Alleviating airway inflammation by inhibiting ERK-NF-κB signaling pathway by blocking Kv1.3 channels.

Allergic asthma is a chronic inflammatory disease of the airways. T lymphocytes play an important role in the pathogenesis of asthma. The voltage-gated Kv1.3 potassium channel is a target for the preferential inhibition of TEM cells. In this study, we investigate the effects of PAP-1, a selective inhibitor of Kv1.3 channel, on the treatment of the neutrophilic asthma model. PAP-1 (40 mg/kg) was injected intraperitoneally into ovalbumin (OVA)-lipopolysaccharide (LPS)-challenged BALB/c mice. We found that the expression of the Kv1.3 channel in the lung tissues, and the intensity of the Kv current in the asthmatic mice increased clearly compared with those in normal control. PAP-1 significantly reduced airway hyperresponsiveness (AHR), inflammatory cell count in the bronchoalveolar lavage fluids (BALF) and serum, and attenuated airway inflammation in a histological examination of the asthmatic mice. Moreover, PAP-1 inhibited the OVA-LPS-induced imbalance of Th1/Th2, Treg/Th17 lymphocytes, and reduced levels of IL-4 and IL-17, inducing an increase in the production of IFN-γ and IL-10. Furthermore, the activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway in the lungs of the asthmatic mice was suppressed by PAP-1. We also found that PD-98059, an inhibitor of ERK, had a similar effect with PAP-1 in terms of regulating the imbalance of Th1/Th2, Treg/Th17 cytokines. However, PD-98059 could not further influence cytokine changes when the cells were treated with PAP-1. The results suggest that ERK acts as a downstream regulator of inhibitors of the Kv1.3 channel in neutrophilic asthma. In conclusion, the inhibitor of the Kv1.3 channel has therapeutic potential for treating asthma.

Shikonin alleviates allergic airway remodeling by inhibiting the ERK-NF-κB signaling pathway.

Shikonin is a naphthoquinone extracted from the root of Lithospermum erythrorhizon, and has been reported to suppress allergic airway inflammation in mice. However, the underlying mechanisms are unclear and need to be further elucidated. In this study, shikonin (0.5, 2 or 4mg/kg) was given intraperitoneally to ovalbumin (OVA)-challenged BALB/c mice. We found that the pathological airway remodeling of asthmatic mice was alleviated by shikonin, and the infiltrated inflammatory cells and collagen deposition in their lungs were reduced. Furthermore, the abnormal activation of extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) pathway and the elevation of matrix metalloproteinase 9 (MMP9) in the lung of asthmatic mice were suppressed by shikonin. The inactivation of NF-κB by shikonin was at least in part via inhibiting IκBα activation. In vitro, the treatment of shikonin inhibited the platelet-derived growth factor (PDGF)-induced proliferation of primary airway smooth muscle cells (ASMCs), and induced a G0/G1 arrest in these cells. In addition, ASMCs exposed to PDGF acquired an enhanced migratory ability, and the activities of MMP9 and matrix metalloproteinase 2 (MMP2) and expression of MMP9 of these cells were significantly up-regulated. These PDGF-induced alterations were also inhibited by shikonin. The inhibitory effects of shikonin on the proliferation and migration of ASMCs were comparable to pyrrolidinedithiocarbamate (PDTC), an inhibitor of NF-κB pathway. In conclusion, the present study sheds lights on how shikonin alleviates allergic airway remodeling.

[Diagnostic values of fractional exhaled nitric oxide for typical bronchial asthma and cough variant asthma in children].

OBJECTIVE: To study the diagnostic values of fractional exhaled nitric oxide (FeNO) for typical bronchial asthma and cough variant asthma in children, and to explore whether FeNO can be applied to differentiate typical bronchial asthma from cough variant asthma in children. METHODS: A total of 150 children who were newly diagnosed with typical bronchial asthma between June 2012 and June 2014, as well as 120 children who were newly diagnosed with cough variant asthma during the same period, were selected as subjects. FeNO measurement, spirometry, and methacholine provocation test were performed for both groups. Meanwhile, 150 healthy children were selected as the control group, and their FeNO was measured. The diagnostic values of FeNO for typical bronchial asthma and cough variant asthma were analyzed using the receiver operating characteristic curve. RESULTS: The FeNO values in the typical bronchial asthma and cough variant asthma groups were significantly higher than in the control group (P<0.01), and the FeNO value in the typical bronchial asthma group was significantly higher than in the cough variant asthma group (P<0.01). FEV1/FVC%, FEV1%pred, and PD20 were significantly lower in the typical bronchial asthma group than in the cough variant asthma group (P<0.01). The optimal cut-off value of FeNO was 19.5 ppb for the diagnosis of typical bronchial asthma, with a sensitivity of 83.3% and a specificity of 86.7%; the optimal cut-off value of FeNO was 15.5 ppb for the diagnosis of cough variant asthma, with a sensitivity of 67.5% and a specificity of 78.0%; the optimal cut-off value of FeNO was 28.5 ppb for the differentiation between typical bronchial asthma and cough variant asthma, with a sensitivity of 60.7% and a specificity of 82.5%. CONCLUSIONS: Measurenment of FeNO may be useful in the diagnosis and differential diagnosis of typical bronchial asthma and cough variant asthma.