Abstract
BackgroundRespiratory viral infections are closely associated with COPD exacerbations, hospitalisations, and significant morbidity and mortality. The consequences of the persisting inflammation and differentiation status in virus associated severe disease is not fully understood. The aim of this study was to evaluate barrier function, cellular architecture, the inflammatory response in severe COPD bronchial epithelium to human rhinovirus (HRV) induced pathological changes and innate immune responses.MethodsWell-differentiated primary bronchial epithelial cells (WD-PBECs) derived from severe COPD patients and age-matched healthy controls were cultured in the air-liquid interface (ALI) model. The differentiation phenotype, epithelial barrier integrity, pathological response and cytokine secreting profile of these cultures before and after HRV infection were investigated.ResultsWD-PBECs derived from severe COPD patients showed aberrant epithelium differentiation with a decreased proportion of ciliated cells but increased numbers of club cells and goblet cells compared with healthy controls. Tight junction integrity was compromised in both cultures following HRV infection, with heightened disruptions in COPD cultures. HRV induced increased epithelial cell sloughing, apoptosis and mucus hypersecretion in COPD cultures compared with healthy controls. A Th1/Th2 imbalance and a strong interferon and pro-inflammatory cytokine response was also observed in COPD cultures, characterized by increased levels of IFNγ, IFNβ, IP-10, IL-10 and decreased TSLP and IL-13 cytokine levels prior to HRV infection. Significantly enhanced basolateral secretion of eotaxin 3, IL-6, IL-8, GM-CSF were also observed in both mock and HRV infected COPD cultures compared with corresponding healthy controls. In response to HRV infection, all cultures displayed elevated levels of IFNλ1 (IL-29), IP-10 and TNFα compared with mock infected cultures. Interestingly, HRV infection dramatically reduced IFNλ levels in COPD cultures compared with healthy subjects.ConclusionAn altered differentiation phenotype and cytokine response as seen in severe COPD WD-PBECs may contribute to increased disease susceptibility and an enhanced inflammatory response to HRV infection.
Highlights
COPD is a heterogeneous respiratory syndrome consisting of two main disease phenotypes, chronic obstructive bronchitis and pulmonary emphysema [1–3]
There was a reduction in the proportion of ciliated cells (β-tubulin) (23 ± 2.2 vs. 28.1 ± 3.3, P < 0.05), and an increase in club cells (CC10) (23 ± 1.6 vs. 16.2 ± 1.4, P < 0.001) and goblet cells (MUC5AC) (25.4 ± 1.8 vs. 20.6 ± 2.0, P < 0.01) in COPD cultures compared to healthy control cultures (Figure 1B)
We investigated the impact of the innate host response and barrier function of severe COPD WDPBECs on human rhinovirus (HRV)-induced innate immune responses
Summary
COPD is a heterogeneous respiratory syndrome consisting of two main disease phenotypes, chronic obstructive bronchitis and pulmonary emphysema [1–3]. The sustained inflammatory response contributes to abnormal tissue repair, mucus hypersecretion, and epithelial cell hyperplasia. This causes irreversible damage and thickening of the small conducting airway, which leads to progressive airflow limitation [1–4]. Severe COPD, often accentuated with episodes of acute exacerbations, contributes to recurrent hospitalisations, morbidity and mortality [5]. More than half of these exacerbations are associated with a range of respiratory viral infections [5–7]. Respiratory viral infections are closely associated with COPD exacerbations, hospitalisations, and significant morbidity and mortality. The aim of this study was to evaluate barrier function, cellular architecture, the inflammatory response in severe COPD bronchial epithelium to human rhinovirus (HRV) induced pathological changes and innate immune responses
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