Optimization of dosing schedule of daily inhalant dexamethasone to minimize phase shifting of clock gene expression rhythm in the lungs of the asthma mouse model
Optimization of dosing schedule of daily inhalant dexamethasone to minimize phase shifting of clock gene expression rhythm in the lungs of the asthma mouse model
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DOI：
10.1210/en.2007-0010
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发表时间：
2007-07-01
期刊：
影响因子：
4.8
通讯作者：
Shibata, Shigenobu
中科院分区：
文献类型：
--
作者：
Hayasaka, Naomi;Yaita, Tsuyoshi;Shibata, Shigenobu
糖皮质激素受体激动剂如地塞米松（DEXA）已被推荐用于治疗哮喘。对于严重或无法控制的哮喘病例，增加这些药物的给药频率似乎更可取。本实验的目的是找到基于慢性给药的DEXA吸入的适当给药方案（频率和时间），以最大限度地减少卵清蛋白治疗的哮喘小鼠肺中时钟功能的相移。时钟基因表达的每日节律在对照组和卵清蛋白处理的小鼠之间是相似的。急性吸入DEXA显著增加mPer1基因在小鼠肺中的表达，而不是肝脏。每日暴露的DEXA在zeitgeber时间0（灯）或在zeitgeber时间18（6小时后，熄灯）6天造成的相位提前或相位延迟的生物发光的节奏在肺部，分别类似于光诱导的运动活动节律的相移。每日zeitgeber时间0暴露于DEXA减弱了mClca3基因的表达水平，这与粘液过度产生有关，并且存在mClca3节律的相位推进峰值时间。目前的结果表明，选择一天中最合适的时间进行DEXA的雾化给药，以尽量减少不良反应，如在哮喘肺的时钟功能的相移的重要性。这是第一个报告的一个成功的协议，可以获得在离体外周器官在体内的时钟基因表达节律的相移。
Glucocorticoid receptor agonists such as dexamethasone ( DEXA) have been recommended for the treatment of asthma. An increased frequency of dosing with these drugs seems preferable for cases of severe or uncontrolled asthma. The purpose of this experiment was to find the appropriate dosing schedule ( frequency and timing) for DEXA inhalation based on chronotherapeutic dosing to minimize phase shifts of clock function in the lungs of the ovalbumin-treated asthmatic mouse. The daily rhythm of clock gene expression was similar between control and ovalbumin-treated mice. Acute inhalation of DEXA significantly increased mPer1 gene expression in the lungs but not the liver of mice. Daily exposure of DEXA at zeitgeber time 0 ( lights on) or at zeitgeber time 18 ( 6 h after lights off) for 6 d caused a phase advance or phase delay of bioluminescence rhythm in the lungs, respectively, similar to light-induced phase shifts in locomotor activity rhythm. Daily zeitgeber time 0 exposure to DEXA attenuated the expression level of the mClca3 gene, which is associated with mucus overproduction, and there was a phase-advancing peak time of the mClca3 rhythm. The present results denote the importance of selecting the most appropriate time of day for nebulizer administration of DEXA to minimize adverse effects such as the phase shifting of clock function in asthmatic lungs. This is the first report of a successful protocol that could obtain phase shifts of clock gene expression rhythm in isolated peripheral organs in vivo.