【摘要】：研究背景:支氣管哮喘(以下簡稱“哮喘”)是一種具有明顯異質(zhì)性的慢性氣道炎癥性疾病。哮喘具有可逆性的氣流受限、氣道高反應(yīng)性和慢性氣道炎癥等臨床特征。根據(jù)哮喘的臨床特征不同可以分為不同的臨床表型,如過敏性和非過敏性哮喘等等。不同臨床表型的哮喘其發(fā)病機(jī)制也有所不同,即存在“哮喘內(nèi)型”差別。不同的內(nèi)型可能解釋不同哮喘“表型”的病理生理過程。目前發(fā)現(xiàn)內(nèi)型為“Th2增高(Th2-high)”的患者,表現(xiàn)為過度增強(qiáng)的Th2型免疫應(yīng)答,Th2細(xì)胞過度活化及其相關(guān)細(xì)胞因子IL-4、IL-5等的產(chǎn)生增多,同時氣道以嗜酸性粒細(xì)胞浸潤為主。臨床上的過敏性哮喘為“Th2增高”的內(nèi)型,通常由吸入的過敏原所誘發(fā),具有明顯的Th2型免疫反應(yīng),同時伴有氣道內(nèi)嗜酸性粒細(xì)胞、肥大細(xì)胞和淋巴細(xì)胞聚集,氣道平滑肌的增生,以及血清Ig E的升高。IL-17A是一種主要由Th17細(xì)胞分泌的細(xì)胞因子,Th17細(xì)胞具有明顯區(qū)別于Th1、Th2細(xì)胞的特征,其分化受到IFN-γ和IL-4的負(fù)性調(diào)控。IL-17A的主要生物學(xué)作用是在機(jī)體內(nèi)通過引起中性粒細(xì)胞的聚集、活化,參與抵抗病原體的感染以及風(fēng)濕類疾病等。IL-17A是參與中性粒細(xì)胞炎癥非常重要的細(xì)胞因子。近年來研究發(fā)現(xiàn)哮喘患者的血和肺中IL-17A因子的濃度增高,并且和哮喘的嚴(yán)重程度相關(guān),提示IL-17A可能參與了哮喘慢性氣道炎癥的發(fā)生和發(fā)展,特別是與中性粒細(xì)胞性哮喘有關(guān)。國內(nèi)外多個研究中發(fā)現(xiàn)IL-17A具有促炎效應(yīng)以及一定的抑炎效應(yīng),即IL-17A可能存在雙重效應(yīng),研究中抑制炎癥的效應(yīng)可能是低濃度IL-17A所引起的。我們既往的研究發(fā)現(xiàn),利用IL-17A基因敲除小鼠建立OVA誘導(dǎo)的哮喘模型同時給予LPS氣道干預(yù)時較野生鼠的氣道嗜酸性粒細(xì)胞炎癥增高及脾臟Th2細(xì)胞分化增多。因此,我們假設(shè)IL-17A能通過直接抑制Th2細(xì)胞分化,減輕哮喘小鼠的氣道嗜酸性粒細(xì)胞炎癥。本研究通過OVA致敏和激發(fā)建立氣道嗜酸性粒細(xì)胞浸潤為主的哮喘小鼠模型,并觀察IL-17A對哮喘小鼠氣道嗜酸性粒細(xì)胞炎癥以及Th2型免疫的影響及其機(jī)制。研究目的:1.探索IL-17A在哮喘小鼠氣道炎癥中的作用,包括肺部炎癥細(xì)胞浸潤程度以及BALF中細(xì)胞分類和細(xì)胞因子的變化。2.探索IL-17A在哮喘小鼠支氣管淋巴結(jié)和脾臟以及體外培養(yǎng)中的Th2細(xì)胞分化中的作用。研究方法:第一章IL-17A對哮喘小鼠氣道炎癥的影響1.OVA誘導(dǎo)的哮喘小鼠模型的建立及氣道干預(yù)處理實驗分為三組,即對照組、模型組、IL-17A處理組。在建模第1、7天,模型組和IL-17A處理組小鼠腹腔注射OVA致敏,第14-18天用1%OVA霧化1h激發(fā),對照組均予以等量生理鹽水;IL-17A處理組小鼠每次激發(fā)前1h麻醉后氣道滴入100 ng IL-17A,對照組及模型組予以等量生理鹽水。2.BALF、肺組織標(biāo)本的檢測收集BALF液計細(xì)胞總數(shù),離心后上清用ELISA法檢測IL-4、IL-5、INF-γ、IL-17A濃度,所得沉淀涂片后染色行分類計數(shù);左肺切片后行HE及PAS染色,于顯微鏡下觀察進(jìn)行半定量評分。第二章IL-17A對哮喘Th2細(xì)胞分化的抑制作用及機(jī)制1.小鼠支氣管淋巴結(jié)及脾臟Th細(xì)胞分化的檢測制備淋巴結(jié)和脾臟單細(xì)胞懸液,刺激培養(yǎng)后利用流式細(xì)胞術(shù)檢測Th1/2/17的分化比例。2.IL-17A在體外誘導(dǎo)幼稚CD4+T細(xì)胞向Th2細(xì)胞分化中的抑制作用制備脾臟單細(xì)胞懸液,用免疫磁珠分選幼稚CD4+T細(xì)胞,用分化因子液加或者不加30 ng IL-17A同完全培養(yǎng)基一起培養(yǎng)細(xì)胞。在48h洗滌細(xì)胞后,用僅含IL-2的完全培養(yǎng)基繼續(xù)培養(yǎng)至96h。利用流式細(xì)胞術(shù)檢測培養(yǎng)24h、96h時Th細(xì)胞分化。利用Annexin V/PI法檢測孵育24h時細(xì)胞凋亡程度。相同的培養(yǎng)條件下利用CCK8法比較培養(yǎng)24h時的增殖活力。研究結(jié)果:第一章IL-17A對哮喘小鼠氣道炎癥的影響1.BALF中細(xì)胞總數(shù)及各類細(xì)胞計數(shù)及其比例的比較模型組較對照組小鼠BALF中的細(xì)胞總數(shù)高,具有顯著的統(tǒng)計學(xué)差異(P0.01),IL-17A處理組小鼠的BALF細(xì)胞總數(shù)明顯低于模型組小鼠(P0.05);模型組BALF嗜酸性粒細(xì)胞數(shù)(P0.05)和比例(P0.01)明顯高于對照組,而IL-17A處理組嗜酸性粒細(xì)胞數(shù)(P0.05)及其比例(P0.01)明顯低于模型組,但I(xiàn)L-17A處理組嗜酸性粒細(xì)胞數(shù)及其比例仍高于對照組(P0.01);模型組及IL-17A處理組中性粒細(xì)胞數(shù)及淋巴細(xì)胞數(shù)較對照組有升高趨勢,但差異無統(tǒng)計學(xué)意義(P0.05)。2.小鼠肺部支氣管和血管周圍炎癥浸的比較對照組小鼠肺部未見有明顯的炎癥細(xì)胞浸潤;模型組較對照組小鼠的支氣管周圍和血管周圍有更明顯的炎癥細(xì)胞浸潤,半定量評分更高(P0.01);予以IL-17A氣道滴入后,IL-17A處理組小鼠支氣管周圍和血管周圍炎癥浸潤程度明顯低于模型組小鼠,且炎癥評分有顯著的統(tǒng)計學(xué)差異(P0.05);相比對照組,IL-17A處理組小鼠肺部的炎癥浸潤仍較顯著(P0.01)。3.小鼠氣道杯狀細(xì)胞化生程度及半定量評分比較對照組小鼠的氣道中未見明顯的杯狀細(xì)胞化生;模型組小鼠氣道中較對照組可見更多的PAS陽性細(xì)胞,半定量評分具有顯著差異(P0.01);IL-17A處理組較模型組小鼠的氣道中杯狀細(xì)胞化生程度低(P0.01)。4.