Misa Kenichi, Tanino Yoshinori, Wang Xintao, Nikaido Takefumi, Kikuchi Masami, Sato Yuki, Togawa Ryuichi, Tanino Mishie, Tanaka Shinya, Kadomatsu Kenji, Munakata Mitsuru
Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan.
Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan
Physiol Rep. 2017 Aug;5(16). doi: 10.14814/phy2.13383.
Midkine is a low-molecular-weight heparin-binding protein that is strongly expressed mainly in the midgestation period and has various physiological activities such as in development and cell migration. Midkine has been reported to be strongly expressed in cancer cells and in inflammation and repair processes, and to be involved in the pathogenesis of various diseases. However, its role in the lung is poorly understood. In this study, we analyzed the clinical characteristics of idiopathic pulmonary fibrosis patients in relation to midkine expression and used a mouse bleomycin-induced pulmonary fibrosis model to investigate the role of midkine in pulmonary fibrosis. In the idiopathic pulmonary fibrosis patients, the serum midkine level was significantly higher than in healthy subjects, and midkine levels in the serum and bronchoalveolar lavage (BAL) fluid correlated positively with the percentage of inflammatory cells in the BAL fluid. In wild-type mice, intratracheal bleomycin administration increased midkine expression in lung tissue. Additionally, compared with wild-type mice, midkine-deficient mice showed low expression of both collagen and -smooth muscle actin, as well as a low value for the pathological lung fibrosis score after bleomycin administration. Furthermore, the total cell count and lymphocyte percentage in the BAL fluid, as well as TNF- and transforming growth factor- expression in lung tissue, were significantly lower in the midkine-deficient mice compared with wild-type mice. These results suggest that midkine is involved in the development of pulmonary fibrosis by regulating inflammatory cell migration into the lung, and TNF- and transforming growth factor- expression.
中期因子是一种低分子量肝素结合蛋白，主要在妊娠中期强烈表达，并具有多种生理活性，如在发育和细胞迁移过程中。据报道，中期因子在癌细胞、炎症和修复过程中强烈表达，并参与多种疾病的发病机制。然而，其在肺部的作用尚不清楚。在本研究中，我们分析了特发性肺纤维化患者与中期因子表达相关的临床特征，并使用小鼠博来霉素诱导的肺纤维化模型来研究中期因子在肺纤维化中的作用。在特发性肺纤维化患者中，血清中期因子水平显著高于健康受试者，血清和支气管肺泡灌洗（BAL）液中的中期因子水平与BAL液中炎症细胞的百分比呈正相关。在野生型小鼠中，气管内给予博来霉素可增加肺组织中中期因子的表达。此外，与野生型小鼠相比，中期因子缺陷小鼠在给予博来霉素后，胶原蛋白和α-平滑肌肌动蛋白的表达较低，肺纤维化病理评分也较低。此外，中期因子缺陷小鼠BAL液中的总细胞计数和淋巴细胞百分比，以及肺组织中肿瘤坏死因子-α和转化生长因子-β的表达，均显著低于野生型小鼠。这些结果表明，中期因子通过调节炎症细胞向肺内的迁移以及肿瘤坏死因子-α和转化生长因子-β的表达，参与了肺纤维化的发展。
