本文選題：變應(yīng)性鼻炎　切入點(diǎn)：鼻黏膜　出處：《南京醫(yī)科大學(xué)》2013年博士論文

【摘要】：第一部分變應(yīng)性鼻炎小鼠急性和慢性模型的建立及評(píng)價(jià)目的建立符合本課題要求的變應(yīng)性鼻炎(AR)小鼠急性和慢性模型。方法采用卵清蛋白(OVA)全身致敏BALB/c、鼠后,8天OVA激發(fā)劑連續(xù)滴鼻激發(fā)出AR急性模型,隨之持續(xù)14周的間斷激發(fā)誘導(dǎo)出AR慢性模型,并從鼻部癥狀學(xué)、鼻黏膜組織病理學(xué)(HE染色、AB-PAS染色和Masson染色)及血清特異性IgE水平(ELISA法)這三個(gè)方面來(lái)評(píng)價(jià)AR動(dòng)物模型建立的成功與否。結(jié)果AR小鼠急性和慢性模型都顯示出了OVA致敏導(dǎo)致的炎癥反應(yīng)表現(xiàn),包括鼻部癥狀、炎性細(xì)胞鼻黏膜浸潤(rùn)、黏膜下嗜酸性粒細(xì)胞(EOS)募集及血清中OVA特異性IgE水平上升等。慢性AR組動(dòng)物鼻黏膜的杯狀細(xì)胞數(shù)目及膠原纖維沉積面積均明顯高于急性AR組及對(duì)照組。結(jié)論本實(shí)驗(yàn)制備出的AR急慢性動(dòng)物模型均符合AR的病理生理特征,而且AR慢性模型具備了鼻黏膜組織重塑的主要特征。第二部分調(diào)控HIF-1α對(duì)變應(yīng)性鼻炎小鼠急性模型鼻黏膜炎癥的影響目的探討低氧誘導(dǎo)因子1α (HIF-1α)在AR小鼠急性模型鼻黏膜炎癥中的作用。方法通過(guò)OVA全身致敏和局部激發(fā)BALB/c小鼠,制備AR小鼠急性模型,并對(duì)其應(yīng)用HIF-1α抑制劑2-甲氧基雌二醇(2ME2)和缺氧模擬劑氯化鉆(CoCl2)進(jìn)行預(yù)處理,檢測(cè)小鼠鼻黏膜中HIF-1α和血管內(nèi)皮生長(zhǎng)因子(VEGF)的含量,同時(shí)評(píng)估多項(xiàng)反映鼻部變應(yīng)性炎癥反應(yīng)的指標(biāo)。結(jié)果研究發(fā)現(xiàn)在AR小鼠模型的鼻黏膜中HIF-1α和VEGF水平顯著升高,AR小鼠急性模型都顯示出了OVA致敏導(dǎo)致的炎癥反應(yīng)表現(xiàn),包括鼻部癥狀、炎性細(xì)胞鼻黏膜浸潤(rùn)及EOS募集、鼻腔灌洗液中的IL-4和IL-5以及血清中OVA特異性IgE水平上升等。2ME2可以抑制鼻黏膜中HIF-1α和VEGF的表達(dá)和上述OVA致敏導(dǎo)致的炎癥反應(yīng),而缺氧模擬劑CoCl2可以增強(qiáng)這些反應(yīng)。HIF-1α在鼻部的表達(dá)水平與AR小鼠鼻部炎癥的嚴(yán)重程度相關(guān)。結(jié)論HIF-1α的活化參與了AR的發(fā)病機(jī)制,抑制HIF-1α可能成為AR治療的一個(gè)新方向。第三部分調(diào)控HIF-1α對(duì)變應(yīng)性鼻炎小鼠慢性模型鼻黏膜炎癥及組織重塑的影響目的探討HIF-1α及其調(diào)控的生長(zhǎng)因子(VEGF、FGF-2、TGF-β1)在AR小鼠慢性模型的鼻黏膜炎癥和組織重塑中的作用。方法通過(guò)OVA全身致敏并長(zhǎng)期局部激發(fā)BALB/c小鼠,制備AR小鼠慢性模型,并對(duì)其應(yīng)用2ME2和CoCl2進(jìn)行預(yù)處理,檢測(cè)小鼠鼻黏膜中HIF-1α, VEGF、FGF-2和TGF-β1的含量,同時(shí)評(píng)估多項(xiàng)反映鼻部變應(yīng)性炎癥反應(yīng)的指標(biāo)以及鼻黏膜重塑的組織病理學(xué)表現(xiàn)。結(jié)果AR小鼠慢性模型的鼻黏膜中HIF-1α蛋白水平顯著升高,除了OVA激發(fā)導(dǎo)致的鼻部變應(yīng)性炎癥反應(yīng)表現(xiàn)以外,病理切片顯示出鼻黏膜組織重塑的重要特征,包括杯狀細(xì)胞大量化生、膠原纖維沉積明顯增強(qiáng)和上皮細(xì)胞大量脫落等。2ME2可以抑制鼻黏膜中HEF-1α的表達(dá),減輕鼻黏膜炎癥反應(yīng)和組織重塑程度；而長(zhǎng)期應(yīng)用CoCl2對(duì)AR小鼠慢性模型的干預(yù)并不能獲得預(yù)期的明顯效果。AR小鼠急慢性模型鼻黏膜中的HIF-1α蛋白水平與VEGF、FGF-2和TGF-β1的蛋白水平明顯相關(guān)。結(jié)論AR小鼠慢性模型中HIF-1α水平與鼻黏膜炎癥和組織重塑程度密切相關(guān)。長(zhǎng)期2ME2干預(yù)可通過(guò)對(duì)HIF-1α的抑制而有效改善持續(xù)OVA刺激所致的鼻黏膜組織重塑,其機(jī)制可能與下調(diào)VEGF、FGF-2和TGF-β1的水平有關(guān)。
[Abstract]:The first part: establishment and evaluation of acute and chronic allergic rhinitis mice model objective: to establish the requirements of the subject of allergic rhinitis (AR) mouse model of acute and chronic. Methods using ovalbumin (OVA) sensitized BALB/c rats body, after 8 days of continuous nasal OVA activator excited by acute AR model, will last for 14 weeks the intermittent excitation induced AR in chronic model, and from the nasal symptoms, nasal mucosa histopathology (HE staining, AB-PAS staining and Masson staining) and serum specific IgE level (ELISA) of these three aspects to evaluate the animal model of AR is built and the success of AR mice. The results of acute and chronic model show the inflammatory reaction in OVA sensitized to the performance, including nasal symptoms, inflammatory cell infiltration in nasal mucosa, submucosal eosinophils (EOS) and raised serum OVA specific IgE levels increased. AR group of nasal mucosa of chronic animal goblet The number of cells and collagen deposition area were significantly higher than those in acute AR group and control group. Conclusion the experiment for the preparation of acute and chronic AR animal model were consistent with the pathophysiological features of AR, and the AR model has the main features of chronic nasal mucosa remodeling. The second part is the