Asthma is a common chronic disease characterised by acute inflammation of the airways. Asthma arises from a complex interaction between genetic factors of the evolving immune system in the infant and the environment it encounters[
]. Despite recent guidelines focusing on asthma control, many asthmatic patients remain poorly controlled under specialist care[
]. Patient outcomes could be improved by earlier diagnosis and better monitoring. Therefore, it is critical to identify new biomarkers to measure and monitor inflammation within the lungs of a patient with asthma. The role of chitinase and chitinase-like proteins in inflammation and tissue remodelling in human disease has become an important issue.
The chitinase-like protein YKL-40 is also termed chitinase 3-like 1 (CHI3L1). It is produced at sites of inflammation in many cells and is secreted from macrophages and smooth muscle cells[
]. YKL-40 binds to ubiquitously expressed chitin but lacks chitinase activity. Previous studies have demonstrated that YKL-40 was associated with pathologic conditions characterised by aberrant cell growth, tissue inflammation and remodelling. Examples of pathologic conditions involving YHL-40 include the following: cancers, diabetes, atherosclerosis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD), liver fibrosis, idiopathic pulmonary fibrosis and Crohn’s disease[
]. The measurement of YKL-40 levels is useful and has diagnostic and prognostic value in several diseases[
YKL-40 is synthesised in neutrophil precursors and is stored in the specific granules of neutrophils. YKL-40 secretion is stimulated by the cytokines IL-6, IL-17, and IL-18 released from neutrophils, vascular smooth muscle, macrophages, chondrocytes and cancer cells[
]. YKL-40 has been shown to induce activation of the mitogen-activated protein kinase pathway, nuclear factor-κB transcriptional activity and protein kinase B (Akt) pathway in cell cultures of human colon cell lines and human chondrocytes and synovial cells[
]. YKL-40 also potently stimulates the growth of several types of human fibroblasts derived from synovium, adult skin, and foetal lung[
]. Moreover, YKL-40 acts a chemoattractant that modulates vascular endothelial cell morphology by promoting the formation of branching tubules[
]. A recent study by Tang et al. demonstrated that YKL-40 may be involved in the inflammation of asthma by induction of IL-8 from epithelium, which subsequently contributes to BSMC proliferation and migration[
]. Collectively, YKL-40 has a role in inflammation, pathological, fibrosis and tissue remodelling.
Chupp et al. demonstrated that YKL-40 was highly unregulated in alveolar macrophages and the subepithelial basement membrane of asthmatic patients. Additionally, the serum YKL-40 level was elevated in asthmatic patients[
]. Duru et al. showed that serum YKL-40 levels were higher in non-smoker asthma patients during acute exacerbation than in control individuals[
]. Kuepper et al. demonstrated that YKL-40 levels were predominantly increased at the site of allergen deposition in response to allergen challenge[
]. A recent study suggested that serum YKL-40 levels were significantly elevated in patients with asthma compared to controls. This result indicates that high levels of serum YKL-40 may be a biological characteristic of asthma exacerbation[
Although previous studies have reported elevated YKL-40 levels in asthmatic patients, the change in serum YKL-40 levels upon treatment in asthmatic patients and its correlation with lung function and the asthma control test (ACT) remain unknown. Therefore, this study was conducted to determine whether serum YKL-40 levels are decreased in patients with asthma after the introduction of appropriate treatment. Furthermore, the relationships between the serum YKL-40 level, lung function and ACT were also investigated to evaluate the clinical significance of the serum YKL-40 level during the course of the disease.
In this study, we explored the potential role of serum YKL-40 measurement in the management of asthma. There were several main findings of our study as follows: (i) elevated YKL-40 levels in asthma patients were associated with disease severity, and serum YKL-40 levels were deceased in asthmatic patients after administration of appropriate treatment; (ii) the serum YKL-40 level is negatively correlated with %FEV
1 and ACT score before asthma treatment; (iii) although these correlations were no longer observed after treatment, changes in serum YKL-40, %FEV
1 and ACT score continued to correlate significantly; and (iv) patients who received ICS showed a significant improvement in serum YKL-40, %FEV
1 and ACT compared with patients without ICS. Patients with elevated levels of YKL-40 had significantly greater corticosteroid use than patients with lower levels. These results suggest that the YKL-40 level is implicated in the pathophysiology of asthma.
