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

Abstract

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-beta1 with lower FEV(1) than ATA patients or HCs (p < .05 for each). NERD patients with higher DPP10 levels had higher TGF-beta1, but lower FEV(1) (p < .05 for all), whilst no differences were noted in ATA patients. Moreover, the seum DPP10 levels had a positive correlation with TGF-beta1 (r = 0.384, p < .001), but a negative correlation with FEV(1) (r = -0.230, p = .016) in NERD patients. In in vitro studies, expression of DPP10 in airway epithelial cells was enhanced by TGF-beta1 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-beta1 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-beta1-mediated airway dysfunction in NERD patients, where blockade of DPP10 may have potential benefits.