小鼠BALF中Th相關(guān)細(xì)胞因子的比較模型組小鼠BALF上清中的Th1相關(guān)因子IFN-γ濃度顯著低于對照組(P0.01),Th2相關(guān)因子IL-4、IL-5濃度顯著高于對照組(P0.01),IL-17A濃度也顯著高于對照組(P0.01);IL-17A處理組小鼠BALF中IL-4、IL-5濃度顯著低于模型組(P0.01),IL-17A濃度顯著高于模型組(P0.01),兩組之間IFN-γ濃度無顯著差異(P0.05);IL-17A處理組小鼠IL-4(P0.01)、IL-5(P0.05)濃度仍顯著高于對照組,IFN-γ濃度顯著低于對照組(P0.01),IL-17A濃度也顯著高于對照組(P0.01)。第二章IL-17A對哮喘Th2細(xì)胞分化的抑制作用及機(jī)制1.小鼠支氣管淋巴結(jié)中Th細(xì)胞分化的比較模型組小鼠淋巴結(jié)中Th1比例低于對照組(P0.01),Th2比例高于對照組(P0.05),兩組之間Th17比例無顯著性差異(P0.05);IL-17A處理組較模型組小鼠有更低的淋巴結(jié)Th2比例(P0.05),兩組Th1和Th17比例之間差異無統(tǒng)計學(xué)意義(P0.05);IL-17A處理組Th2比例顯著高于對照組小鼠(P0.05),Th1比例顯著低于對照組小鼠(P0.01),兩組小鼠Th17比例之間差異無統(tǒng)計學(xué)意義(P0.05)。2.小鼠脾臟Th細(xì)胞分化程度比較模型組小鼠脾臟Th1比例低于對照組(P0.01),Th2比例顯著高于對照組(P0.01),兩組Th17比例之間無顯著差異(P0.05);給予IL-17A氣道滴入后,IL-17A處理組小鼠脾臟Th2比例顯著低于模型組(P0.01),兩組之間Th1和Th17均無顯著差異(P0.05);IL-17A處理組小鼠脾臟Th1細(xì)胞比例仍低于對照組(P0.01),兩組之間Th17比例差異不顯著(P0.05)。3.IL-17A在體外誘導(dǎo)幼稚CD4+T細(xì)胞向Th2細(xì)胞分化中的抑制作用在24h時,Th2極化組和Th2+IL-17A極化組之間細(xì)胞凋亡和增殖均無顯著差異(P0.05)。Th2+IL-17A極化組中Th2細(xì)胞分化比例在培養(yǎng)24h時較Th2極化組呈下降趨勢(P0.05),在培養(yǎng)至96h,IL-17A明顯抑制Th2細(xì)胞分化(P0.01)。研究結(jié)論:1.給OVA復(fù)制的哮喘模型氣道滴入IL-17A后可減輕肺部嗜酸性粒細(xì)胞浸潤和降低BALF中Th2相關(guān)因子IL-4、IL-5的濃度。而且,不導(dǎo)致氣道中性粒細(xì)胞炎癥。2.哮喘小鼠中支氣管淋巴結(jié)和脾臟的Th2細(xì)胞比例明顯高于對照組,IL-17A氣道滴入后可以降低Th2細(xì)胞分化比例,而不影響Th1細(xì)胞比例。IL-17A在體外還可抑制幼稚CD4+T細(xì)胞向Th2細(xì)胞分化,而對其增殖和凋亡無顯著影響。研究意義:哮喘的“衛(wèi)生學(xué)說”認(rèn)為,兒童時期接觸細(xì)菌內(nèi)毒素等可以通過刺激Th1細(xì)胞分化,來抑制Th2的分化,改善Th2/Th1失衡,從而減少哮喘的發(fā)病。本文的研究證實了,通過氣道內(nèi)給予IL-17A處理,也可以抑制Th2的分化,改善哮喘氣道的嗜酸細(xì)胞性炎癥。因為細(xì)菌內(nèi)毒素是刺激機(jī)體Th17分化的重要原因。因此,本文結(jié)果豐富了對“衛(wèi)生學(xué)說”免疫調(diào)節(jié)機(jī)制的認(rèn)識。我們實驗室既往的研究顯示,過強(qiáng)的內(nèi)毒素刺激可以導(dǎo)致過強(qiáng)的Th17細(xì)胞反應(yīng),從而導(dǎo)致哮喘氣道的嗜酸細(xì)胞性炎癥轉(zhuǎn)換為中性粒細(xì)胞炎癥,給哮喘的治療帶來困難。但我們研究所有相對較低劑量的IL-17A處理哮喘模型,并沒有導(dǎo)致明顯的中性粒細(xì)胞炎癥。
[Abstract]:Background: bronchial asthma (hereinafter referred to as "asthma") is a chronic airway inflammatory disease with distinct heterogeneity. Asthma has the clinical characteristics of reversible airflow limitation, airway hyperresponsiveness, and chronic airway inflammation. The clinical characteristics of asthma can be divided into different clinical phenotypes, such as anaphylaxis and anaphylaxis. Asthma and so on. The pathogenesis of asthma in different clinical phenotypes is also different, that is, the difference in the "type of asthma type". Different internal types may explain the pathophysiological process of different asthma "phenotypes". The patients with "Th2 increase (Th2-high") "are currently found to be over enhanced Th2 type immune response and Th2 cell overactivity. The production of IL-4, IL-5, and other related cytokines are increased and the airway is mainly eosinophil infiltration. The clinical allergic asthma is the internal type of "Th2 increase", usually induced by inhaled allergens, with an obvious Th2 type immune response, accompanied by the accumulation of eosinophils, mast cells and lymphocytes