At baseline, the serum YKL-40 levels in the partly controlled group and uncontrolled group were significantly higher than the levels in the controlled group. However, there were no differences in the serum YKL-40 levels between the partly controlled group and the uncontrolled group. The reason for this finding is unclear, but it may be explained by the well-known individual variability in the perception of symptoms. The patients with uncontrolled ACT (≤19)/YLK-40 levels below the median (≤75.2) (Additional file
: Figure S1A) may have adequately addressed the atopic inflammation in their airways after treatment. However, these patients continue to have symptom persistence for other reasons including co-morbidities (e.g., rhinitis, gastroesophageal reflux disease), non-eosinophilic asthma and other conditions that may be similar to asthma. The patients who had ACT controlled (>19)/YLK-40 levels above the median (>75.2) (Additional file
: Figure S1B) were symptomatically controlled but have evidence of persistent inflammation and could be at risk for future asthma problems. Moreover, those who were ACT uncontrolled (≤19)/YLK-40 levels above the median (>75.2) (Additional file
: Figure S1C) may be part of the symptom controlled/high level of YKL-40 (>75.2) asthmatics group. This result could be partly explained by a poor symptom-perception due to adaptation to their level of disease. These data were consistent with previous reports that suggested that asthma evaluation cannot be inferred from single measures of ACT score[
]. GINA also recommends that questionnaires addressing the level of asthma control need to be considered in combination with objective measurements such as lung function and inflammatory cytokines[
]. To reconcile this issue, we further performed a separate analysis and reanalysed the data using the asthma severity according to GINA. The data showed that serum YKL-40 levels for patients in the severe asthma group were higher than the levels in the moderate and mild asthma groups. To confirm this result, bronchial biopsy specimens were specifically stained for YKL-40 in patients with asthma and were then further evaluated. The quantification of lung YKL-40 expression revealed that YKL-40 expression was higher in mild asthma patients than healthy controls. The subgroup analysis revealed that severe asthma patients have significantly higher YKL-40 levels than mild and moderate asthma patients. These findings suggest that the ACT questionnaire may convey something that inflammatory markers and spirometry cannot assess. However, asthma evaluation control cannot be inferred from single measures of ACT score and should be considered with objective measurements (e.g., biomarkers, lung function). The YKL-40 level is upregulated in human asthma and is associated with disease severity, which suggests that high levels of YKL-40 may be a biological characteristic of asthma severity.
We observed statistically significant correlations between the serum YKL-40 level and %FEV
and between the serum YKL-40 level and ACT score. Specjalski et al. showed that in a Polish population, the serum levels of YKL-40 were significantly higher in patients with uncontrolled and partly controlled asthma than in controlled asthmatic patients and healthy subjects[
]. Chupp et al. demonstrated that the circulating YKL-40 level was correlated with lung function, asthma severity, and the thickness of the subepithelial basement membrane[
]. Additionally, a recent study by Tang et al. showed that serum YKL-40 levels correlated positively with exacerbation attacks and blood eosinophils. However, the levels were correlated inversely with lung function[
]. The exact role of the serum YKL-40 level in asthma is still unclear and controversial[
]. Specjalski et al. showed that there were no relationships between YKL-40 and asthma severity or total serum IgE[
]. A recent study by Sohn et al. suggested that there were no significant associations between CHI3L1 single nucleotide polymorphisms (SNPs) and asthma in an East Asian population[
]. The basis for these discrepancies may be due to ethnic background and differences in CHI3L1 haplotype structures. The CHI3L1 polymorphisms have been associated with features of asthma and serum YKL-40 levels[
]. This suggests that the CHI3LI gene polymorphism may lead to a reduction in YKL-40.
At visit 2, no correlations between serum YKL-40 and %FEV
or ACT score were observed. One explanation may be that a majority of patients in our study were mild asthmatics and showed a response in all three measurements after administration of appropriate therapy, which minimised the range of their distribution. However, the changes in serum YKL-40, %FEV
and ACT score were significantly correlated. Furthermore, the serum YKL-40 level declined in asthmatic patients after appropriate treatment. One possible explanation for this result could be that ACT scores were significantly improved in most patients who presented with a mild or stable condition after treatment. This result is consistent with previous studies by Chupp et al. and Tang et al. that showed that serum YKL-40 levels were higher in patients with exacerbated asthma than in stable patients[
]. In addition, our data demonstrated that patients with asthma receiving regular ICS therapy had a significant improvement in serum YKL-40, %FEV
, and ACT. Patients with elevated levels of YKL-40 had significantly greater corticosteroid use than patients with lower levels. This result suggests that YKL-40 production may be refractory to current asthma treatments and may represent an alternative therapeutic target for severe asthma[
]. A previous study demonstrated that serum YKL-40 levels in patients with active rheumatoid arthritis decreased rapidly during prednisolone therapy, which suggests that steroids may have a direct effect on expression of YKL-40[
]. However, it should be noted that patients were treated with ICS, but differences in dosing and compliance existed and serum YKL-40 levels may be influenced by the CHI3LI gene polymorphism or other medications such as bronchodilators.
There are some limitations to this study that need to be considered. Asthmatic patients with newly diagnosis asthma were enrolled in our study, and most patients (69.9%, 72/103) had mild asthma. Our results may not fully reflect the general population of asthmatic patients, especially patients with severe therapy-resistant asthma. Additionally, we did not consider the Asthma Control Questionnaire (ACQ) because the ACQ has not been validated in the Chinese population and the ACT is easier to score and provides the same screening accuracy[
The authors declare they have no competing interests.
LTW: performed experiments, analyzed data, wrote manuscript; CM: aided in data collection and analyses; LYY: performed analyses and assisted in procuring human blood samples; WD and LDM: performed ELISA and produced graphs and tables; WB and DZC: designed the study and assisted in generating the final manuscript. All authors have read and approved the final manuscript.