The chitinase-like protein YKL-40 modulates cystic fibrosis lung disease

Abstract

The chitinase-like protein YKL-40 was found to be increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD), two disease conditions featuring neutrophilic infiltrates. Based on these studies and a previous report indicating that neutrophils secrete YKL-40, we hypothesized that YKL-40 plays a key role in cystic fibrosis (CF) lung disease, a prototypic neutrophilic disease. The aim of this study was (i) to analyze YKL-40 levels in human and murine CF lung disease and (ii) to investigate whether YKL-40 single-nucleotide polymorphisms (SNPs) modulate CF lung disease severity. YKL-40 protein levels were quantified in serum and sputum supernatants from CF patients and control individuals. Levels of the murine homologue BRP-39 were analyzed in airway fluids from CF-like βENaC-Tg mice. YKL-40SNPs were analyzed in CF patients. YKL-40 levels were increased in sputum supernatants and in serum from CF patients compared to healthy control individuals. Within CF patients, YKL-40 levels were higher in sputum than in serum. BRP-39 levels were increased in airways fluids from βENaC-Tg mice compared to wild-type littermates. In both CF patients and βENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with the severity of pulmonary obstruction. Two YKL-40 SNPs (rs871799 and rs880633) were found to modulate age-adjusted lung function in CF patients. YKL-40/BRP-39 levelsare increased in human and murine CF airway fluids, correlate with pulmonary function and modulate CF lung disease severity genetically. These findings suggest YKL-40 as a potential biomarker in CF lung disease.

Figure 1. YKL-40 levels in human and murine CF lung disease.

A. YKL-40 levels in CF patients and healthy controls YKL-40 protein levels were quantified by means of ELISA in sera and sputum supernatants from cystic fibrosis (CF) or healthy control subjects. The left graph depicts means ± SDs, the right scatter graph depicts individual patients with horizontal bars as medians; *P<0.05 ** P<0.01 disease group compared to the control group. Horizontal bars indicate comparisons among the disease groups. B. BRP-39 levels in murine CF-like lung disease. BRP-39 protein levels were quantified by means of ELISA in BAL fluids from βENaC-Tg (n = 9) and WT mice (n = 7). *P<0.05; C. YKL-40/BRP-39 airway levels and lung function in human and murine CF lung disease. Left panel: YKL-40 protein levels were quantified by means of ELISA in sputum supernatants from CF patients (n = 59). FEV1: Forced expiratory volume in 1 second (% of predicted). Right panel: BRP-39 protein levels were quantified by means of ELISA in BAL fluids from βENaC-Tg (n = 9, grey fill) and WT mice (n = 7, white fill).

Figure 2. YKL-40 SNPs.

A. Location and linkage disequilibrium (R²) of YKL-40 polymorphisms genotyped in the CF population. B. YKL-40 serum levels in CF patients stratified for the respective rs871799 (upper panel) or the rs4950928 (lower panel) genotype. *P<0.05, **P<0.01.