發(fā)布時(shí)間：2018-01-07 05:18

  本文關(guān)鍵詞：IL-17在中性粒細(xì)胞性哮喘中的作用及其調(diào)控氣道炎癥表型的機(jī)制研究　出處：《第三軍醫(yī)大學(xué)》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 中性粒細(xì)胞性哮喘 IL-17 CD4+Th17細(xì)胞

【摘要】：研究背景與目的支氣管哮喘(簡(jiǎn)稱哮喘)本質(zhì)上屬于氣道慢性炎癥疾病,遺傳因素和外界環(huán)境因素均可影響其發(fā)病。全球約有三億哮喘患者,中國(guó)就占十分之一,而且中國(guó)是哮喘致死率最高的國(guó)家之一。支氣管哮喘還具有明顯異質(zhì)性,不同病人之間及同一病人不同時(shí)期其哮喘臨床表現(xiàn)、病情嚴(yán)重程度、治療反應(yīng)等可能不同。這種“不同”其實(shí)是個(gè)體內(nèi)因(遺傳因素)和外因(環(huán)境因素)共同作用的結(jié)局。以往認(rèn)為嗜酸性粒細(xì)胞(Eos)在氣道內(nèi)聚集和浸潤(rùn)是哮喘的主要炎癥特征或表型,但近期研究發(fā)現(xiàn),哮喘病人氣道內(nèi)并非全部以嗜酸性粒細(xì)胞浸潤(rùn)為主,大量的中性粒細(xì)胞(Neu)出現(xiàn)在哮喘急性發(fā)作期和一些致死性哮喘發(fā)作的病人氣道內(nèi)。目前認(rèn)為中性粒細(xì)胞浸潤(rùn)氣道是重癥哮喘氣道炎癥的重要表型之一,而且與糖皮質(zhì)激素治療反應(yīng)性差相關(guān)。雖然只占哮喘病例的5%至10%不等,但重癥哮喘病人對(duì)現(xiàn)有的治療藥物如吸入性糖皮質(zhì)激素聯(lián)合長(zhǎng)效β2腎上腺素能受體激動(dòng)劑(ICS+LABA)、白三烯受體拮抗劑(LTRA)、茶堿、長(zhǎng)效膽堿能受體拮抗劑(LAMA)等反應(yīng)差,因此構(gòu)成了哮喘防治的巨大醫(yī)療支出負(fù)擔(dān)。研究中性粒細(xì)胞性哮喘表型及其病理生理機(jī)制對(duì)于哮喘的預(yù)防和治療,尤其是對(duì)于重癥哮喘、激素抵抗性哮喘的防治有著非常重要的意義。過(guò)去認(rèn)為過(guò)敏性哮喘發(fā)病的免疫學(xué)機(jī)制為“Th1/Th2失衡”,氣道內(nèi)Th2反應(yīng)增強(qiáng),Th2細(xì)胞因子IL-4、IL-5和IL-13等增高,形成嗜酸性粒細(xì)胞氣道炎癥。在此理論基礎(chǔ)上,研究者研發(fā)了針對(duì)Th2因子的靶向治療藥物,如抗IL-5和IL-13的單克隆抗體及人重組IL-4受體等,試圖逆轉(zhuǎn)Th1/Th2失衡,但一些臨床試驗(yàn)結(jié)果并不令人滿意。另一方面,使用Th1細(xì)胞因子治療哮喘也基本無(wú)效。因此,“Th1/Th2失衡”學(xué)說(shuō)不能完全闡明嗜酸性粒細(xì)胞性哮喘的發(fā)病機(jī)制,更不能解釋中性粒細(xì)胞性哮喘的病理生理改變,后者可能存在不同免疫學(xué)機(jī)制。在隨后的臨床研究中觀察到,IL-17、IL-1β、IL-6、IL-8等炎癥因子在中性粒細(xì)胞性哮喘病人的誘導(dǎo)痰上清、支氣管肺泡灌洗液(BALF)及支氣管肺組織標(biāo)本中表達(dá)增高,且IL-17可能與中性粒細(xì)胞性哮喘病人氣道高反應(yīng)性(AHR)正相關(guān),但確切的機(jī)制仍不明。CD4+輔助性T淋巴細(xì)胞(Th)是幾乎參與機(jī)體所有免疫反應(yīng)的重要免疫細(xì)胞之一。IL-17及其分泌細(xì)胞CD4+Th17細(xì)胞參與了機(jī)體對(duì)病原菌如細(xì)菌、真菌、支原體、衣原體等的清除,并可引起中性粒細(xì)胞和/或單核細(xì)胞向炎癥部位聚集。因此我們推測(cè),在中性粒細(xì)胞性哮喘中,CD4+Th17細(xì)胞及其分泌的IL-17是引起氣道中性粒細(xì)胞性炎癥的重要機(jī)制,對(duì)此機(jī)制的深入研究可能給臨床上重癥哮喘的防治提供新的思路。目的本課題擬使用卵清蛋白(ovalbumin,OVA)聯(lián)合脂多糖(lipopolysaccharide,LPS)對(duì)C57BL/6J小鼠進(jìn)行致敏以建立哮喘中性粒細(xì)胞性炎癥模型,并與單純OVA致敏的嗜酸性粒細(xì)胞性炎癥模型相比較:氣道炎癥特點(diǎn)、AHR、BALF中炎癥因子表達(dá)及脾臟、淋巴結(jié)CD4+Th細(xì)胞分化情況。最后利用IL-17基因敲除小鼠探討Th17/IL-17在哮喘中性粒細(xì)胞性炎癥形成中的作用及機(jī)制。方法1.C57BL/6J小鼠30只隨機(jī)分為3組:對(duì)照組(NS組),嗜酸性粒細(xì)胞性哮喘組(OVA組)和中性粒細(xì)胞性哮喘組(OVA+LPS組),每組10只。于實(shí)驗(yàn)第1天、7天致敏小鼠,麻醉小鼠后腹腔注射OVA(50μg)與等容積氫氧化鋁混合液100μl,經(jīng)鼻腔緩緩滴入0.2%OVA 50μl(OVA組)或加LPS 1μg(OVA+LPS組);NS組小鼠給予等體積的生理鹽水致敏。實(shí)驗(yàn)第14天開始,用1%OVA液進(jìn)行霧化激發(fā)小鼠(OVA組和OVA+LPS組),每次1小時(shí),每天1次,連續(xù)5天,對(duì)照組用生理鹽水代替OVA激發(fā)。2.完成激發(fā)后的小鼠行氣道高反應(yīng)性(AHR)測(cè)定及支氣管肺泡灌洗(BAL),對(duì)BALF細(xì)胞進(jìn)行計(jì)數(shù)并分類,BALF上清用ELISA方法檢測(cè)IL-1β、IL-4、IL-5、IL-8、IL-17表達(dá)。3.摘取小鼠完整左肺行病理學(xué)檢查,觀察支氣管及肺組織炎癥(HE染色)和氣道上皮細(xì)胞杯狀化生程度(PAS染色)。4.無(wú)菌取脾及肺引流淋巴結(jié)(LN)制備單細(xì)胞懸液,用流式細(xì)胞技術(shù)分別檢測(cè)其CD4+Th細(xì)胞分化情況。5.參照OVA+LPS組小鼠建模方法用IL-17基因敲除小鼠復(fù)制中性粒細(xì)胞性哮喘模型,檢測(cè)氣道中炎癥細(xì)胞總數(shù)及分類、炎癥因子表達(dá)水平,測(cè)定氣道高反應(yīng)性(AHR),并觀察肺組織病理炎癥損害及氣道粘液分泌狀態(tài)。