Sputum Neurturin Levels in Adult Asthmatic Subjects

Abstract

Background: Neurturin (NRTN) is a neurotrophic factor that was originally identified in the development and maintenance of neural cells. Recent studies involving NRTN knockout mice have reported its anti-inflammatory effects in allergic airway conditions. However, the role of NRTN in human asthma has not yet been identified.

Objective: The purposes of the present study were to confirm the presence of NRTN in the airways and to investigate the clinical and pathogenetic roles of NRTN in asthma.

Methods: The NRTN levels in the induced sputum were measured by enzyme-linked immunosorbent assay (ELISA). Relationships between NRTN and clinical characteristics, asthma control status, and airway inflammation were assessed.

Results: Sixty-four asthmatic subjects were enrolled in the study. All asthmatic subjects had detectable sputum NRTN levels, with a mean (SD) level of 2.03 (1.29) ng/mL. The sputum NRTN levels had significant positive correlations with sputum eosinophil and exhaled nitric oxide levels and were significantly higher in the atopic subjects than in the non-atopic subjects. No significant difference in sputum NRTN levels were observed for asthma control status and asthma exacerbation. In sputum inflammatory analyses, sputum NRTN level was positively correlated with interleukin (IL)-5 and IL-13 levels, and negatively correlated with matrix metalloproteinase (MMP)-9 level.

Conclusion: It is plausible that sputum NRTN could serve as a new marker for Type 2 airway inflammation, implicating its role in the process of airway remodeling in asthma. Future studies should investigate the clinical relevance of sputum NRTN level in prospective analyses.

Keywords: airway inflammation; asthma; neurturin; sputum; type 2 inflammation.

Figure 1

Relationship between sputum NRTN levels and serum NRTN levels in asthmatic subjects (n = 15). Open circles indicate levels below the lower limit of the measurement range.

Figure 2

Comparisons of sputum NRTN levels between asthmatic subjects by atopic status (A), by different asthma severities (B), by asthma control status (C), with or without a fixed airflow obstruction (D), with or without asthma exacerbations with unscheduled visits the outpatient clinic in the previous year (E), and with or without asthma exacerbations with occasional uses of systemic corticosteroids in the previous year (F). The box signifies the 25th and 75th percentiles, and the median is represented by a short line within the box. The open circle indicates sputum NRTN level in asthmatic subjects. *p < 0.05.

Figure 3

Relationships between sputum NRTN level and FeNO level (A), ACT score (B), and % predicted FEV₁ (C). A comparison of sputum NRTN levels between asthmatic subjects with FeNO < 20 ppb and those with FeNO ≥ 20 ppb (D). The result of linear regression analysis of the data that reveal a significant correlation is represented by the solid line. The box signifies the 25th and 75th percentiles, and the median is represented by a short line within the box. The open circle indicates sputum NRTN level in asthmatic subjects.

Figure 4

Receiver operating characteristic (ROC) analysis of sputum NRTN level and FeNO as predictors of sputum eosinophilia (eosinophils ≥ 2%). The area under the curves of sputum NRTN and FeNO were 0.578 and 0.945, respectively.

Figure 5

Correlations between sputum NRTN level and sputum eosinophils (A), sputum neutrophils (B), sputum macrophages (C), and sputum lymphocytes (D) in asthmatic subjects.

Figure 6

Comparisons of sputum NRTN levels between asthmatic subjects by airway inflammatory phenotypes. *p < 0.05.

Figure 7

Correlations between sputum NRTN level and IL-4 (A), IL-5 (B), IL-13 (C), IFN-γ (D), IL-6 (E), MMP-2 (F), and MMP-9 (G) levels in sputum supernatant. The results of linear regression analysis of the data that reveal significant correlations are represented by the solid line. Dashed lines indicate the limit of each measurement, and open circles indicate levels outside the measurement range.