Exploring the roles of airway dipeptidyl peptidase 1 in obstructive airway disease

Abstract

Background: Dipeptidyl peptidase 1 (DPP1) exacerbates airway neutrophilic inflammation in bronchiectasis, which is characterised by airway dysfunction and dilation and chronic bacterial infection. However, little is known about the pathogenetic roles of DPP1 in obstructive airway diseases, including COPD, asthma and asthma-COPD overlap (ACO). Here, we tested the hypothesis that airway DPP1 could enhance neutrophilic inflammation and affect mucus plugging, airway dilation and the airway microbiome in patients with these diseases.

Methods: Sputum DPP1, cell differential count and microbiome were cross-sectionally evaluated in patients with COPD, asthma with airflow limitation and ACO. Sputum high mobility group box 1 (HMGB1) was measured to estimate airway epithelial damage. Chest computed tomography was also performed to visually assess mucus plugs and airway dilation with the Reiff score and quantify the total airway count and wall area percentage.

Results: 68 patients were classified into high-DPP1/high-neutrophil (n=17), low-DPP1/high-neutrophil (n=37) and low-neutrophil (n=14) groups based on sputum DPP1 levels and neutrophil percentages. The rate of mucus plugging and the relative abundance of the phylum Firmicutes were significantly lower and the level of sputum HMGB1 was significantly greater in the high-DPP1/high-neutrophil group than in the low-DPP1/high-neutrophil group. Moreover, airway dilation without mucus plugging was observed only in the high-DPP1/high-neutrophil group (prevalence 29%).

Conclusions: High sputum DPP1 levels may reduce colonisation by the phylum Firmicutes and mucus plugging, but increase airway epithelial damage, which could induce airway dilation without mucus plugging in patients with obstructive airway disease with neutrophilic inflammation.

FIGURE 1

Patient stratification based on sputum dipeptidyl peptidase 1 (DPP1) levels and neutrophil counts and their associations with sputum eosinophil count and airway disease diagnosis. a) Distribution of sputum DPP1 levels and sputum neutrophil percentages. Patients were classified into three groups according to the sputum neutrophil percentage (61%) and the 75th percentile of the sputum DPP1 level (227.1 ng·mL⁻¹): high-DPP1/high-neutrophil, low-DPP1/high-neutrophil and low-neutrophil groups. b) The sputum eosinophil and macrophage counts were greater in the low-neutrophil group than in the other groups. c) The proportions of patients with asthma, COPD and asthma–COPD overlap (ACO) did not significantly differ among the three groups. *: p<0.05 based on the Wilcoxon rank test followed by the post hoc Dunnett test.

FIGURE 2

Computed tomography findings of mucus plugging and airway dilation in patients stratified by sputum dipeptidyl peptidase 1 (DPP1) concentration and neutrophil percentage. Patients were classified into three groups according to the sputum neutrophil (61%) percentage and the 75th percentile of the sputum DPP1 level (227.1 ng·mL⁻¹): high-DPP1/high-neutrophil, low-DPP1/high-neutrophil and low-neutrophil groups. a) The rate of mucus plugging, defined as a mucus plug score ≥1, was significantly lower in the high-DPP1/high-neutrophil group than in the other groups. b) The rate of airway dilation, defined as a Reiff score ≥1, tended to be greater in the high-DPP1/high-neutrophil group. c) Airway dilation without mucus plugging, defined as a combination of a Reiff score ≥1 and a mucus plug score 0, was observed in the high-DPP1/high-neutrophil group (29%) but not in the other groups (0% and 0%). *: p<0.05 based on Fisher's exact test followed by multiple Fisher comparisons with Holm correction.

FIGURE 3

Sputum high mobility group box 1 (HMGB1) levels and the microbiome in patients stratified by sputum dipeptidyl peptidase 1 (DPP1) concentration and neutrophil percentage. Patients were classified into three groups according to the sputum neutrophil percentage (61%) and the 75th percentile of the sputum DPP1 level (227.1 ng·mL⁻¹): high-DPP1/high-neutrophil, low-DPP1/high-neutrophil and low-neutrophil groups. a) HMGB1 levels and b) the relative abundance of the phylum Firmicutes in the sputum were significantly higher and lower, respectively, in the high-DPP1/high-neutrophil group than in the low-DPP1/high-neutrophil group. c) The relative abundance of the genus Haemophilus did not differ between the high-DPP1/high-neutrophil group and the low-DPP1/high-neutrophil group but was significantly lower in the low-neutrophil group. *: p<0.05 based on the Wilcoxon rank test followed by the post hoc Dunnett test.