6.流式細(xì)胞技術(shù)檢測(cè)IL-17基因敲除小鼠脾臟及肺引流巴結(jié)CD4+Th細(xì)胞分化情況。結(jié)果1.由OVA聯(lián)合LPS致敏建立的中性粒細(xì)胞性哮喘小鼠BALF中炎癥細(xì)胞以中性粒細(xì)胞為主,與單純OVA致敏建立的嗜酸性粒細(xì)胞性哮喘小鼠相比較,具有更高的氣道反應(yīng)性和更嚴(yán)重的肺組織炎癥,但其氣道上皮細(xì)胞杯狀化生降低;2.中性粒細(xì)胞性哮喘小鼠BALF中IL-1β(P0.05)、IL-8(P0.001)和IL-17(P0.05)因子水平顯著高于嗜酸性粒細(xì)胞性哮喘小鼠,而Th2細(xì)胞因子IL-4(P0.01)和IL-5(P0.001)水平顯著低于嗜酸性粒細(xì)胞性哮喘小鼠;3.中性粒細(xì)胞性哮喘小鼠脾臟及肺引流淋巴結(jié)(LN)中CD4+Th細(xì)胞分化與嗜酸性粒細(xì)胞性哮喘小鼠相比較,CD4+IL-17+Th17細(xì)胞分化增多(脾:P0.05;LN:P0.05),CD4+IL-4+Th2細(xì)胞分化減少(脾:P0.001;LN:P0.001),而CD4+IFNγ+Th1細(xì)胞分化無(wú)明顯變化(脾:P0.05;LN:P0.05);4.與野生型中性粒細(xì)胞性哮喘小鼠相比較,IL-17基因敲除小鼠氣道反應(yīng)性降低、BALF中細(xì)胞總數(shù)(P0.01)及中性粒細(xì)胞(P0.001)明顯減少,肺組織炎癥減輕,但BALF中嗜酸性粒細(xì)胞數(shù)(P0.01)增多,氣道上皮杯狀化生增加;5.IL-17基因敲除小鼠BALF中Th2細(xì)胞因子IL-4(P0.05)和IL-5(P0.05)表達(dá)高于野生型中性粒細(xì)胞性哮喘小鼠,IL-1β(P0.05)、IL-8(P0.001)和IL-17(P0.001)明顯低于野生型中性粒細(xì)胞性哮喘小鼠;6.與野生型中性粒細(xì)胞性哮喘組小鼠相比較,IL-17基因敲除鼠脾臟及肺引流淋巴結(jié)中CD4+IL-17+Th17細(xì)胞分化明顯降低(P0.001),CD4+IL-4+Th2細(xì)胞分化升高(脾:P0.01;LN:P0.001);脾CD4+IFNγ+Th1細(xì)胞分化減少(P0.05),而淋巴結(jié)CD4+IFNγ+Th1細(xì)胞分化無(wú)變化(P0.05)。結(jié)論及意義1.用OVA聯(lián)合LPS復(fù)制的中性粒細(xì)胞性哮喘小鼠模型,表現(xiàn)為典型的中性粒細(xì)胞性炎癥,與僅用OVA致敏的嗜酸性粒細(xì)胞性哮喘小鼠相比較,有更高的氣道反應(yīng)性和更重的肺組織炎癥損害。2.CD4+IL-17+Th17細(xì)胞分化增加及其分泌的IL-17是引起哮喘中性粒細(xì)胞性炎癥表型的重要機(jī)制;3.CD4+IL-17+Th17細(xì)胞的增高及IL-17的高表達(dá)抑制了CD4+IL-4+Th2細(xì)胞分化,并進(jìn)一步抑制了哮喘的Th2反應(yīng),即抑制了氣道內(nèi)嗜酸性粒細(xì)胞浸潤(rùn)、粘液高分泌及Th2細(xì)胞因子過(guò)表達(dá)。本文結(jié)果的意義在于,在動(dòng)物模型中證實(shí)了,反復(fù)細(xì)菌感染接觸內(nèi)毒素可以使哮喘氣道炎癥表型從嗜酸性粒細(xì)胞性炎癥轉(zhuǎn)變?yōu)橹行粤＜?xì)胞性炎癥,其機(jī)制依賴于CD4+Th17細(xì)胞的分化及其分泌的IL-17。此機(jī)制的發(fā)現(xiàn)為“衛(wèi)生假說(shuō)”補(bǔ)充了免疫學(xué)機(jī)制的證據(jù)。Th17細(xì)胞途徑是哮喘中性粒細(xì)胞性炎癥發(fā)生發(fā)展的關(guān)鍵環(huán)節(jié),是治療中性粒細(xì)胞性哮喘的潛在靶點(diǎn)。
[Abstract]:Background and objective bronchial asthma (asthma) belongs to chronic inflammatory airway diseases, affecting its incidence may be genetic factors and environmental factors. There are about three hundred million asthma patients worldwide, China accounted for 1/10, and Chinese is one of the country the highest rate of fatal asthma. Asthma has obvious heterogeneity, different clinical manifestations between patients and the same patient in different periods of their asthma severity, treatment response may be different. This "different" is the individual internal factors (genetic factors) and external factors (environmental factor) interaction outcome. The past that eosinophils (Eos) in airway inflammation is the main accumulation and infiltration characteristics the phenotype of asthma, but recent studies have found that not all patients with asthma airway eosinophil infiltration of a large number of neutrophils (Neu) in acute asthma. For the period and some fatal asthma patients. The airway neutrophil infiltration in the airway is one of the important phenotypes of severe