A molecular pharmacological therapy for asthma based on phenotype changing in the structural cells in airways

基于气道结构细胞表型变化的哮喘分子药理学治疗

• 批准号: 22590846
• 负责人: KUME Hiroaki
• 金额: $ 2.91万
• 依托单位: Kinki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590846/
• 关键词: 気道平滑筋細胞; 肺血管内皮細胞; 好酸球; 気道過敏性亢進; β_2 アドレナリン受容体; 気管支喘息; 低分子量G蛋白; Rho-kinase; 細胞骨格; リモデリング; Ca2+動態; 過剰進展刺激; フェノタイプ; 気道平滑筋; 細胞遊走; サイトカイン; サリドマイド; S1P

Sphinosine-1-phosphate (S1P) is released from mast cells by the inflammatory reaction in asthma. The inhibitory effects of β_2-adrenergic receptor agonists were markedly attenuated after exposure of airway smooth muscle to S1P. The expression of adhesion molecules (VCAM-1, ICAM-1) were enhanced after exposure of human pulmonary microvascular endothelial cells to S1P. Adherence of eosinophil to the endothelial cells was also increased under this experimental condition. When an antigen was administrated to sensitized mice, eosinophils and inflammatory cytokines were significantly elevated around airways. Moreover, respiratory resistance in response to methacholine was markedly augmented. All of the phenomena were suppressed by Rho-kinase inhibitors. Hence, RhoA/Rho-kinase pathways may be contributed to the pathophysiology of asthma (β_2-adrenerigic desensitization, eosinophil inflammation, airway hyperresponsiveness etc) implicated in phonotype changes of the structural cells the airways. Rho-kinase may be target protein for asthma therapy.

1-磷酸鞘氨醇(S1P)在哮喘时通过炎症反应从肥大细胞中释放出来。β_2-肾上腺素能受体激动剂对S1P的抑制作用明显减弱。人肺微血管内皮细胞暴露于S1P后，黏附分子(VCAM-1、ICAM-1)表达增强。在此实验条件下，嗜酸性粒细胞与内皮细胞的粘附性也增加。当给致敏的小鼠注射抗原时，呼吸道周围的嗜酸性粒细胞和炎性细胞因子显著增加。此外，对乙酰甲胆碱的呼吸阻力显著增加。所有这些现象都被Rho-Kinase抑制剂抑制。因此，RhoA/Rho-Kinase通路可能参与了哮喘的病理生理过程(β_2-肾上腺素脱敏、嗜酸性粒细胞炎症、气道高反应性等)，参与了呼吸道结构细胞的表型改变。Rho-Kinase可能是哮喘治疗的靶蛋白。

项目成果

Role of Sphingosine-1-Phosphate in β-adrenoceptor Desensitization via Ca²⁺ Sensitization in Airway Smooth Muscle

1-磷酸鞘氨醇的作用

• DOI: 10.2332/allergolint.11-oa-0350
• 发表时间: 2012
• 期刊: Allergology International
• 影响因子: 6.8
• 作者: 似内郊雄;他14名;Makino Y
• 通讯作者: Makino Y

慢性閉塞性肺疾患の新たな表現型-好酸球性気道炎症と気道過敏性からみた病型分類

慢性阻塞性肺疾病新表型——基于嗜酸性气道炎症和气道高反应性的疾病类型分类

• 发表时间: 2012
• 作者: 久米裕昭;沖本奈美;深井有美;忌部 周;宮嶋宏之;西山 理;岩永賢司;東本有司;に鹿島宏和;東田有智
• 通讯作者: 東田有智

高齢者喘息の問題点～患者に適した治療を求めて～

老年人哮喘问题 - 寻找适合患者的治疗方法 -

• 发表时间: 2010
• 作者: 久米裕昭;東田有智
• 通讯作者: 東田有智

Actin Cytoskeleton Regulates Stretch-Activated Ca2+Influx in Human Pulmonary Microvascular Endothelial Cells

• DOI: 10.1165/rcmb.2009-0073oc
• 发表时间: 2010-07-01
• 期刊: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
• 影响因子: 6.4
• 作者: Ito, Satoru;Suki, Bela;Sokabe, Masahiro
• 通讯作者: Sokabe, Masahiro

好酸球性気道炎症に基づく吸入ステロイド薬の有効性 COPD と喘息:治療の接点

基于嗜酸性粒细胞性气道炎症 COPD 和哮喘的吸入皮质类固醇的疗效：治疗界面

• 发表时间: 2012
• 作者: 久米裕昭;東田有智
• 通讯作者: 東田有智