發(fā)布時間：2018-05-07 06:42

  本文選題：哮喘 + 甲苯二異氰酸酯��； 參考：《南方醫(yī)科大學(xué)》2017年博士論文

【摘要】：背景及目的甲苯二異氰酸酯(TDI)是哮喘重要的致病因素之一。其所致的哮喘主要病理特征為氣道中性粒和嗜酸性粒細胞浸潤及氣道重塑,然具體發(fā)病機制不明。研究表明,晚期糖基化終末產(chǎn)物受體(RAGE)及β-catenin信號在哮喘發(fā)病中扮演重要角色,但其在TDI哮喘中的作用尚未闡明。本研究意在探討RAGE和β-catenin在TDI哮喘中的作用及其中機制。內(nèi)容與方法一、建立TDI哮喘模型第1、8天用0.3%TDI經(jīng)小鼠耳背皮膚致敏,第15、18、21天霧化吸入激發(fā),按激發(fā)所用TDI濃度及次數(shù)分組:①1%TDI1組:第15天用1%TDI激發(fā)1次;②1%TDI2組:第15、18天用1%TDI激發(fā)2次;③1%TDI3組:第15、18、21天用1%TDI激發(fā)3次;④3%TDI1組:第15天用3%TDI激發(fā)1次;⑤3%TDI2組:第15、18天用3%TDI激發(fā)2次;⑥3%TDI3組:第15、18、21天用3%TDI激發(fā)3次。檢測各組小鼠的氣道反應(yīng)性、氣道周圍炎癥細胞、血清IgE、Th1/Th2炎癥指標。二、在TDI哮喘模型上干預(yù)RAGE按“一”中的方法建立TDI哮喘小鼠模型,激發(fā)前經(jīng)腹腔給RAGE拮抗劑[FPS-ZM1及RAGE antagonist peptide(RAP)],觀察各項哮喘指標的變化,同時檢測肺組織內(nèi)β-catenin的表達和分布情況。三、體內(nèi)干預(yù)β-catenin信號構(gòu)建TDI哮喘小鼠模型,自第1次激發(fā)開始連續(xù)7天每天給小鼠腹腔注射β-catenin信號阻斷劑(XAV-939及ICG-001),觀察各項哮喘指標的變化。結(jié)果--一、皮膚致敏后經(jīng)霧化吸入3%TDI激發(fā)3次可建立TDI哮喘模型與對照相比,1%TDI1、1%TDI2及3%TDI1組的氣道反應(yīng)性無明顯增高,氣道周圍幾無炎癥浸潤,淋巴上清IL-4、IFN-γ及血清IgE水平亦不高;1%TDI3及3%TDI2組的氣道周圍可見少許炎癥細胞,BALF中性粒細胞數(shù)目稍增多,但氣道高反應(yīng)性、IL-4及IFN-γ水平都不高;3%TDI3組的氣道反應(yīng)性增高,支氣管周圍炎癥細胞浸潤明顯,BALF中炎癥細胞顯著增多,IL-4、IFN-γ及IgE均升高。二、阻斷RAGE可減輕TDI哮喘小鼠氣道炎癥并抑制TDI誘導(dǎo)的β-catenin活化拮抗RAGE可下調(diào)TDI哮喘小鼠RAGE及其配體的表達,減輕TDI誘導(dǎo)的氣道高反應(yīng)性及氣道周圍炎癥浸潤,減少BALF中炎癥細胞數(shù)目,并抑制Th2炎癥。同時我們發(fā)現(xiàn),β-catenin在TDI哮喘小鼠肺組織細胞膜上的表達減少,在胞漿及胞核的表達增多;與此一致的是,磷酸化Akt(Ser473)、磷酸化GSK3β(Ser9)及活化的β-catenin水平均升高,而使用RAGE抑制劑可以部分逆轉(zhuǎn)上述這些表現(xiàn),同時下調(diào)TDI誘導(dǎo)的β-catenin靶基因表達。三、阻斷β-catenin信號可減輕TDI哮喘小鼠氣道炎癥β-catenin抑制劑明顯減輕了 TDI哮喘小鼠的氣道高反應(yīng)性、氣道炎癥、氣道上皮細胞杯狀化生及上皮下膠原沉積,降低了 Th1/Th2炎癥介質(zhì)的水平。結(jié)論一、致敏后再經(jīng)霧化吸入激發(fā)可成功建立TDI哮喘模型;二、RAGE參與了 TDI哮喘發(fā)病,并參與穩(wěn)定β-catenin信號;三、β-catenin參與調(diào)控TDI哮喘氣道炎癥及氣道重塑。
[Abstract]:Background and objective toluene diisocyanate (TDI) is one of the important pathogenic factors of asthma. The main pathological features of asthma were airway neutrophil and eosinophil infiltration and airway remodeling. It has been shown that the advanced glycosylation end product receptor rage) and 尾 -catenin signal play an important role in the pathogenesis of asthma, but its role in TDI asthma has not been clarified. The purpose of this study was to investigate the role and mechanism of RAGE and 尾-catenin in TDI asthma. Contents and methods: 1. The TDI asthma model was sensitized with 0.3%TDI on the first day of the eighth day by the skin of the mouse's dorsal ear, and then stimulated by atomization inhalation on the 21st day of the 15th day. According to the concentration and times of the TDI used in the stimulation, the mice were divided into two groups: group 1: the TDI was stimulated once with 1%TDI on the 15th day; 21%TDI2 group: on day 1518, 1%TDI was used to excite twice and 31TDI3 group: on the 15th day 1821 days, 3 times with 1%TDI, 3 times with TDI1 group: on the 15th day with 3%TDI, once with 53TDI2 group: on the 15th day with 3%TDI, 2 times with 3%TDI, 3 times with 3%TDI. The airway reactivity, inflammatory cells around the airway and serum IgE Th1 / Th2 inflammation index were measured in each group. Secondly, the mouse model of TDI asthma was established by intervention of RAGE on TDI asthma model according to the method of "one". The changes of asthma indexes were observed by intraperitoneal administration of RAGE antagonists (FPS-ZM1 and RAGE antagonist peptidea Rapp) before stimulation, and the expression and distribution of 尾 -catenin in lung tissue were detected. 