asthma airway inflammation, and treatment with glucocorticoid responsiveness. Although the difference accounted for only 5% to 10% of asthma cases differ, but in patients with severe asthma to drugs such as inhaled existing corticosteroids and long-acting beta 2 adrenergic receptor agonist (ICS+LABA), leukotriene receptor antagonist (LTRA), theophylline, long-acting muscarinic antagonist (LAMA) and poor response, therefore constitutes a huge burden of medical expenses for prevention and treatment of asthma. Study of neutrophilic asthma phenotype and its pathophysiological mechanism for prevention and for the treatment of asthma, especially for severe asthma, has a very important significance for prevention and treatment of steroid resistant asthma. In the past that the immunological mechanism of the incidence of allergic asthma is Th1/Th2 Hengshui, enhanced Th2 reaction in airway, Th2 cytokines IL-4, IL-5 and IL-13 increased, the formation of eosinophilic airway inflammation. On the basis of this theory, the researchers developed for Th2 factor targeted therapy, such as anti IL-5 and anti IL-13 monoclonal antibody and recombinant human IL-4 receptor, trying to reverse the balance of Th1/Th2, but some clinical trial results are not satisfactory. On the other hand, the use of Th1 cell factor in the treatment of asthma is invalid. Therefore, "Th1/Th2 imbalance" theory can not fully explain the pathogenesis of eosinophilic asthma, but can not explain the pathophysiology of neutrophilic asthma changes, which may have different immunological to observe the mechanism. And in subsequent clinical studies in IL-17, IL-1, IL-6, beta, IL-8 and other inflammatory cytokines in induced sputum supernatant of neutrophils in patients with asthma, bronchoalveolar lavage fluid (BALF) and bronchial lung Increased expression of tissue samples, and IL-17 may be related to neutrophil cells of patients with asthma and airway hyperresponsiveness (AHR) positive correlation, but the exact mechanism is still unknown.CD4+ T helper lymphocytes (Th) is involved in almost all the immune response is one of the important immune cells and the secretion of.IL-17 cells and CD4+Th17 cells in the body of the pathogen bacteria such as bacteria, fungus, mycoplasma, chlamydia and clear, can cause neutrophil and / or aggregation of monocytes to sites of inflammation. Therefore we speculate that in neutrophilic asthma, CD4+Th17 cells and the secretion of IL-17 is an important mechanism of airway neutrophilic inflammation caused by deep research on this mechanism may provide new ideas for clinical prevention and treatment of severe asthma. The purpose of this project intends to use ovalbumin (ovalbumin, OVA) and lipopolysaccharide (lipopolysaccharide, LPS) of C57BL/6J in mice For sensitization to establish asthma