1、咪喹莫特對小鼠哮喘模型氣道炎癥和STAT6表達的影響            咪喹莫特對小鼠哮喘模型氣道炎癥和STAT6表達的影響    2008-5-9 12:19:21                      

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3、160;              作者：金淑賢，殷凱生，卞濤，陳子慶     【關鍵詞】  哮喘        Effects of imiquimod on airway inflammation and STAT6 expression in mouse models of asthma    【Abs

4、tract】 AIM:  To observe the effects of aerosol imiquimod on the antigeninduced airway inflammation and the expressions of Th2type chemokines Eotaxin, macrophagederived chemokine  (MDC) and thymus and activation regulated chemokine (TARC) in mouse models of asthma. METHODS:  Imiquimod

5、and dexamethasone were administered to immunized mice before antigen challenge. At 24 h after the final OVA inhalation, the left superior lung tissue was taken, HE stained and the changes of inflammation were observed. Bronchial alveolar lavage fluid (BALF) was collected to count the number of cells

6、 and classify them. The expressions of signal transducers and activators of transcription 1(STAT1) and signal transducers and activators of transcription 6(STAT6) in lungs were detected by immunohistochemistry and western blot. The mRNA expressions of STAT1, STAT6, IL4, eotaxin and IFN   i

7、n lungs were examined by reverse transcriptasepolymerase chain reaction. RESULTS: Imiquimod and dexamethasone attenuated the airway inflammation of asthmatic mice. Imiquimod decreased the totol cell counts, EOS and lymphocyte counts in BALf. The expressions of STAT1 and STAT6 were  mainly on th

8、e bronchial epithelium. STAT1 and STAT6 proteins and mRNA levels increased in lung tissues in asthma group. Imiquimod significantly reduced STAT1 and STAT6 protein and mRNA expression. Dexamethasone significantly reduced the levels of STAT6 protein and mRNA, but failed to inhibit the expression of S

9、TAT1. Imiquimod modulated the Th1/Th2 response by enhancing Th1 cytokine IFN  mRNA and inhibiting the Th2 cytokine IL4 mRNA expression in lung tissues. CONCLUSION:   Imiquimod aerosol inhalation may inhibit antigeninduced airway inflammation and decrease the over expression of STAT6 p

10、rotein and mRNA  in asthmatic mouse but has no influence on STAT1 expression.    【Keywords】 asthma; signal transducers and activator  of transcription 1; signal transducers and activator of transcription 6; imiquimod    【摘要】 目的： 觀察咪喹莫特對小鼠哮喘模型氣道炎癥和肺組織

11、信號轉導與轉錄激活因子1（STAT1）和STAT6表達的影響. 方法： 建立哮喘模型，自14 d時霧化吸入OVA前0.5 h， 干預組分別霧化吸入咪喹莫特30 min及ip地塞米松. OVA霧化結束后24 h取左上葉肺組織做HE染色觀察肺組織炎癥改變；收集肺泡灌洗液進行細胞計數和分類；用免疫組化和West blot方法檢測肺組織STAT1和STAT6的表達；用逆轉錄聚合酶鏈反應半定量檢測肺組織STAT1, STAT6, IL4, eotaxin和IFN   mRNA表達水平. 結果： HE染色示地塞米松組和咪喹莫特組小鼠肺組織炎癥程度較哮喘小鼠減輕. 哮喘組小鼠BALF中細

12、胞總數及各種炎癥細胞較正常組顯著增加，咪喹莫特治療組嗜酸性粒細胞、淋巴細胞比哮喘組明顯減少(P<0.01). STAT1和STAT6均在氣道上皮細胞表達，哮喘組肺組織STAT1和STAT6表達較正常組增強，咪喹莫特組STAT1表達與哮喘組無明顯區別，較正常組增加. 哮喘組小鼠肺組織STAT1, STAT6, eotaxin, IL4 mRNA表達較正常組增強(P<0.01), IFN  mRNA表達減少，咪喹莫特組STAT1 mRNA表達與哮喘組無明顯區別，STAT6, eotaxin和IL4 mRNA的表達較哮喘組降低，較正常組增加,IFN  mRNA表達較哮

13、喘組增加，但低于正常組. 結論： 霧化吸入咪喹莫特可在一定程度上減輕哮喘小鼠的氣道炎癥，抑制肺組織STAT6蛋白和mRNA的過度表達.    【關鍵詞】 哮喘；信號轉導與轉錄激活因子1；信號轉導與轉錄激活因子6；咪喹莫特    0引言    哮喘是一種由嗜酸性粒細胞，淋巴細胞以及肥大細胞等多種炎癥細胞參與的復雜氣道炎癥性疾病，在這一炎癥反應過程中T細胞是重要的啟動與調節細胞. 目前多項研究表明，哮喘是一種Th2型細胞優勢反應的疾病，表現為Th2型細胞因子的表達增多. 而轉錄信號轉導子和激活子（STAT）的激活，是細胞因子發揮生物學作用的重要環節. STAT6缺乏的小鼠無法誘發氣道高反應性和嗜酸性粒細胞性氣道炎癥1-2，研究證實氣道高反應性的發生需要IL4介導的信號傳導通路和信號分子STAT6的參與3. 咪喹莫特是一種免疫調節劑，它能促進培養的T淋巴細胞產生IL12和IFN，抑制IL4和IL5的表達4，使原始Th細胞向Th1細胞分化，提示咪喹莫特可能對治療以Th2反應為主的支氣管哮喘有效. 鑒于