纤维化（IPF）是一种预后不良且无治愈疗法的进行性疾病。SCF-Skp2 E3 连接酶是癌症治疗的靶点，但尚无 Skp2 作为 IPF 靶点的报道。在这里，我们证明 Skp2 是 IPF 的一个有前途的治疗靶点。我们研究了破坏 Skp2 是否能抑制博来霉素（BLM）诱导的小鼠模型中的肺纤维化，结果发现与对照组相比，Skp2 缺陷小鼠的肺纤维化明显受到抑制。BLM 处理的小鼠肺中纤维化标志物如胶原 1 型和纤连蛋白的肺内积累在 Skp2 缺陷小鼠中减少。此外，伴有肺纤维化的支气管肺泡灌洗液细胞数量显著减少。BLM 处理后，野生型小鼠中 Skp2 靶标 p27 的水平显著降低，但在 Skp2 缺陷小鼠中恢复。在波形蛋白阳性间充质成纤维细胞中，BLM 处理导致的 p27 阳性细胞减少和 Ki67 阳性细胞增加被 Skp2 缺陷所抑制。由于这些结果表明抑制 Skp2 可能对 BLM 诱导的肺纤维化有效，因此我们接下来使用 Skp2 抑制剂 SZL-P1-41 进行了治疗实验。正如预期的那样，SZL-P1-41 显著抑制了 BLM 诱导的肺纤维化。此外，SZL-P1-41 治疗增加了 p27 水平，表明 p27 可能是 BLM 诱导的肺纤维化的一个重要 Skp2 靶点。我们的研究表明 Skp2 是人类肺纤维化（包括 IPF）的一个潜在分子靶点。
