*Department of Respiratory, Inflammation and Autoimmunity, MedImmune, Granta Park, Cambridge CB21 6GH, U.K.
Clin Sci (Lond). 2014 Apr;126(8):567-80. doi: 10.1042/CS20130149.
Viral respiratory tract infections are known triggers of asthma exacerbations in both adults and children. The current standard of care, inhaled CS (corticosteroids) and LABAs (long-acting β2-adrenoceptor agonists), fails to prevent the loss of control that manifests as an exacerbation. In order to better understand the mechanisms underlying viral asthma exacerbations we established an in vivo model using the clinically relevant aeroallergen HDM (house dust mite) and the viral mimetic/TLR3 (Toll-like receptor 3) agonist poly(I:C). Poly(I:C) alone induced a similar neutrophilic inflammatory profile in the BAL (bronchoalveolar lavage) to that of HRV1b (human rhinovirus 1b) alone, accompanied by both elevated BAL KC (keratinocyte-derived chemokine) and IL-1β (interleukin-1β). When mice allergic to HDM were also challenged with poly(I:C) the neutrophilic inflammatory profile was exacerbated. Increased CD8(+) T-cell numbers, increased CD4(+) and CD8(+) cell activation and elevated KC and IL-1β were observed. No increases in Th2 cytokines or the eosinophil chemoattractant CCL11 [chemokine (C-C motif) ligand 11], above those induced by HDM alone, were observed. The poly(I:C)-exacerbated neutrophilia did not translate into changes in AHR (airways hyper-responsiveness), indicating that in this model inflammation and AHR are two mechanistically independent events. To test the clinical relevance of this model CS sensitivity was assessed using prednisone, a synthetic oral CS used to manage exacerbations in asthmatic patients already on maximal doses of inhaled CS. The increased neutrophils, and accompanying cytokines/chemokines KC and IL-1β induced by poly(I:C) challenge of HDM-sensitized and challenged mice were insensitive to oral prednisone therapy. In summary we have described a CS-resistant mouse model mimicking the key aspects of viral asthma exacerbation using the clinically relevant aeroallergen HDM and the viral mimic poly(I:C). This model may provide better understanding of disease mechanisms underlying viral exacerbations and could be used to build early confidence in novel therapeutic axes targeting viral asthma exacerbations in Th2 asthmatics.
病毒引起的呼吸道感染是成人和儿童哮喘恶化的已知诱因。目前的治疗标准，吸入皮质类固醇（CS）和长效β2-肾上腺素受体激动剂（LABAs），都无法预防控制的丧失，而这种控制的丧失表现为恶化。为了更好地理解病毒引起的哮喘恶化的机制，我们建立了一个体内模型，使用临床相关的变应原 HDM（尘螨）和病毒模拟物/TLR3（Toll 样受体 3）激动剂 poly(I:C)。Poly(I:C) 单独诱导 BAL（支气管肺泡灌洗）中的中性粒细胞炎症谱类似于 HRV1b（人类鼻病毒 1b）单独诱导的炎症谱，同时伴有 BAL KC（角质细胞衍生的趋化因子）和 IL-1β（白细胞介素-1β）升高。当对 HDM 过敏的小鼠也接受 poly(I:C) 挑战时，中性粒细胞炎症谱加剧。观察到 CD8+T 细胞数量增加、CD4+和 CD8+细胞活化增加以及 KC 和 IL-1β 升高。与单独的 HDM 诱导相比，没有观察到 Th2 细胞因子或嗜酸性粒细胞趋化因子 CCL11[趋化因子（C-C 基序）配体 11]的增加。Poly(I:C) 加剧的中性粒细胞增多并没有转化为 AHR（气道高反应性）的变化，表明在这种模型中，炎症和 AHR 是两个在机制上独立的事件。为了测试该模型的临床相关性，使用泼尼松评估了 CS 敏感性，泼尼松是一种合成的口服 CS，用于治疗已经接受最大剂量吸入 CS 治疗的哮喘患者的恶化。Poly(I:C) 对 HDM 致敏和挑战的小鼠的挑战引起的增加的中性粒细胞以及伴随的细胞因子/趋化因子 KC 和 IL-1β 对口服泼尼松治疗不敏感。总之，我们描述了一种 CS 抵抗的小鼠模型，该模型使用临床相关的变应原 HDM 和病毒模拟物 poly(I:C) 模拟病毒引起的哮喘恶化的关键方面。该模型可以更好地理解病毒恶化背后的疾病机制，并可用于在 Th2 哮喘患者中针对病毒哮喘恶化的新型治疗轴建立早期信心。