in the airway. The proliferation of airway smooth muscle and the increase of Ig E in serum.IL-17A is a cytokine secreted mainly by Th17 cells. Th17 cells have distinct characteristics that are distinct from Th1, Th2 cells, and their differentiation by IFN- gamma and IL-4's negative regulation of.IL-17A is the main biological function of neutrophils in the body by causing aggregation and activation of neutrophils. .IL-17A, which is involved in resistance to pathogens and rheumatic diseases, is a very important cytokine involved in the inflammation of neutrophils. In recent years, it has been found that the concentration of IL-17A in the blood and lungs of the asthmatic patients is higher and is associated with the severity of asthma, suggesting that IL-17A may be involved in the occurrence and development of chronic airway inflammation in asthma. The development of IL-17A is particularly associated with neutrophil asthma. Many studies have found that IL-17A has a proinflammatory effect and a certain anti inflammatory effect, that is, IL-17A may have double effects. The effect of inhibition of inflammation in the study may be caused by low concentration of IL-17A. Our previous study found that the use of IL-17A gene knockout mice to establish OVA The induced asthma model also gave LPS airway intervention to increase airway eosinophil inflammation and splenic Th2 cell differentiation in the wild rats. Therefore, we hypothesized that IL-17A could reduce airway eosinophil inflammation in asthmatic mice by directly inhibiting the differentiation of Th2 cells. This study established airway eosinophilia through OVA sensitization and stimulation. The effect of IL-17A on airway eosinophil inflammation and Th2 type immunity in asthmatic mice and its mechanism were observed. 1. the purpose of this study was to explore the role of IL-17A in airway inflammation in asthmatic mice, including the degree of infiltration of inflammatory cells in the lungs, and the changes in cell classification and cytokine in BALF. 2. to explore the role of IL-17A in the differentiation of Th2 cells in bronchial lymph nodes, spleen and in vitro culture of asthmatic mice. Research methods: the first chapter: the effect of IL-17A on the airway inflammation in asthmatic mice, the establishment of 1.OVA induced asthma mice model and the airway intervention treatment were divided into three groups: the control group, the model group and the IL-17A treatment group. On day 1,7, the mice in the model group and the IL-17A treatment group were intraperitoneally sensitized by OVA, and 1H was stimulated with 1%OVA atomization on day 14-18. The control group was equal to the same amount of physiological saline; the airway was dropped into 100 ng IL-17A before each time of 1H anesthesia in the IL-17A treatment group and the control group and the model group were equal to the same amount