neutral model granulocytic inflammation and eosinophilic inflammation model sensitivity compared with OVA: AHR, features of airway inflammation, the expression of inflammatory cytokines in BALF and spleen, lymph node differentiation of CD4+Th cells. The IL-17 gene knockout mice to investigate the effect and mechanism of Th17/IL-17 formation in neutrophilic inflammation in asthma. Methods 30 1.C57BL/6J mice were randomly divided into 3 groups: control group (group NS), eosinophilic asthma group (OVA group) and neutrophilic asthma group (OVA+LPS group), 10 rats in each group. On the first day, 7 day of sensitization mice, mice were anesthetized after intraperitoneal injection of OVA (50 g) and the volume of the mixture of aluminum hydroxide 100 L, slowly through the nose drops 0.2%OVA 50 L (OVA group) or LPS 1 g (OVA+LPS group); NS group were given an equal volume of saline sensitization. The fourteenth day of the experiment, for the fog with 1%OVA solution Of challenged mice (OVA group and OVA+LPS group), 1 hours each time, 1 times a day, for 5 consecutive days, the control group with saline instead of OVA.2. mice were stimulated airway hyperresponsiveness after excitation (AHR) determination and bronchoalveolar lavage (BAL), count the number of BALF cells and BALF. The supernatant of IL-1 beta, ELISA was detected by IL-4, IL-5, IL-8, IL-17 expression of.3. mice at the left lung pathology, lung tissue and bronchial inflammation were observed (HE staining) and airway epithelial goblet cell metaplasia degree (PAS staining).4. of spleen and lung draining lymph node (LN) for preparing single the cell suspension by flow cytometry was used to detect the differentiation of CD4+Th cells of.5. mice according to OVA+LPS modeling method in IL-17 gene knockout mice model replication of neutrophilic asthma, detection of total number of inflammatory cells in the airways and the classification, the level of expression of inflammatory cytokines, determination of airway hyperresponsiveness (of AHR), and to observe the pathological damage of lung tissue inflammation and airway mucus secretion.6. flow cytometry IL-17 knockout mice spleen and lung draining lymph node CD4+Th cell differentiation. Results 1. by OVA combined with LPS induced inflammatory cells to establish the sensitivity of neutrophilic asthma mice BALF in neutrophils, and the simple OVA established by sensitization of eosinophils of asthmatic mice compared with airway hyperresponsiveness and more severe inflammation of lung tissue, but the goblet cell metaplasia of lower airway epithelium; 2. of neutrophilic asthma mice BALF IL-1 beta (P0.05), IL-8 (P0.001) and IL-17 factor (P0.05) level was significantly higher than that of mouse eosinophils eosinophil asthma, and Th2 cell factor IL-4 (P0.01) and IL-5 (P0.001) was significantly lower