Rationale: Some children with moderate or severe asthma poorly respond to standard therapies used to manage asthma symptoms and exacerbations. This is partially due to development of corticosteroid resistance, leading to increased frequency of exacerbations and overall morbidity. Although typically characterized by Th2 inflammation (e.g. IL-13), emerging studies show increased Th1 inflammation (e.g. TNFα, IFNγ) in patients with steroid-resistant asthma. In the present study, we used an adolescent mouse model of corticosteroid-resistant allergic airway inflammation to assess airway responses and cytokine profiles. Methods and Results: Newborn C57Bl/6 mice were 1) intranasally challenged with sterile PBS or 0.5 μg c-di-GMP, a bacterial second messenger, and mixed allergen (Ovalbumin, Alternaria alternata, Aspergillus fumigatus and Dermatophagoides farinae; 10 μg each) (c-di-GMP + MA) administered 3 times per week for 7 weeks or 2) sensitized I.P. PBS/alum or 20 μg Ovalbumin/alum in week 1 and subsequently intranasally challenged with 100 μg Ovalbumin on 3 consecutive days in week 7 (OVA). During the final 2 weeks, mice were IP injected with vehicle, 1, or 3 mg/kg fluticasone propionate (FP) on days of intranasal challenge. Lung function was assessed using SciReq Flexivent. Airway inflammation was assessed by H&E staining and lung expression of pro-inflammatory cytokines (TNFα, IFNγ, IL-13; ELISA). Airway hyperresponsiveness (AHR) and inflammation were increased in OVA and c-di-GMP + MA challenged mice. FP, 1 and 3 mg/kg, blunted effects of OVA on AHR and airway inflammation. However in c-di-GMP + MA mice, AHR and airway inflammation remained elevated even with 1 or 3 mg/kg FP treatment. Lung expression of IL-13 and TNFα, but not IFNγ, was increased in OVA mice but reduced by both doses of FP. Mice challenged with c-di-GMP + MA showed increased IL-13, TNFα, and IFNγ, while expression of IL-13 and IFNγ remained elevated in c-di-GMP + MA mice treated with FP. Conclusions: These studies show that c-di-GMP + MA challenge results in AHR and airway inflammation in young mice that are resistant to corticosteroids. These effects were associated with increased expression of IFNγ in the presence of corticosteroids. Together, our data suggests that Th1 inflammation may play a role in promoting corticosteroid resistance in asthma. Further studies are needed to understand the mechanisms by which Th1 inflammation contributes to steroid resistance in neonatal/pediatric asthma. Supported by NIH grants K99 HL131682 (Britt), R01 HL056470 (Prakash) and R01 HL138402 (Pabelick).
Full conference title:
- ATS 2018