Department of Pediatrics, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Department of Allergy and Pulmonology, Fukuoka Children's Hospital, Fukuoka, Japan.
Immun Inflamm Dis. 2021 Jun;9(2):457-465. doi: 10.1002/iid3.406. Epub 2021 Jan 20.
Severe asthma exacerbation is an important comorbidity of the 2009 HIN1 pandemic (A(H1N1)pdm09) in asthmatic patients. However, the mechanisms underlying severe asthma exacerbation remain unknown. In this study, airway hyperresponsiveness (AHR) was measured in pediatric asthma patients infected with A(H1N1)pdm09. We also evaluated AHR in asthmatic mice with A(H1N1)pdm09 infection and those with seasonal influenza for comparison.
AHRs in asthmatic children were defined as the provocative acetylcholine concentration causing a 20% reduction in forced expiratory volume in 1 s (PC ). To investigate the pathophysiology using animal models, BALB/c mice aged 6-8 weeks were sensitized and challenged with ovalbumin. Either mouse-adapted A(H1N1)pdm09, seasonal H1N1 virus (1 × 10 pfu/20 μl), or mock treatment as a control was administered intranasally. At 3, 7, and 10 days after infection, each group of mice was evaluated for AHR by methacholine challenge using an animal ventilator, flexiVent. Lung samples were resected and observed using light microscopy to assess the degree of airway inflammation.
AHRs in the children with bronchial asthma were temporarily increased, and alleviated by 3 months after discharge. AHR was significantly enhanced in A(H1N1)pdm09-infected asthmatic mice compared to that in seasonal H1N1-infected mice (p < .001), peaking at 7 days postinfection and then becoming similar to control levels by 10 days postinfection. Histopathological examination of lung tissues showed more intense infiltration of inflammatory cells and severe tissue destruction in A(H1N1)pdm09-infected mice at 7 days postinfection than at 10 days postinfection.
Our results suggest that enhanced AHR could contribute to severe exacerbation in human asthmatic patients with A(H1N1)pdm09 infection.
严重哮喘发作是 2009 年 H1N1 大流行（A(H1N1)pdm09）中哮喘患者的重要合并症。然而，严重哮喘发作的机制尚不清楚。在这项研究中，我们测量了感染 A(H1N1)pdm09 的儿科哮喘患者的气道高反应性（AHR）。我们还评估了感染 A(H1N1)pdm09 的哮喘小鼠和季节性流感感染的哮喘小鼠的 AHR 以进行比较。
哮喘儿童的 AHR 定义为引起用力呼气量 1 秒（FEV1）减少 20%的乙酰胆碱浓度（PC）。为了使用动物模型研究病理生理学，我们用卵白蛋白对 6-8 周龄的 BALB/c 小鼠进行致敏和攻毒。用滴鼻的方式分别给予适应小鼠的 A(H1N1)pdm09、季节性 H1N1 病毒（1×10 pfu/20μl）或作为对照的假处理。感染后 3、7 和 10 天，用动物呼吸机 flexiVent 对每组小鼠进行乙酰胆碱激发试验以评估 AHR。切除肺样本，用光学显微镜观察，评估气道炎症程度。
患有支气管哮喘的儿童的 AHR 暂时增加，并在出院后 3 个月内得到缓解。与季节性 H1N1 感染的小鼠相比，A(H1N1)pdm09 感染的哮喘小鼠的 AHR 显著增强（p<0.001），在感染后 7 天达到峰值，然后在感染后 10 天降至对照水平。肺部组织的组织学检查显示，感染后 7 天的 A(H1N1)pdm09 感染小鼠比感染后 10 天的小鼠有更强烈的炎症细胞浸润和更严重的组织破坏。
我们的结果表明，增强的 AHR 可能导致感染 A(H1N1)pdm09 的人类哮喘患者出现严重恶化。
