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Title: [Expression of RAGE in asthmatic rats and the intervention of Roxithromycin].
Author: Gu XF, Chen HJ, Chen XM, Xu TT, Qiu ZW, Wu LQ, Dai W, Ying SM, Dai YR.
Journal: Zhonghua Yi Xue Za Zhi; 2019 Aug 27; 99(32):2542-2546. PubMed ID: 31484284.
Abstract:
Objective: To observe the expression of the Receptor of Advanced glycation end products (RAGE) in asthmatic rats, and explore the intervention of Roxithromycin. Methods: A total of 18 Specific Pathogen Free-class Brown Norway male rats were randomly divided into control group, asthma model group and Roxithromycin group, with 6 rats in each group. The asthmatic model was sensitized by intraperitoneal injection of Ovalbumin (OVA)+Al(OH)(3), and challenged with OVA. Rats in Roxithromycin group were given Roxithromycin 30 mg/kg 30 minutes before each challenge. Rats in control group and asthma model group were treated with equal volume of saline. The concentrations of RAGE and interleukin (IL)-4 in serum and bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent (ELISA); the pathological changes of lung tissues were observed by HE-staining; the thickness of airway wall and airway smooth muscle were measured by Image-Pro Plus; the relative expression of RAGE in lung tissues were detected by Western blot. Results: In asthma model group, the concentrations of RAGE and IL-4 in the serum and BALF were obviously higher than those in control group [(494±32) vs (327±45) ng/L; (32.4±5.8) vs (13.1±2.9) ng/L; (553±38) vs (399±56) ng/L; (37.8±3.4) vs (19.4±2.5) ng/L] (all P<0.01); in Roxithromycin group, the concentrations of RAGE and IL-4 in the serum and BALF were obviously lower than those in asthma model group [(438±18) vs (494±32) ng/L; (22.8±6.0) vs (32.4±5.8) ng/L; (444±42) vs (553±38) ng/L; (25.6±4.5) vs (37.8±3.4) ng/L] (all P<0.05). In asthma model group, the bronchial wall was thickened, the lumen was narrow, the mucosal wrinkles were significantly increased, edema appeared under the mucosa, and a large number of inflammatory cells infiltrated and aggregated in the bronchi, perivascular and alveolar spaces; the thickness of airway wall and airway smooth muscle were significantly increased than those in control group (P<0.01); in Roxithromycin group, airway inflammation and remodeling were alleviated compared with those in asthma model group (P<0.05). In asthma model group, the expression of RAGE in lung tissues were significantly increased than those in control group (P<0.01); in Roxithromycin group, the expression of RAGE were significantly decreased than those in asthma model group (P<0.01). There were positive correlations between the expression of RAGE and IL-4 in BALF and serum (r=0.782, 0.804, all P<0.01); there were positive correlations between RAGE and total white cell counts, eosinophil counts, smooth muscle thickness (r=0.897, 0.927, 0.860, all P<0.01). Conclusions: The increasing of RAGE in asthmatic rats are positively correlated with airway inflammation and airway remodeling. Roxithromycin may inhibit the development of asthma by reducing the expression of RAGE. 目的： 探讨晚期糖基化终产物受体（RAGE）在哮喘大鼠中的表达及罗红霉素的干预作用。 方法： 将18只雄性无特定病原体动物（SPF）级Brown Norway大鼠，按随机数字表法随机分为正常对照组、哮喘模型组、罗红霉素组各6只。通过卵白蛋白（OVA）+Al（OH）(3)联合致敏，OVA雾化激发构建大鼠哮喘模型，在每次激发前30 min，罗红霉素组予以罗红霉素30 mg/kg灌胃，正常对照组和哮喘模型组分别用等体积生理盐水代替。采用酶联免疫吸附测定（ELISA）法检测各组大鼠血清和支气管肺泡灌洗液（BALF）中RAGE、白细胞介素（IL）-4的浓度；HE染色法观察各组大鼠肺组织气道炎症和细胞浸润情况；Image-Pro Plus图像分析软件测量并计算支气管壁厚度及平滑肌厚度；Western印迹法检测各组大鼠肺组织RAGE蛋白相对表达量。 结果： 哮喘模型组血清和BALF中RAGE、IL-4浓度显著均高于正常对照组[（494±32）比（327±45）ng/L、（32.4±5.8）比（13.1±2.9）ng/L和（553±38）比（399±56）ng/L、（37.8±3.4）比（19.4±2.5）ng/L]（均P<0.01），罗红霉素组血清和BALF中RAGE、IL-4浓度均显著低于哮喘模型组[（438±18）比（494±32）ng/L、（22.8±6.0）比（32.4±5.8）ng/L和（444±42）比（553±38）ng/L、（25.6±4.5）比（37.8±3.4）ng/L]（均P<0.05）；哮喘模型组支气管壁增厚，管腔狭窄，黏膜皱折明显增多，黏膜下水肿，支气管、血管周围及肺泡腔内大量炎症细胞浸润、聚集；支气管壁厚度、平滑肌厚度明显厚于正常对照组（均P<0.01），罗红霉素组气道炎症及重塑改变优于哮喘模型组（P<0.05）；哮喘模型组肺组织RAGE蛋白表达显著高于正常对照组（P<0.01），罗红霉素组肺组织RAGE蛋白表达显著低于哮喘模型组（P<0.01）。各组BALF及血清中RAGE和IL-4表达呈正相关（r=0.782、0.804，均P<0.01）；肺组织中RAGE与白细胞总数、嗜酸粒细胞数量及平滑肌厚度呈正相关（r=0.897、0.927、0.860，均P<0.01）。 结论： 哮喘大鼠肺组织、血清和BALF中RAGE表达升高，且与气道炎症及气道重塑呈正相关，罗红霉素可能通过降低哮喘大鼠RAGE的表达来达到治疗哮喘的目的。.

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