Because the pathophysiology of asthma has diverse characteristics, to manage the disease effectively, it is important for clinicians to distinguish among the clinical phenotypes. Among them, adult-onset asthma, that is, late-onset asthma (LOA), is increasing because of the aging of the population. The phenotype of LOA is largely divided into two types according to the presence or absence of eosinophilic inflammation, T-helper (Th)2- and non–Th2-associated LOA. Especially in Th2 LOA related to rhinosinusitis, as pulmonary function at onset is poor and asthma exacerbations occur frequently, it is important to detect this phenotype in the early phase by using a biomarker of Th2-type inflammation such as fractional exhaled nitric oxide (FE_NO). As non–Th2-LOA is often resistant to corticosteroids, this phenotype often requires another treatment strategy such as macrolide, diet, or smoking cessation. We often struggle with the management of LOA patients due to a lack of evidence; therefore, the elucidation of the mechanism of LOA contributes to increased efficiency of diagnosis and treatment of LOA. Age-related immune system and structural changes are thought to be associated with the pathophysiology of LOA. In the former case, changes in inflammatory cell function such as variations in the innate immune response and acquisition of autoimmunity or upregulation of oxidative stress are thought to be involved in the mechanism. Meanwhile, the latter can also become triggers or exacerbating factors of LOA via enhancement of airway hyperresponsiveness, decline in lung function, increased air trapping, and reduction in chest wall compliance. Therefore, appropriate individualized management in LOA may be possible through precisely assessing the pathophysiology based on age-related functional changes, including the immune and structural system.

Virus infections are a major cause of chronic obstructive pulmonary disease (COPD) exacerbations. Recently, Toll-like receptor 3 (TLR3) has been demonstrated to react to double-stranded RNA (dsRNA) and to be involved in the immune responses after viral infections. In the present study, we examined whether oxidative stress, which is involved in the pathogenesis of COPD, enhances the responses of TLR3 in airway epithelial cells. The effect of hydrogen peroxide (H2O2) on the release of IL-8 from BEAS-2B cells and primary human bronchial epithelial cells after stimulation with polyinosine-polycytidylic acid [poly(I:C)], a synthetic analog of viral dsRNA and a ligand for TLR3, and the signal transduction were examined. One hundred to 150 μM H2O2 significantly potentiated the release of IL-8 from the epithelial cells after stimulation with 10 μg/ml poly(I:C). The H2O2-augmented IL-8 release was inhibited by treatment with N-acetylcysteine. One hundred micromoles of H2O2 enhanced the translocation of nuclear factor (NF)-κB p65, but not that of interferon regulatory factor-3 (IRF-3), into the nucleus and the NF-κB DNA binding activity after poly(I:C) stimulation, which effect was inhibited not by the silencing of IRF-3 but by MG132, a proteasome inhibitor, or dexamethasone. One hundred micromoles of H2O2 potentiated the TLR3 expression on the airway epithelial cells treated with poly(I:C). These data suggest that oxidative stress augments the response of TLR3 in airway epithelial cells via NF-κB and that this effect might be partly mediated by the enhancement of TLR3 expression. Modulation of this pathway may be a therapeutic target for viral-induced exacerbations of COPD.

Airway remodeling is observed in the airways of patients with asthma, and differentiation of fibroblasts to myofibroblasts plays a critical role in the progress of airway remodeling. Viral infection induces not only the disease development and exacerbations but also airway remodeling. The aim of this study was to evaluate whether the activation of Toll-like receptor 3 (TLR3) can affect the differentiation of fibroblasts to myofibroblasts and the extracellular matrix (ECM) protein production. Human fetal lung fibroblasts (HFL-1) and adult lung fibroblasts were treated with a synthetic double-stranded RNA, polyinosine-polycytidylic acid (poly[I:C]) and the expression of α-smooth muscle actin (α-SMA), a marker of myofibroblast differentiation, was evaluated. The release of transforming growth factor-β1 (TGF-β1) and ECM protein production were assessed. The effect of anti-TGF-β antibody on the α-SMA and ECM production was also assessed. Poly(I:C) significantly augmented the α-SMA expression (P < 0.01) and release of TGF-β1 (P < 0.01) compared with control. Bafilomycin, an inhibitor of TLR3 signaling, diminished poly(I:C)-augmented TGF-β1 release. Anti–TGF-β1 antibody inhibited the poly(I:C)-augmented α-SMA expression. Poly(I:C) enhanced translocation of nuclear factor-kB (NF-κB) and interferon regulatory factor-3 (IRF-3) into the nucleus. Poly(I:C)-augmented TGF-β1 release was almost completely blocked by NF-κB inhibitors, but not by silencing IRF-3. The production of fibronectin and collagen I expression were significantly increased by poly(I:C) (P < 0.01) and they were inhibited by anti–TGF-β antibody. These results suggest that activation of TLR3 can affect the differentiation to myofibroblasts and enhance ECM production via the NF-κB–TGF-β1–dependent pathway.

It remains unclear whether a persistently high exhaled nitric oxide fraction (FeNO) in patients with controlled asthma is associated with the progressive loss of lung function. This was a 3-year prospective study. We examined the changes in pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1) and FeNO in 140 patients with controlled asthma. We initially determined the FeNO cut-off point for identifying patients with a rapid decline in FEV1 (>40 mL/yr). Next, a total of 122 patients who maintained high or non-high FeNO were selected, and the associations between the FeNO trend and changes in FEV1 and bronchodilator response (BDR) were investigated. A FeNO level >40.3 ppb yielded 43% sensitivity and 86% specificity for identifying patients with a rapid decline in FEV1. Patients with persistently high FeNO had higher rates of decline in FEV1 (42.7 ± 37.5 mL/yr) than patients with non-high FeNO (16.7 ± 31.5 mL/yr) (p < 0.0005). The changes in BDR from baseline to the end of the study, in patients who had high or non-high levels of FeNO were -0.8% and 0.1%, respectively (p < 0.01). In a multivariate analysis adjusted by age, body mass index, asthma control, blood eosinophil numbers, and FEV1% of predicted, a FeNO level of ≥40 ppb was independently associated with an accelerated decline in FEV1 (p < 0.05). This study suggests that FeNO is potentially valuable tool for identifying individuals who are at risk of a progressive loss of lung function among patients with controlled asthma.