We demonstrated in this study that serum NGAL levels of non-smoking people with stable asthma and obstructive ventilatory disorder were higher than those of people with asthma without obstructive ventilatory disorder. There were negative correlations between serum NGAL level and spirometric variables related to the distal airway. Although serum NGAL levels were also correlated with age and duration of asthma, we confirmed that serum NGAL level was independently associated with obstructive ventilatory disorder by performing a multiple regression analysis.
The role of NGAL has been investigated with respect to neutrophilic inflammation associated with smoking in the field of respiratory medicine. Blood NGAL level has been explored in COPD, which is mainly caused by smoking and characterized by neutrophilic airway inflammation. Plasma NGAL levels in patients with COPD were reported to be higher than those in healthy subjects . Among people with COPD who smoke, serum NGAL levels were correlated with serum levels of neutrophil elastase . Moreover, a previous study showed a tendency for plasma NGAL levels to be higher in patients with asthma-COPD overlap (ACO) than in people with only asthma . People with asthma who have a long smoking history may develop ACO [20,21]. In such cases, plasma NGAL levels have been suggested to be useful for identifying patients in whom a change was observed from asthma alone to ACO [22-24].
Regarding the relationship between airflow obstruction and serum NGAL level, serum NGAL levels in patients with severe/very severe COPD (GOLD 3/4) were reported to be higher than those in patients with mild/moderate COPD (GOLD 1/2), indicating that serum NGAL level may have some associations with airflow obstruction . In the present study, we found that serum NGAL levels were associated with airway obstruction, especially of the distal airway, even in non-smoking patients with stable asthma. The mechanism for explaining how serum NGAL level is affected by airflow obstruction is unknown. However, neutrophilic airway inflammation is thought to be involved in airflow remodeling, which is a cause of persistent airflow obstruction in asthma. Thus, we speculate that NGAL is involved in airway obstruction via airway remodeling caused by neutrophilic inflammation.
Airway remodeling is generally a result of chronic airway inflammation in people with asthma. Mucosal gland hyperplasia, airway smooth muscle hypertrophy, and reticular basement membrane thickening are typical features of airway remodeling in asthma. These pathological changes cause progressive and irreversible decline in lung function . Although neutrophils play an important role in pathogen clearance, persistent airway neutrophilia and the consequent increase in protease secretion cause airway remodeling .
NGAL has been reported to potentially promote airway remodeling through epithelial-mesenchymal transition (EMT). According to an in vitro study, NGAL down-regulates E-cadherin expression and up-regulates α-SMA expression in 16HBE cells via the WNT/glycogensynthase-3β (GSK-3β) pathway. NGAL has also been reported to promote the proliferation and migration of human bronchial smooth muscle cells (HASMC) .
There are several limitations of this study. First, this was a retrospective, single-center study with a small number of patients. Second, we did not evaluate the potential effect of second-hand smoke exposure. There is a possibility that our results were affected by second-hand smoke exposure. Third, we did not evaluate the number of neutrophils in the sputum or BAL fluid. Thus, the association between serum NGAL level and neutrophilic airway inflammation was not evaluated in this study.
This is the first report to evaluate the relationship between serum NGAL levels and clinical parameters in patients with asthma. We found that serum NGAL levels were elevated in non-smoking patients with stable asthma and obstructive ventilatory disorder and were correlated with variables related to the distal airway. Our findings suggest that NGAL is involved in airway remodeling of the distal airway and possibly mediated by neutrophilic inflammation. Clinically, serum NGAL level is a proposed candidate biomarker of persistent airway obstruction in asthma. Additional studies are required to further analyze the association between serum NGAL level and neutrophilic airway inflammation and remodeling in asthma.