3. TDI asthma model was established by in vivo intervention of 尾 -catenin signal. The mice were injected intraperitoneally with 尾 -catenin signal blocker (XAV-939) and ICG-001 (ICG-001) every day since the first stimulation for 7 days to observe the changes of asthma indexes. Results: first, the airway reactivity of 1 TDI 1 TDI 2 and 1 TDI 2 and 3%TDI1 group was not significantly increased and there was no inflammatory infiltration around the airway in the model of TDI asthma induced by atomization inhalation of 3%TDI 3 times after skin sensitization compared with the control group. The levels of IL-4, IFN- 緯 and serum IgE in the lymphoid supernatant were also not high. In the TDI3 and 3%TDI2 groups, the number of inflammatory cells and neutrophils was slightly increased, but the levels of IL-4 and IFN- 緯 in the airway hyperreactivity were not high and the airway reactivity was increased in the TDI3 group. The infiltration of inflammatory cells around the bronchus was obvious and the number of inflammatory cells in BALF was significantly increased. The levels of IFN- 緯 and IgE in BALF were higher than those in BALF. Second, blocking RAGE could reduce airway inflammation in TDI asthmatic mice and inhibit 尾 -catenin activation induced by TDI. Antagonistic RAGE could down-regulate the expression of RAGE and its ligand in TDI asthmatic mice, reduce the airway hyperresponsiveness induced by TDI and the infiltration of inflammation around the airway. Reduce the number of inflammatory cells in BALF and inhibit Th2 inflammation. At the same time, we found that the expression of 尾 -catenin in lung cell membrane of TDI asthmatic mice was decreased, and the expression of 尾 -catenin in cytoplasm and nucleus was increased, which was consistent with the increase of phosphorylated GSK3 尾 -Ser9 and activated 尾 -catenin. RAGE inhibitor could partially reverse these findings and down-regulate 尾 -catenin target gene expression induced by TDI. Thirdly, blocking 尾 -catenin signal could reduce airway inflammation, airway hyperresponsiveness, airway inflammation, goblet metaplasia and collagen deposition in TDI asthmatic mice. The level of Th1/Th2 inflammatory mediators was decreased. Conclusion: first, the model of TDI asthma can be successfully established after sensitization and then stimulated by atomization inhalation; second, rage is involved in the pathogenesis of TDI asthma and participate in the stabilization of 尾 -catenin signal; third, 尾 -catenin is involved in regulating airway inflammation and airway remodeling of TDI asthma.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R562.25

