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.

为了探索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控机制。本研究的结果总结如下：1）Sp1，Sp3和ETS转录因子调节肺泡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，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的调控。2）脂多糖通过p38 MAP激酶介导改变肺泡I型细胞水通道蛋白水通道蛋白5的亚细胞定位，使其由胞内囊泡区向质膜转移。但糖皮质激素严重的副作用限制了其长期应用。通过体外报告基因分析，我们发现在不激活糖皮质激素受体的情况下，白藜芦醇苷（GL）具有糖皮质激素样的转录调节作用。在几项体内研究中证实了GL的糖皮质激素样作用，GL强烈抑制肺部炎症以及糖皮质激素，但不降低体重和胸腺体积。

项目成果

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
• 期刊: Resipatory Molecular Medicine 7
• 作者: Isohama Y;Morsy MAM;Hisatsune A;Miyata T
• 通讯作者: Miyata T

Lu Z, Kim KA, Suico MA, Uto A, Seki Y, Shuto T, Isohama Y, Miyata T, Kai H.: "ETS2 is involved in protein kinase C-activated expression of granulocyte-macrophage colony-stimulating factor in human non-small lung carcinoma cell line A549."Biochem. Biophys.

Lu Z、Kim KA、Suico MA、Uto A、Seki Y、Shuto T、Isohama Y、Miyata T、Kai H.：“ETS2 参与人类非粒细胞巨噬细胞集落刺激因子的蛋白激酶 C 激活表达。

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)。

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
• 期刊: Am J Physiol Lung Cell Physiol (In press)
• 作者: Kuwahara I;Lillehoi EP;Hisatsune A;Lu W;Isohama Y.;Miyata T;Kim KC
• 通讯作者: Kim KC

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

• DOI: 10.1152/ajplung.00471.2005
• 发表时间: 2006-09-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
• 影响因子: 4.9
• 作者: Kuwahara, Ippei;Lillehoj, Erik P.;Kim, K. Chul
• 通讯作者: Kim, K. Chul