罗红霉素通过缺氧诱导因子-1α对吸烟哮喘小鼠组蛋白去乙酰化酶表达的影响

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (6): 606-610.

罗红霉素通过缺氧诱导因子-1α对吸烟哮喘小鼠组蛋白去乙酰化酶表达的影响

徐慧,戴元荣,夏梦玲

温州医科大学附属第二医院

收稿日期:2014-09-04 修回日期:2014-10-07 出版日期:2015-06-26 发布日期:2015-06-29
通讯作者: 戴元荣 E-mail:daiyr@126.com
基金资助:
Caveolae和caveolae-1在哮喘大鼠气道平滑肌重塑中的作用及罗红霉素对caveolae-1表达的影响;PI3K/HDAC2在吸烟哮喘大鼠中的作用及药物的调控

The effect of Roxithromycin on expressions of HDAC2 though HIF-1α in smoking asthma mice

Received:2014-09-04 Revised:2014-10-07 Online:2015-06-26 Published:2015-06-29

摘要/Abstract

摘要： 【摘要】目的探讨罗红霉素通过缺氧诱导因子-1α（HIF-1α）对吸烟哮喘小鼠组蛋白去乙酰化酶（HDAC2）表达的影响。方法 SPF级雌性BALB/c小鼠40只，按随机数字表法随机平均分为正常对照组、哮喘组、吸烟哮喘组，罗红霉素干预4组。用卵白蛋白（OVA）致敏和激发的方法制备哮喘和吸烟哮喘模型，其中吸烟哮喘组在激发后置于自制熏箱内被动吸烟，对照组则用生理盐水代替OVA。分析支气管肺泡灌洗液（BALF）中的细胞分类计数；观察各组小鼠肺组织病理学变化；酶联免疫吸附（ELISA）法测定BALF中肿瘤坏死因子（TNF）-α水平，并采用Western blot测定各组小鼠肺组织中HIF-1α及HDAC2表达情况，并作相关性分析。结果哮喘组和吸烟哮喘组嗜酸性粒细胞，中性粒细胞，淋巴细胞，巨噬细胞计数比例与正常对照组相比有显著性差异（P<0.01），吸烟哮喘组中性粒细胞计数比例显著高于哮喘组（P<0.01）；罗红霉素干预组嗜酸性粒细胞，中性粒细胞，淋巴细胞计数比例与吸烟哮喘组相比有显著性差异（P<0.01）。哮喘组和吸烟哮喘组肺组织HIF-1α表达均显著高于对照组（0.67±0.03、0.85±0.07比0.42±0.03）且吸烟哮喘组显著高于哮喘组,罗红霉素干预组（0.52±0.05）低于吸烟哮喘组（均P<0.01）；哮喘组和吸烟哮喘组肺组织HDAC2表达均显著低于对照组（2.04±0.12、1.74±0.06比3.93±0.08）(均P<0.01)且吸烟哮喘组显著低于哮喘组，罗红霉素干预组（2.53±0.09）高于吸烟哮喘组（均P<0.05）。吸烟哮喘组肺组织中HIF-1α与HDAC2的表达呈显著负相关（r=－0.879，P<0.01）吸烟哮喘组BALF中TNF-α水平显著高于哮喘组、对照组（均P<0.01），罗红霉素干预组TNF-α水平显著低于吸烟哮喘组（P<0.01）。结论罗红霉素可能通过抑制HIF-1α的表达上调吸烟哮喘小鼠HDAC2，从而改善气道炎症。

Abstract: 【Abstract】 Objective To explore the effect of Roxithromycin on expression of HDAC2 though HIF-1α in smoking asthma mice.Methods Forty female SPF BALB/c mice were divided randomly into 4 groups: control group (group C), asthma group (group A) ,smoking asthma group (group S) and Roxithromycin group(group R). To establish asthmatic and smoking asthma models with challenge of OVA and intervention with Roxithromycin. The different cells counts of bronchoalveolar fluid (BALF) were analysed. The change of pathematology in different groups were observed. The level of TNF-α in BALF was detected by Sand-wich ELISA.The level of HIF-1α and HDAC2 in lung homogenate were measured by Western blot. Results The ratios of eosinophil (EOS) neutrophile (Neu) 、lymphocyte（Lym）to the total cell numbers of BALF in group A and group S were significantly higher than that in group C (all P<0.01), while in group S the ratio of Neu was higher than that in group A (P<0.01). The ratio of EOS、Neu and Lym in group R were significantly decreased than those in group S (all P<0.01).Western blot showed the expression of HIF-1α in lung homogenate of group A（0.67±0.03）and group S(0.85±0.07) were higher than those in group C（0.42±0.03）.Meantime the expression of HIF-1α in group S was higher than that of group A , while the expression of HIF-1α in group R was lower than that of group S(all P<0.01).The expressions of HDAC2 in group A and group S were significantly decreased than those in group C (both P<0.01), while the HDAC2 level of group S was lower than that of group A and its level in group R was higher than that in group S (both P<0.05). There were significantly negative correlations between the expressions of HIF-1α and HDAC2 (r=－0.879，P<0.01)in lung .The level of TNF-α in BALF of group S was significantly higher than those of group A and group C,but it in group R was decreased than that in group S (all P<0.01). Conclusion Roxithromycin can decrease the airway inflammation of cigarette smoking asthma mice via increasing the expression of HDAC2 by down-regulating the expression of HIF-1α.

徐慧, 夏梦玲, 戴元荣. 罗红霉素通过缺氧诱导因子-1α对吸烟哮喘小鼠组蛋白去乙酰化酶表达的影响[J]. 中国临床药理学与治疗学, 2015, 20(6): 606-610.

XU Hui, XIA Meng-Ling, DAI Yuan-Rong. The effect of Roxithromycin on expressions of HDAC2 though HIF-1α in smoking asthma mice[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(6): 606-610.