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Research of sphingosine kinase modification in acute lung injury

鞘氨醇激酶修饰在急性肺损伤中的研究

基本信息

批准号：
18590848
负责人：
NISHIMURA Yoshihiro
金额：
$ 2.57万
依托单位：
Kobe 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

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590848/
关键词：
sphingosine 1-phosphate sphingosine kinase lung fibroblast bronchial asthma

项目摘要

The metabolism of sphingosine kinase (SPHK)/sphingosine 1-phosphate (SIP) system in lung diseases has been reported recently. In this project, we focused on the role of SPHK in lung epithelial cells and fibroblasts in injured lungs.1. We investigated the mechanism of myofibroblast differentiation in lung fibroblasts of acute lung injury. Bleomycin treatment increased SPHK expression and fibrotic changes in injured lungs. Our study reported that TGF-beta treatment increased SPHK1 activation in lung fibroblasts. S1P produced by SPHK1 induced the transactivation of S1P receptors and recruitment of activated RhoA. This data was accepted in Am J Respir Cell Mol Biol in 2007.2. Using mouse asthmatic model, we examined whether the effect of SPHK inhibitors attenuates airway inflammation. The inhalation of SPHK inhibitors by nebulizing maneuver showed significant decrease of airway hyperresponsiveness and eosinophilic inflammation induced by ovalbumin treatment, whereas intravenous delivery showed limited effects. Our data indicated that intratracheal treatment of SPHK inhibitor may be one of therapeutic approach for lung inflammation. This data was accepted in Am J Physiol Lung Cell Mol Physiol in 2008.3. In this animal model, we found that SPHK activity was increased in bronchial epithelial areas in asthmatic lungs. Then we examined the function of SPHK in goblet cell formation around epithelial walls. In vitro studies using airway liquid interface demonstrated that SPHK was activated and played a pivotal role in cell changes by IL-13 treatment. This data will be exhibited in American Thoracic Society in 2008. Thus, our studies clarified that SPHK works for morphological cell changes in lung inflammation.

鞘氨醇激酶（SPHK）/1-磷酸鞘氨醇（SIP）系统在肺部疾病中的代谢是近年来研究的热点。本课题主要研究SPHK在肺损伤后肺上皮细胞和成纤维细胞中的作用.我们研究了急性肺损伤肺成纤维细胞中肌成纤维细胞分化的机制。博来霉素治疗增加SPHK表达和损伤肺的纤维化变化。我们的研究报告，TGF-β治疗增加肺成纤维细胞中SPHK 1的活化。SPHK 1产生的S1 P诱导S1 P受体的反式激活和激活的RhoA的募集。该数据于2007年2月被Am J Respir Cell Mol Biol接受。使用小鼠哮喘模型，我们检查SPHK抑制剂的作用是否减轻气道炎症。雾化吸入SPHK抑制剂可显著降低卵白蛋白诱导的气道高反应性和嗜酸性粒细胞炎症，而静脉给药效果有限。提示肺内注射SPHK抑制剂可能是治疗肺部炎症的一种方法。该数据于2008年3月被Am J Physiol Lung Cell Mol Physiol接受。在该动物模型中，我们发现SPHK活性在哮喘肺的支气管上皮区域增加。然后我们研究了SPHK在上皮细胞壁周围杯状细胞形成中的功能。使用气道液体界面的体外研究表明，SPHK被激活，并在IL-13处理的细胞变化中发挥关键作用。该数据将于2008年在美国胸科学会上展出。因此，我们的研究阐明了SPHK对肺部炎症中的形态学细胞变化起作用。