regulation of HIF-1 alpha in acute mouse model of allergic rhinitis objective to investigate the nasal mucosal inflammation of hypoxia inducible factor 1 alpha (HIF-1 alpha) in acute AR mice nasal mucosa inflammation. Methods by OVA systemic sensitization and local stimulation of BALB/c mice, preparation of acute AR mice model, and the use of HIF-1 alpha inhibitor 2- methoxyestradiol (2ME2) and hypoxia mimetic cobalt chloride (CoCl2) pretreatment, detection of HIF-1 in the nasal mucosa of the mice alpha and vascular endothelial growth factor (VEGF) were assessed at the same time, a number reflecting the nasal allergic inflammation index. The research results found In the nasal mucosa of AR mice model of HIF-1 alpha and VEGF levels were significantly elevated in acute AR mice showed inflammation caused by OVA sensitization, including nasal symptoms, nasal mucosa inflammatory cell infiltration and EOS to raise the inflammation in the nasal lavage fluid of IL-4 and IL-5 and serum OVA specific IgE the level of rising.2ME2 can inhibit the expression of HIF-1 and VEGF in nasal mucosa and the OVA sensitized to the severity of hypoxia simulating agent CoCl2 can enhance the reaction of.HIF-1 alpha in the nose and expression of AR in mice nasal inflammation. Conclusion the HIF-1 alpha activation involved in the pathogenesis of AR, inhibition of HIF-1 alpha may become a new target for the treatment of AR. Objective to investigate the growth factor HIF-1 alpha and control effect of third part of regulation of HIF-1 alpha on the model of chronic nasal mucosa inflammation and tissue remodeling in mice with allergic rhinitis (VEGF, FGF-2, T GF- beta 1) in nasal mucosa of chronic inflammation and tissue remodeling in AR mice model in vivo. Methods OVA systemic sensitization and long-term local stimulation in BALB/c mice, AR mice were prepared for chronic model, and the application of 2ME2 and CoCl2 pretreatment, detection of HIF-1 in the nasal mucosa of the mice alpha, VEGF, and FGF-2 content TGF- beta 1, while evaluating a number reflecting the performance of nasal allergic inflammation of the nasal mucosa remodeling index and pathology. Results the level of HIF-1 protein in nasal mucosa of chronic AR mouse model increased significantly, in addition to the nasal allergic inflammatory reaction caused by the excitation of OVA, pathological section showed important features of nasal mucosa tissue remodeling, including a large number of goblet cells, the expression of collagen deposition was significantly enhanced and a large number of epithelial cells shedding.2ME2 can inhibit HEF-1 alpha in nasal mucosa, reduce nasal inflammation and tissue The degree of plastic; while the long-term application of CoCl2 on AR mice model of chronic intervention can obtain the HIF-1 protein levels and VEGF expected significant effect of.AR mice model of acute and chronic nasal mucosa, significantly related protein levels of FGF-2 and TGF- beta 1. Conclusion AR is closely related to the model of mice with chronic HIF-1 alpha level and nasal mucosal inflammation and the degree of tissue remodeling. The long-term intervention of 2ME2 by inhibiting HIF-1 alpha and effectively improve the sustained stimulation of OVA nasal mucosa remodeling caused by, and to investigate the possible mechanism of VEGF, the levels of FGF-2 and TGF- beta 1.

【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R765.21

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