【相似文獻】

相關(guān)期刊論文 前10條

1 石磊;抗哮喘氣道炎癥藥物的研究近況[J];浙江中西醫(yī)結(jié)合雜志;2001年03期

2 倪偉;抗哮喘氣道炎癥藥物的研究近況及對策[J];中國中醫(yī)藥信息雜志;2001年S1期

3 楊炯,涂海燕,李清泉;茶堿對哮喘氣道炎癥的作用(英文)[J];Acta Pharmacologica Sinica;2001年05期

4 高寶安;哮喘氣道炎癥與炎性細胞凋亡[J];山西醫(yī)藥雜志;2002年03期

5 李寅,馬福家;一氧化氮與哮喘氣道炎癥實驗研究[J];東南國防醫(yī)藥;2004年01期

6 王力寧;鐘華;;中醫(yī)藥對哮喘氣道炎癥防治研究概況[J];四川中醫(yī);2006年06期

7 靳英麗;李琦;韓軍;魯繼榮;;過氧化物酶體增殖物激活受體γ在哮喘氣道炎癥中的作用[J];中國實驗診斷學(xué);2007年09期

8 毛山;痰液分析在哮喘氣道炎癥研究中的應(yīng)用[J];國外醫(yī)學(xué).呼吸系統(tǒng)分冊;1996年04期

9 張偉;哮喘氣道炎癥的非創(chuàng)傷性檢測[J];國外醫(yī)學(xué).呼吸系統(tǒng)分冊;1997年03期

10 鄧火金,陳晶,孫濱;哮喘氣道炎癥非創(chuàng)傷性監(jiān)測方法的探討[J];醫(yī)師進修雜志;1998年12期

相關(guān)會議論文 前8條

1 廖華;陳榮昌;;呼吸道病毒感染對哮喘氣道炎癥的影響[A];中華醫(yī)學(xué)會呼吸病學(xué)年會——2013第十四次全國呼吸病學(xué)學(xué)術(shù)會議論文匯編[C];2013年

2 華雯;夏麗霞;田寶平;金嫣;陳志華;李雯;沈華浩;;細胞自噬在哮喘氣道炎癥和嗜酸粒細胞分化中的作用研究[A];中華醫(yī)學(xué)會呼吸病學(xué)年會——2013第十四次全國呼吸病學(xué)學(xué)術(shù)會議論文匯編[C];2013年

3 楊悅;陳平;;哮喘氣道炎癥與COX-2表達[A];第七屆全國老年醫(yī)學(xué)學(xué)術(shù)會議暨海內(nèi)外華人老年醫(yī)學(xué)學(xué)術(shù)會議論文匯編[C];2004年

4 甄國華;康冠楠;顧乃兵;趙建平;徐永健;張珍祥;;Intelectin在哮喘氣道炎癥中的作用[A];中華醫(yī)學(xué)會第七屆全國哮喘學(xué)術(shù)會議暨中國哮喘聯(lián)盟第三次大會論文匯編[C];2010年

5 李亞男;盧清華;成煥吉;;柔嫩梭菌誘導(dǎo)Treg活化在哮喘氣道炎癥中的作用[A];中華醫(yī)學(xué)會第十三屆全國兒科呼吸學(xué)術(shù)會議論文匯編[C];2012年

6 席云祝;樊慧珍;于化鵬;鄧火金;夏虎;龔雨新;;caspase-1活化在哮喘氣道炎癥中的作用[A];中華醫(yī)學(xué)會呼吸病學(xué)年會——2013第十四次全國呼吸病學(xué)學(xué)術(shù)會議論文匯編[C];2013年

7 鮑燕敏;劉燦霞;鄭躍杰;王莉;劉萍;;呼出氣一氧化氮對兒童哮喘氣道炎癥水平評估作用的前瞻性研究[A];中華醫(yī)學(xué)會第十七次全國兒科學(xué)術(shù)大會論文匯編（上冊）[C];2012年

8 鮑燕敏;劉燦霞;鄭躍杰;王莉;劉萍;;呼出氣一氧化氮對兒童哮喘氣道炎癥水平評估作用的前瞻性研究[A];中華醫(yī)學(xué)會第十三屆全國兒科呼吸學(xué)術(shù)會議論文匯編[C];2012年

相關(guān)重要報紙文章 前3條

1 胡德榮;上海瑞金醫(yī)院揭示哮喘氣道炎癥中的抗炎新機制[N];中國醫(yī)藥報;2007年

2 衣曉峰;李建輝;測ECP可評估哮喘氣道炎癥[N];中國醫(yī)藥報;2003年

3 張超群；范曉莉;NO對哮喘氣道炎癥具有調(diào)控作用[N];中國醫(yī)藥報;2004年

相關(guān)博士學(xué)位論文 前10條

1 李鴻佳;槲皮素通過TLR4/NF-κB信號調(diào)節(jié)哮喘氣道炎癥機制研究[D];山東大學(xué);2015年

2 廉倩倩;胸腺免疫抑制五肽TIPP的抗哮喘氣道炎癥作用及其機制研究[D];山東大學(xué);2015年

3 姚利紅;晚期糖基化終末產(chǎn)物受體通過穩(wěn)定β-catenin信號參與調(diào)控TDI哮喘氣道炎癥[D];南方醫(yī)科大學(xué);2017年

4 王彰暉;哮喘氣道炎癥中的肺局部淋巴細胞的記憶[D];四川大學(xué);2004年

5 韓偉;過氧化物酶體增殖物活化受體γ在哮喘氣道炎癥和重建中的作用[D];復(fù)旦大學(xué);2006年

6 喬峗;龍，

本文編號：1855813