Basic study to develop a new therapeutic drug in chronic obstructive pulmonary disease

开发慢性阻塞性肺疾病新治疗药物的基础研究

• 批准号: 15390030
• 负责人: MIYATA Takeshi
• 金额: $ 9.6万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390030/
• 关键词: COPD; Neutrophil elastase; Airway Inflammation; Glucocorticoid; Tanscription factor; COPD; グリチルリチン; 気道粘液; Sp1転写因子; レチノイン酸; 杯細胞; 肺胞上皮細胞; Sp3転写因子; aquaporin-5; MUC1ムチン; 慢性閉塞性呼吸器疾患; 肺上皮細胞; 粘液遺伝子; ETS転写因子; GM-CSF

To develop a new therapeutic way in chronic obstructive pulmonary disease, we have studied the regulatory mechanisms of various functions in lung epithelial cells. The findings in this study were summarized below.1)Sp1, Sp3 and ETS transcription factors regulate transdifferentiation from alveolar type II to type I epithelial cells. Sp1 increased type I cell-specific gene expression, and Sp3 competitively inhibited the effect of Sp1. In addition, the activity of ETS transcription factor, MEF, was controlled by protein kinase C.2)Lipopolysaccaride changed subcellualr sidtribution of aquaporin-5, a water channel protein in alveolar type I cells, from intracellular vesicle compartment to plasma membrane, which is mediated by p38 MAP kinase.3)Glucocorticoid is the most effective to treat the lung inflammation, but severe adverse effects of glucocorticoid restricts its chronic use. We found that glycyrrhizin (GL) has glucocorticoid-like transcriptional regulatory effect the without activating glucocorticoid receptor, using in vitro reporter gene assay. The glucocorticoid-like effect of GL was confirmed in several in vivo studies, GL strongly inhibited lung inflammation as well as glucocorticoid, but did not decrease body weight and thymus volume.

为了开辟慢性阻塞性肺疾病的治疗新途径，我们研究了肺上皮细胞各种功能的调节机制。本研究的结果总结如下：1)Sp1、Sp3和ETS转录因子调控肺泡II型上皮细胞向I型上皮细胞的转分化。 Sp1增加I型细胞特异性基因表达，而Sp3竞争性抑制Sp1的作用。此外，ETS转录因子MEF的活性受蛋白激酶C控制。2)脂多糖改变了肺泡I型细胞中水通道蛋白aquaporin-5的亚细胞分布，从细胞内囊泡区室转移到质膜，从而p38 MAP激酶介导的3）糖皮质激素是治疗肺部炎症最有效的药物，但糖皮质激素严重的不良反应限制了其应用长期使用。通过体外报告基因检测，我们发现甘草甜素（GL）具有类糖皮质激素的转录调节作用，且不激活糖皮质激素受体。 GL的类糖皮质激素作用在多项体内研究中得到证实，GL与糖皮质激素一样强烈抑制肺部炎症，但不会降低体重和胸腺体积。

项目成果

Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NFκB activation via EGFR transactivation in a lung epithelial cell line.

在肺上皮细胞系中，中性粒细胞弹性蛋白酶通过 EGFR 反式激活激活 p38/NFκB，从而诱导 IL-8 基因转录和蛋白质释放。

• 发表时间: 2006
• 作者: Kuwahara I; Lillehoi EP; Lu W; Singh IS; Isohama Y; Miyata T; Kim KC
• 通讯作者: Kim KC

ETS2 is involved in protein kinase C-activated expression of granulocyte-macrophage colony-stimulating factor in human non-small lung carcinoma cell line, A549.

ETS2 参与人非小肺癌细胞系 A549 中蛋白激酶 C 激活的粒细胞-巨噬细胞集落刺激因子的表达。

• 发表时间: 2003
• 作者: Lu Z; Kim KA; Suico MA; Uto A; Seki Y; Shuto T; Isohama Y; Miyata T; Kai H
• 通讯作者: Kai H

Neutrophil elastase induces IL-8 gene expression in lung epithelial cell

中性粒细胞弹性蛋白酶诱导肺上皮细胞IL-8基因表达

• 发表时间: 2006
• 作者: Kuwahara I; Lillehoi EP; Hisatsune A; Lu W; Isohama Y.; Miyata T; Kim KC
• 通讯作者: Kim KC

礒濱洋一郎, Mohamed AM Morsy, 久恒昭哲, 宮田 健: "肺サーファクタント分泌におけるProstaglandin E2の役割"分子呼吸病. 7. 207-211 (2003)

Yoichiro Isohama、Mohamed AM Morsy、Akihisa Hisatsune、Ken Miyata：“前列腺素 E2 在肺表面活性物质分泌中的作用”《分子呼吸疾病》7. 207-211 (2003)。

The role of prostagrandin E2 in pulmonary surfactant secretion.

前列腺素 E2 在肺表面活性物质分泌中的作用。

• 发表时间: 2003
• 作者: Isohama Y; Morsy MAM; Hisatsune A; Miyata T
• 通讯作者: Miyata T