Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Fusion of Regenerative Medicine With DDS, Research Institute for Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Department of Pharmaceutics and Drug Delivery, Faculty of Pharmaceutical Sciences, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
J Steroid Biochem Mol Biol. 2020 Jul;201:105696. doi: 10.1016/j.jsbmb.2020.105696. Epub 2020 May 12.
Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. However, no drugs can regenerate lung tissue in COPD patients, and differentiation-inducing drugs that can effectively treat damaged alveoli are needed. In addition, the presence of systemic comorbidities is also considered problematic. Our previous study revealed that a retinoic acid derivative improved emphysema in elastase-induced COPD model mice at a dose of 1.0 mg/kg, whereas 1α,25-dihydroxyvitamin D3 (1,25(OH)D) showed an emphysema-improving effect in the same model at 0.1 μg/kg. Elastase-induced COPD model mice do not exhibit a systemic disease state, so evaluation in a model that better reflects the human disease state is considered necessary. To solve this problem, we focused on the adiponectin-deficient mouse and examined the effects of 1,25(OH)D on alveolar regeneration. Fifty-week-old adiponectin-deficient mice were treated with 1,25(OH)D (0.1 μg/kg) twice a week, for 30 weeks. The effects of pulmonary administration on alveolar repair were evaluated according to the distance between alveolar walls (Lm values) and computed tomography (CT) parameters. Bone density was evaluated based on CT. The administration of 1,25(OH)D was confirmed to show a significant therapeutic effect. The Lm values in the control and 1,25(OH)D-treated groups were 98 ± 4 μm and 63 ± 1 μm, respectively. However, on CT, the average CT value and % of low attenuation area showed no significant change. In adiponectin-deficient mice, the reduction of bone density (cortical, spongy, and total bone), which is a systemic symptom of COPD, was significantly suppressed by 1,25(OH)D at 80 weeks of age. The present study suggests that 1,25(OH)D could be a potential candidate drug that may provide a radical cure for the lung disease and comorbidities of COPD patients. This work can lead to the development drugs that may provide a radical cure for COPD.
慢性阻塞性肺疾病（COPD）是全球主要的死亡原因。然而，目前没有药物可以使 COPD 患者的肺部组织再生，因此需要能够有效治疗受损肺泡的诱导分化药物。此外，全身性合并症的存在也被认为是一个问题。我们之前的研究表明，视黄酸衍生物在 1.0mg/kg 的剂量下可改善弹性蛋白酶诱导的 COPD 模型小鼠的肺气肿，而 1α,25-二羟维生素 D3（1,25(OH)D）在相同模型中以 0.1μg/kg 的剂量显示出改善肺气肿的作用。弹性蛋白酶诱导的 COPD 模型小鼠没有表现出全身性疾病状态，因此需要评估更能反映人类疾病状态的模型。为了解决这个问题，我们专注于脂联素缺陷小鼠，并研究了 1,25(OH)D 对肺泡再生的影响。将 50 周龄的脂联素缺陷小鼠用 1,25(OH)D（0.1μg/kg）每周两次处理 30 周。根据肺泡壁之间的距离（Lm 值）和计算机断层扫描（CT）参数评估肺内给药对肺泡修复的影响。根据 CT 评估骨密度。结果证实 1,25(OH)D 的给药具有显著的治疗效果。对照组和 1,25(OH)D 治疗组的 Lm 值分别为 98±4μm 和 63±1μm。然而，在 CT 上，平均 CT 值和低衰减区百分比没有明显变化。在脂联素缺陷小鼠中，1,25(OH)D 可显著抑制骨密度（皮质、海绵和总骨）的降低，这是 COPD 的全身性症状。本研究表明，1,25(OH)D 可能是一种潜在的候选药物，可提供 COPD 患者肺部疾病和合并症的根治方法。这项工作可以为 COPD 的治疗药物开发提供新的思路。
