Background: There has been growing evidence of small-airway dysfunction in patients with asthma. Few studies have evaluated the mechanism of small-airway dysfunction in mouse models of asthma.
Purpose: We explored the correlation between small-airway spirometric variables and large-airway function or inflammation in different endotypes of asthma.
Methods: Ovalbumin (OVA) sensitization/challenge was used to produce a type 2 (T2)-high asthma model, and OVA combined with ozone exposure (OVA + ozone) was used for the T2-low asthma model with increased neutrophils. Spirometry, airway responsiveness, cytokine levels in bronchoalveolar lavage fluid (BALF), and pathological analyses of lung slices stained with hematoxylin-eosin, periodic acid–Schiff, and Masson’s trichrome stain were all determined. Muc5ac expression in lung tissue was evaluated by the reverse transcription-polymerase chain reaction (RT-PCR), and alpha-smooth muscle actin was measured by immunohistochemistry.
Results: Inflammatory cells infiltrated the lung tissue and inflammatory cytokines were increased in the BALF of both the OVA and OVA + ozone groups, compared with the control group. Peribronchial hypersecretion and collagen deposition were evident in the models. The OVA + ozone group showed greater neutrophilic infiltration and peribronchial smooth muscle proliferation than the OVA group. Large-airway obstruction, small-airway dysfunction, and airway hyperresponsiveness were confirmed in both models. Small-airway functional variables, such as MMEF (mean midexpiratory flow, average flow from 25 to 75% forced vital capacity [FVC]) and FEF50 (forced expiratory flow at 50% of FVC), were positively correlated with large-airway function and had a stronger negative correlation with airway inflammation, mucus secretion, and responsiveness than large-airway function.
Conclusion: Small-airway dysfunction was evident in the two endotypes of asthma and was correlated with severe airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. The small airways may be an important target in asthma treatment, and further research in the role of small-airway variables in the pathogenesis of asthma is warranted.



中文翻译：

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小气道功能障碍与哮喘发病机制有关：来自两种小鼠模型的证据

背景：越来越多的证据表明哮喘患者存在小气道功能障碍。很少有研究评估哮喘小鼠模型中小气道功能障碍的机制。
目的：我们探讨了不同哮喘内型中小气道肺活量变量与大气道功能或炎症之间的相关性。
方法：卵白蛋白 (OVA) 致敏/激发用于产生 2 型 (T2) 高哮喘模型，OVA 与臭氧暴露 (OVA + 臭氧) 结合用于中性粒细胞增加的 T2 低哮喘模型。肺活量测定、气道反应性、支气管肺泡灌洗液 (BALF) 中的细胞因子水平，以及用苏木精-伊红、高碘酸-希夫和马森三色染色的肺切片的病理学分析都进行了测定。通过逆转录聚合酶链反应 (RT-PCR) 评估肺组织中的Muc5ac表达，并通过免疫组织化学测量 α-平滑肌肌动蛋白。
结果：与对照组相比，OVA 组和 OVA + 臭氧组的 BALF 中炎性细胞浸润肺组织，炎性细胞因子增加。模型中支气管周围分泌过多和胶原沉积很明显。OVA + 臭氧组显示出比 OVA 组更大的中性粒细胞浸润和支气管周围平滑肌增殖。在两种模型中都证实了大气道阻塞、小气道功能障碍和气道高反应性。小气道功能变量，如 MMEF（平均呼气中流量，25% 至 75% 用力肺活量 [FVC] 的平均流量）和 FEF50（50% FVC 的用力呼气流量）与大气道功能和与气道炎症、粘液分泌、
结论：小气道功能障碍在哮喘的两种内型中都很明显，并且与严重的气道炎症、粘液分泌过多和气道高反应性相关。小气道可能是哮喘治疗的重要靶点，需要进一步研究小气道变量在哮喘发病机制中的作用。