than that of mouse eosinophils eosinophil asthma; 3. neutrophils in spleen and lung cells of asthmatic mice lymph drainage Node (LN) in the differentiation of CD4+Th cells and eosinophils of asthmatic mice, CD4+IL-17+Th17 cells increased (spleen: P0.05; LN:P0.05), CD4+IL-4+Th2 cell differentiation decreased (spleen: P0.001; LN:P0.001), and CD4+IFN gamma differentiation of +Th1 cells had no obvious change (spleen: P0.05; LN:P0.05; 4.) and wild type neutrophilic asthma mice compared to IL-17 knockout mice airway reactivity decreased, the total cell number in BALF (P0.01) and neutrophil (P0.001) significantly reduced the lung tissue inflammation, but BALF in the number of eosinophils (P0.01) increased airway goblet metaplasia increased; 5.IL-17 gene knockout in addition to Th2 cytokines in BALF mice IL-4 (P0.05) and IL-5 (P0.05) were higher than that of the wild type mouse granulocyte neutral asthma, IL-1 beta (P0.05), IL-8 (P0.001) and IL-17 (P0.001) was significantly lower than wild-type neutrophils in asthmatic mice and wild-type neutrophils; 6. Cells of asthmatic mice compared to IL-17 knockout mice spleen and lung drainage in the differentiation of CD4+IL-17+Th17 cells in lymph nodes was significantly lower (P0.001), CD4+IL-4+Th2 cell differentiation increased (spleen: P0.01; LN:P0.001); spleen CD4+IFN gamma +Th1 cell differentiation (P0.05), and the reduction of lymph node CD4+IFN gamma +Th1 cell differentiation (P0.05 no change). Conclusion and significance of 1. OVA combined with LPS replication in a mouse model of neutrophilic asthma, is characterized by neutrophilic inflammation, compared with sensitized with only OVA eosinophils of asthmatic mice, IL-17.2.CD4+IL-17+Th17 cells increased and the secretion of airway responsiveness and more the inflammation of lung tissue damage is an important mechanism of asthma neutrophil inflammatory phenotype by overexpression of 3.CD4+IL-17+Th17 and IL-17 increased; the cells inhibit the differentiation of CD4+IL-4+Th2 cells, and further inhibit asthma Th2 reaction of asthma, which inhibits airway eosinophilia, mucus hypersecretion and overexpression of Th2 cytokines. This is the significance of the results was confirmed in the animal model, can make the airway inflammation of asthma phenotype transition from eosinophils inflammation to neutrophilic inflammation contact endotoxin repeated bacterial infection the mechanism depends on the differentiation, CD4+Th17 cells and IL-17. secretion mechanism the findings add to the "hygiene hypothesis" evidence.Th17 cell pathway immunological mechanism is a key link in asthma neutrophilic inflammation development, is a potential target for the treatment of neutrophilic asthma.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R562.25

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