The effect of Bruton's tyrosine kinase (BTK) inhibitor in the eosinophilic asthma model of mouse.

Bruton's Tyrosine kinase (BTK) plays a pivotal role as the key mediator in B cell signaling. Recent research has revealed that it is also expressed in cells critical to asthma development, such as T cells, and eosinophils. This study aims to investigate the potential of BTK inhibitor in eosinophilic asthma mouse model. BALB/c mice were sensitized with ovalbumin (OVA) via intraperitoneal injections and followed by OVA nebulizations. The mice were treated with 250 µg/ml or 500 µg/ml of ibrutinib before the second intraperitoneal injection and the first nebulization. Two days after the last OVA challenge, airway hyperresponsiveness (AHR) was assessed with methacholine, and differential cell count in bronchoalveolar lavage fluid (BALF) was performed. The cytokines were measured in BALF, and serum OVA-specific IgE and IgG antibody levels were evaluated by ELISA. The inhibitory effect of ibrutinib was also evaluated in splenic mononuclear cells, mast cells, eosinophils, and T cells in vitro. Treatment with ibrutinib significantly attenuated AHR and airway inflammation, compared to the OVA-induced positive control. The treatment also reduced IL-4, IL-5, IL-13 and IFN-γ cytokine levels and suppressed OVA-specific IgE and IgG production compared to the OVA-induced positive control. Additionally, ibrutinib decreased beta-hexosaminidase release from mast cells, type 2 cytokine productions from mononuclear cells and T cells, and eosinophilic activation markers in vitro. The results of this study suggest that ibrutinib treatment could exert anti-allergic effects by inactivating B cells and other BTK-expressing cells. Further studies are needed to investigate the potential therapeutic effect of ibrutinib on allergic diseases.

Contribution of dipeptidyl peptidase 10 to airway dysfunction in patients with NSAID-exacerbated respiratory disease.

BACKGROUND: Genetic variants of dipeptidyl peptidase 10 (DPP10) have been suggested to contribute to the development of NSAID-exacerbated respiratory disease (NERD). However, the mechanisms of how DPP10 contributes to NERD phenotypes remain unclear. OBJECTIVE: To demonstrate the exact role of DPP10 in the pathogenesis of NERD. METHODS: Patients with NERD (n = 110), those with aspirin-tolerant asthma (ATA, n = 130) and healthy control subjects (HCs, n = 80) were enrolled. Clinical characteristics were analysed according to the serum DPP10 levels in both NERD and ATA groups. The function of DPP10 in airway inflammation and remodelling was investigated with in vitro, ex vivo and in vivo experiments. RESULTS: NERD patients had higher levels of serum DPP10 and TGF-ß1 with lower FEV1 than ATA patients or HCs (p < .05 for each). NERD patients with higher DPP10 levels had higher TGF-ß1, but lower FEV1 (p < .05 for all), whilst no differences were noted in ATA patients. Moreover, the seum DPP10 levels had a positive correlation with TGF-ß1 (r = 0.384, p < .001), but a negative correlation with FEV1 (r = -0.230, p = .016) in NERD patients. In in vitro studies, expression of DPP10 in airway epithelial cells was enhanced by TGF-ß1 treatments. Furthermore, DPP10 was found to be produced from immune cells and this molecule induced the ERK phosphorylation in airway epithelial cells, which was suppressed by anti-DPP10 treatment. In asthmatic mouse models, increased levels of DPP10 in the serum and TGF-ß1 in the bronchoalveolar lavage fluid were noted, which were suppressed by anti-DPP10 treatment. Moreover, anti-DPP10 treatment inhibited the ERK phosphorylation and extracellular matrix deposition in the lungs. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that increased production of DPP10 may contribute to TGF-ß1-mediated airway dysfunction in NERD patients, where blockade of DPP10 may have potential benefits.