of normal saline.2.BALF, and the detection collection of lung tissue specimens was collected BALF. The total number of cells in the liquid meter, after centrifugation, the concentration of IL-4, IL-5, INF- gamma, IL-17A was detected by ELISA method. After the precipitation smear, the staining was classified. The left lung slices were stained with HE and PAS, and the semi quantitative score was observed under the microscope. Second chapter IL-17A on the differentiation of asthma Th2 cells and mechanism 1. mice bronchial lymph node and spleen T. H cell differentiation was used to prepare the lymphoid and splenic single cell suspension. After stimulation, the differentiation ratio of Th1/2/17 was detected by flow cytometry,.2.IL-17A was used to induce the splenic single cell suspension in vitro induced by the inhibition of the immature CD4+T cells to the Th2 cell differentiation. The immunomagnetic beads were used to separate the infantile CD4+T cells, and the differentiation factor solution was added to the cell suspension. The cells were cultured together with the complete medium without 30 ng IL-17A. After 48h scrubbing cells, a complete medium containing only IL-2 was used to continue to be cultured to 96h. by flow cytometry to detect the differentiation of Th cells when 24h and 96h were cultured. Annexin V/PI method was used to detect the degree of apoptosis when incubating 24h. The effect of IL-17A on airway inflammation in asthmatic mice: the total number of cells and the number of cells in 1.BALF and the proportion of cells in the model group were higher than those in the control group of BALF, and there were significant statistical differences (P0.01). The total number of BALF cells in the IL-17A group was significantly lower than that of the model group. The BALF eosinophil number (P0.05) and proportion (P0.01) in the model group were significantly higher than that in the control group, but the eosinophil number (P0.05) and its proportion (P0.01) in the IL-17A treatment group were significantly lower than that in the model group, but the eosinophil number and the proportion of the IL-17A treated group were still higher than that of the control group (P0.01); the number of neutrophils in the model group and the IL-17A treatment group was more than that of the control group (P0.01). The number of eosinophils and the proportion of the IL-17A treatment group were still higher than the control group (P0.01). The number of neutrophils in the model group and the IL-17A treatment group was more than that of the control group (P0.01). There was no significant difference in the number of lymphocytes in the control group, but the difference was not statistically significant (P0.05). There was no obvious inflammatory cell infiltration in the lungs of the bronchi and blood vessels around the lung of the.2. mice. The model group had more obvious