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Identification of transcription factors of contractile element of bronchial smooth muscle and its change in activity at airway hyperresponsiveness

支气管平滑肌收缩元件转录因子的鉴定及其在气道高反应性时的活性变化

基本信息

批准号：
18590246
负责人：
MISAWA Miwa
金额：
$ 2.45万
依托单位：
Hoshi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

The mechanisms of pathogenesis of airway hyperresponsiveness(AHR) in allergic bronchial asthma were investigated pharmacologically and molecular biologically. The following results were obtained.1. The contractile responsiveness to endothelin-1(ET-1) was increased in the bronchi isolated from rats subjected with repeated antigen challenges. In the augmented ET-1-induced contractility an increase in Ca^<2+> sensitization phenomenon was involved ; phosphorylations(activations) of CTI-17 and myosin light chain kinase were enhanced. 2. The expressions and activations of matrix metalloproteinase(MMP)-12 mRNA and protein of bronchial muscle were increased by repeated antigen challenges, suggesting that MMP-12 is responsible for ABR. 3. The probable transcription factors in bronchial smooth muscle which are activated by antigen exposure were examined covering it using nuclear extraction of the muscle by the method of protein/DNA array method. Among the transcription factors activated by exposuring antigen, it was found that USF-1, Sp1, NF-El, STAT5 and STAT6 are the transcription factors that have potency to bind to the elements of RhoA promoter area 4. Interleukin-13 was demonstrated to induce AHR through the transcription factor STAT6. 5. Lovastatin, one of the statins, when administered in vivo, inhibited the AHR in rats generated by repeated antigen challenges ex they It was shown that at that time, lovastatin also inhibited the translocation of RhoA to cell membrane. These findings suggest that statins may be effective for improvement of AHR in patients with bronchial asthma. 6. It was also suggested that glucocorticoids exert effectiveness for bronchial asthma by inhibiting the RhoA upregulation seen in the bronchial smooth muscle at antigen-exposure.

本文从分子生物学角度探讨了过敏性支气管哮喘气道高反应性（AHR）的发病机制。得到以下结果.在反复抗原激发的大鼠离体支气管中，对内皮素-1（ET-1）的收缩反应性增加。在增强的ET-1诱导的收缩中，涉及Ca^<2+>敏化现象的增加; CTI-17和肌球蛋白轻链激酶的磷酸化（激活）增强。2.反复抗原刺激后，支气管肌基质金属蛋白酶（MMP-12）mRNA和蛋白的表达和活化均增加，提示MMP-12参与了ABR的发生。3.应用蛋白质/DNA芯片技术，对支气管平滑肌细胞核进行了覆盖，研究了抗原暴露后支气管平滑肌细胞中可能被激活的转录因子。在由抗原激活的转录因子中，发现USF-1、Sp1、NF-E1、STAT 5和STAT 6是具有与RhoA启动子区4的元件结合的效力的转录因子。白细胞介素-13被证明通过转录因子STAT 6诱导AHR。5.他汀类药物之一的洛伐他汀在体内给药时，可抑制由抗原反复攻击所产生的大鼠AHR。这些结果表明，他汀类药物可能是有效的改善支气管哮喘患者的AHR。6.还表明糖皮质激素通过抑制抗原暴露时在支气管平滑肌中观察到的RhoA上调而对支气管哮喘发挥有效性。