Increased YKL-40 and Chitotriosidase in Asthma and Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Serum chitinases may be novel biomarkers of airway inflammation and remodeling, but less is known about factors regulating their levels.Objectives: To examine serum chitotriosidase activity and YKL-40 levels in patients with asthma and chronic obstructive pulmonary disease (COPD) and evaluate clinically relevant factors that may affect chitinase levels, including genetic variability, corticosteroid treatment, disease exacerbations, and allergen exposure.Methods: Serum chitotriosidase (CHIT1) activity and YKL-40 (CHI3L1) levels, as well as the CHIT1 rs3831317 and CHI3L1 rs4950928 genotypes, were examined in subsets of patients with mild to moderate asthma (n = 76), severe asthma (n = 93), and COPD (n = 64) taking part in the European multicenter BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) study. Blood was obtained at baseline, before and after a 2-week oral steroid intervention, up to six times during a 1-year period, and during exacerbations. Baseline chitinase levels were also measured in 72 healthy control subjects. The effect of allergen inhalation on blood and sputum YKL-40 levels was measured in two separate groups of patients with mild atopic asthma; one group underwent repeated low-dose allergen challenge (n = 15), and the other underwent high-dose allergen challenge (n = 16).Measurements and Main Results: Serum chitotriosidase and YKL-40 were significantly elevated in patients with asthma and those with COPD compared with healthy control subjects. Genotype and age strongly affected both YKL-40 and chitotriosidase activity, but associations with disease remained following adjustment for these factors. Correlations were observed with lung function but not with other biomarkers, including exhaled nitric oxide, blood eosinophils, periostin, and IgE. Generally, acute exacerbations, allergen-induced airway obstruction, and corticosteroid treatment did not affect circulating chitinase levels.Conclusions: YKL-40 and chitotriosidase are increased in asthma and more so in COPD. The data in the present study support these substances as being relatively steroid-insensitive, non-T-helper cell type 2-type biomarkers distinctly related to chronic inflammatory disease processes.

Characterisation of asthma subgroups associated with circulating YKL-40 levels

“…However, unsupervised learning models to more precisely define the phenotypes associated with YKL-40 have not been tested (2). …”

“…(3, 4) While human and mechanistic studies have demonstrated that YKL-40 is involved in airway remodeling(5, 6), they have not demonstrated a clear association between markers of Type 2 (T2) inflammation and YKL-40. (1, 2, 7) This suggests that YKL-40 may influence or be influenced by non-T2 inflammatory responses in asthma.…”

Protein Biomarkers in Asthma

“…Correlations between lung function and expression of chiotriosidase and YKL40 have been demonstrated; levels of circulating chitinase were not affected by acute exacerbations, allergen-induced airway obstruction, or corticosteroid treatment. It can be concluded that chitotriosidase and YKL40 are relatively steroid-insensitive substances and could be used as non-T helper cell type 2 biomarkers that have a distinct relation to chronic inflammatory disease processes [86].…”

Biomarkers for the Phenotyping and Monitoring of Asthma in Children

“…A mediator which has shown potential for this purpose is YKL-40, a chitinase-like protein which is elevated in the serum of both school-age children and adults with severe asthma. Increased circulating YKL-40 consistently associates with reduced lung function, strengthening a possible relationship with disease severity [59–62]. The exact biological function of YKL-40 remains unclear, but the fact that it associates with measures of airway remodeling such as bronchial wall thickness and subepithelial fibrosis [59, 60] and increases the proliferation of bronchial smooth muscle cells [63, 64] is in line with an involvement in airway remodeling and fibrotic lung disease [65].…”

“…YKL-40 levels are higher in adults with COPD compared to asthma [62] and, preliminarily, in children with BPD compared to asthma [66], suggesting that the chitinases are not Th2-specific markers of airway disease. Also, correlations often exist between YKL-40 levels and neutrophilic, rather than eosinophilic inflammation [60, 67].…”