inflammatory cell infiltration around the bronchi and around the blood tube in the control group than the control group. The score was higher (P0.01). After IL-17A airway drip, the inflammatory infiltration around and around the bronchi in IL-17A treatment group was significantly lower than that in the model group, and the inflammatory score was significantly different (P0.05). Compared with the control group, the inflammatory infiltration in the lung of the IL-17A treatment group was still more significant (P0.01).3. mouse airway goblet cells No obvious goblet cell metaplasia was found in the airway of the control group. More PAS positive cells were found in the model group than the control group, and the semi quantitative score was significantly different (P0.01) in the model group. The IL-17A treatment group was lower than the goblet cell metaplasia in the model mice (P0.01).4. mice BALF The concentration of Th1 related factors IFN- gamma in BALF supernatant was significantly lower than that of control group (P0.01), and the concentration of Th2 related factor IL-4, IL-5 concentration was significantly higher than that of control group (P0.01), and IL-17A concentration was significantly higher than that of control group (P0.01), and the concentration of Th1 was significantly lower than that of the model group. The concentration of A was significantly higher than that of the model group (P0.01), and there was no significant difference in IFN- gamma concentration between the two groups (P0.05). The concentration of IL-4 (P0.01) and IL-5 (P0.05) in the IL-17A treatment group was still significantly higher than that of the control group. The concentration of IFN- gamma was significantly lower than the control group (P0.01), and the IL-17A concentration was significantly higher than that of the control group. The inhibitory effect of the second chapter on the differentiation of asthma cells was significantly higher than that of the control group. The proportion of Th1 in the lymph node of 1. mice was lower than that of the control group (P0.01), and the proportion of Th2 was higher than that of the control group (P0.05). There was no significant difference in the proportion of Th17 between the two groups (P0.05), and the IL-17A treatment group had lower lymph node Th2 ratio (P0.05), and the two groups of Th1 and Th17 ratios were between the two groups. The difference was not statistically significant (P0.05), the proportion of Th2 in the IL-17A treatment group was significantly higher than that of the control group (P0.05), and the proportion of Th1 was significantly lower than that of the control group (P0.01). There was no significant difference in the proportion of Th17 in the two groups (P0.05) the Th1 proportion of the spleen Th cells in the spleen of the mice was lower than that of the control group (P0.01), and the proportion of the