BACKGROUND The respiratory system is exposed to various allergens via inhaled and intranasal routes. Murine models of allergic lung disease have been developed to clarify the mechanisms underlying inflammatory responses and evaluate the efficacy of novel therapeutics. However, there have been no comparative studies on differences in allergic phenotypes following inhaled vs. intranasal allergen challenge. In this study, we compared the asthmatic features of mice challenged via different routes following allergen sensitization and investigated the underlying mechanisms. METHODS To establish ovalbumin (OVA)-induced allergic asthma models, BALB/c mice were sensitized to 20 μg OVA with 1 mg aluminum hydroxide by the intraperitoneal route and then challenged by inhalation or intranasal administration with 5% OVA for 3 consecutive days. Cellular changes and immunoglobulin (Ig) E levels in bronchoalveolar lavage fluid (BALF) and serum, respectively, were assessed. Histological changes in the lungs were examined by hematoxylin and eosin (H&E) and periodic acid Schiff (PAS) staining. Levels of T helper (Th)2 cytokines including interleukin (IL)-4, -5, and -13 in BALF and epithelial cytokines including IL-25 and -33 in BALF and lung tissues were measured by enzyme-linked immunosorbent assay and western blotting. Airway hyperresponsiveness (AHR) was evaluated by assessing airway resistance (Rrs) and elastance (E) via an invasive method. RESULTS OVA-sensitized and challenged mice showed typical asthma features such as airway inflammation, elevated IgE level, and AHR regardless of the challenge route. However, H&E staining showed that inflammation of pulmonary vessels, alveolar ducts, and alveoli were enhanced by inhaled as compared to intranasal OVA challenge. PAS staining showed that intranasal OVA challenge induced severe mucus production accompanied by inflammation in bronchial regions. In addition, Th2 cytokine levels in BALF and AHR in lung were increased to a greater extent by inhalation than by intranasal administration of OVA. Epithelial cytokine expression, especially IL-25, was increased in the lungs of mice in the inhaled OVA challenge group. CONCLUSION OVA-sensitized mice exhibit different pathophysiological patterns of asthma including expression of epithelial cell-derived cytokines depending on the OVA challenge route. Thus, some heterogeneous phenotypes of human asthma can be replicated by varying the mode of delivery after OVA sensitization.

中文翻译：

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通过吸入和鼻内途径攻击的OVA诱导的小鼠哮喘表型的比较。

背景技术呼吸系统通过吸入和鼻内途径暴露于各种过敏原。已经开发了过敏性肺疾病的鼠模型以阐明炎症反应的潜在机制并评估新型疗法的功效。然而，目前尚无关于吸入与鼻内过敏原激发后过敏表型差异的比较研究。在这项研究中，我们比较了变应原致敏后通过不同途径攻击的小鼠的哮喘特征，并研究了其潜在机制。方法为了建立卵清蛋白（OVA）诱发的过敏性哮喘模型，将BALB / c小鼠通过腹膜内途径用1 mg氢氧化铝对20μgOVA致敏，然后连续3天通过吸入或经鼻内用5％OVA刺激。分别评估支气管肺泡灌洗液（BALF）和血清中的细胞变化和免疫球蛋白（Ig）E水平。用苏木精和曙红（H＆E）和高碘酸席夫（PAS）染色检查肺的组织学变化。用酶联免疫吸附法和Western Western blot检测BALF中白细胞介素（IL）-4，-5和-13的T辅助（Th）2细胞因子和BALF和肺组织中IL-25和-33的上皮细胞因子的水平印迹。通过侵入性方法评估气道阻力（Rrs）和弹性（E）来评估气道高反应性（AHR）。结果不论激发途径如何，OVA致敏和激发小鼠均表现出典型的哮喘特征，例如气道炎症，IgE水平升高和AHR。但是，H＆E染色显示肺血管发炎，与鼻内OVA刺激相比，吸入增强了肺泡管和肺泡。PAS染色显示，鼻内OVA刺激可引起严重的粘液产生，并伴有支气管区域的炎症。另外，通过吸入比通过鼻内施用OVA更大程度地提高了肺中BALF和AHR中Th2细胞因子的水平。吸入OVA攻击组小鼠的肺中上皮细胞因子表达，特别是IL-25增加。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。与鼻内OVA刺激相比，吸入增强了肺泡和肺泡。PAS染色显示，鼻内OVA刺激可引起严重的粘液产生，并伴有支气管区域的炎症。另外，通过吸入比通过鼻内施用OVA更大程度地提高了肺中BALF和AHR中Th2细胞因子的水平。吸入OVA攻击组小鼠的肺中上皮细胞因子表达，特别是IL-25增加。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。与鼻内OVA刺激相比，吸入增强了肺泡和肺泡。PAS染色显示，鼻内OVA刺激可引起严重的粘液产生，并伴有支气管区域的炎症。另外，通过吸入比通过鼻内施用OVA更大程度地提高了肺中BALF和AHR中Th2细胞因子的水平。吸入OVA攻击组小鼠的肺中上皮细胞因子表达，特别是IL-25增加。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。PAS染色显示鼻内OVA刺激可导致严重的粘液产生，并伴有支气管区域的炎症。另外，通过吸入比通过鼻内施用OVA更大程度地提高了肺中BALF和AHR中Th2细胞因子的水平。吸入OVA攻击组小鼠的肺中上皮细胞因子表达，特别是IL-25增加。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。PAS染色显示，鼻内OVA刺激可引起严重的粘液产生，并伴有支气管区域的炎症。另外，通过吸入比通过鼻内施用OVA更大程度地提高了肺中BALF和AHR中Th2细胞因子的水平。吸入OVA攻击组小鼠的肺中上皮细胞因子表达，特别是IL-25增加。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。通过吸入比通过鼻内施用OVA，肺中BALF和AHR中的Th2细胞因子水平增加的程度更大。吸入OVA攻击组小鼠的肺中上皮细胞因子表达，特别是IL-25增加。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。通过吸入比通过鼻内施用OVA，肺中BALF和AHR中的Th2细胞因子水平增加的程度更大。吸入OVA攻击组小鼠的肺中上皮细胞因子表达，特别是IL-25增加。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。结论OVA致敏小鼠表现出不同的哮喘病理生理模式，包括取决于OVA激发途径的上皮细胞衍生细胞因子的表达。因此，通过改变OVA致敏后的递送方式，可以复制人类哮喘的某些异质表型。