spleen was lower than the control group. Significantly higher than the control group (P0.01), there was no significant difference in the proportion of Th17 between the two groups (P0.05). After the infusion of IL-17A airway, the proportion of Th2 in the spleen of the IL-17A treatment group was significantly lower than that in the model group (P0.01), and there was no significant difference between the Th1 and Th17 (P0.05) between the two groups (P0.05), and the proportion of the splenic Th1 cells in the IL-17A treatment group was still lower than that of the control group, between the two groups. The inhibition effect of.3.IL-17A on the differentiation of CD4+T cells to Th2 cells in vitro was not significant (P0.05). There was no significant difference in the cell apoptosis and proliferation between the Th2 polarization group and the Th2+IL-17A polarization group at 24h (P0.05) in the.Th2+IL-17A polarization group, the percentage of Th2 cells in the.Th2+IL-17A polarization group was lower than that in the Th2 polarization group. IL-17A significantly inhibited Th2 cell differentiation (P0.01) in the culture of 96h. Conclusions: 1. after IL-17A in the airway of the OVA replicated asthma model, the infiltration of eosinophils and the decrease of Th2 related factors IL-4, IL-5 concentration in BALF are reduced, and the bronchial lymph nodes and spleen in the asthmatic mice of airway neutrophilic granulocytic inflammation are not caused. The proportion of Th2 cells was significantly higher than that in the control group. The percentage of Th2 cell differentiation could be reduced after IL-17A airway drip, without affecting the proportion.IL-17A of Th1 cells to inhibit the differentiation of infant CD4+T cells to Th2 cells in vitro, but there was no significant effect on its proliferation and apoptosis. Endotoxin and so on can stimulate the differentiation of Th1 cells to inhibit the differentiation of Th2, improve the Th2/Th1 imbalance, and reduce the incidence of asthma. This study confirmed that IL-17A treatment in the airway can also inhibit the differentiation of Th2 and improve the eosinophilic inflammation in the airway of asthma, because bacterial endotoxin is the heavy stimulation of the body's Th17 differentiation. The results of this paper enrich the understanding of the immunomodulatory mechanism of the "health doctrine". Previous studies in our laboratory have shown that excessive endotoxin stimulation can lead to excessive Th17 cell responses, leading to the conversion of eosinophilic inflammation in the airway to neutrophil inflammation, but it is difficult for the treatment of asthma. We studied all the relatively low doses of IL-17A in the treatment of asthma models without causing significant neutrophil inflammation.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R562.25

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