Abstract
BackgroundDespite the high disease burden of chronic obstructive pulmonary disease (COPD) and risk of acute COPD exacerbation, few COPD biomarkers are available. As developmental endothelial locus-1 (DEL-1) has been proposed to possess beneficial effects, including anti-inflammatory effects, we hypothesized that DEL-1 could be a blood biomarker for COPD.ObjectiveTo elucidate the role of plasma DEL-1 as a biomarker of COPD in terms of pathogenesis and for predicting acute exacerbation.MethodsCigarette smoke extract (CSE) or saline was intratracheally administered to wild-type (WT) and DEL-1 knockout (KO) C57BL/6 mice. Subsequently, lung sections were obtained to quantify the degree of emphysema using the mean linear intercept (MLI). Additionally, plasma DEL-1 levels were compared between COPD and non-COPD participants recruited in ongoing prospective cohorts. Using negative binomial regression analysis, the association between the plasma DEL-1 level and subsequent acute exacerbation risk was evaluated in patients with COPD.ResultsIn the in vivo study, DEL-1 KO induced emphysema (KO saline vs. WT saline; P = 0.003) and augmented CSE-induced emphysema (KO CSE vs. WT CSE; P < 0.001) in 29 mice. Among 537 participants, patients with COPD presented plasma log (DEL-1) levels lower than non-COPD participants (P = 0.04), especially non-COPD never smokers (P = 0.019). During 1.2 ± 0.3 years, patients with COPD in the lowest quartile of Log(DEL-1) demonstrated an increased risk of subsequent acute exacerbation, compared with those in the highest quartile of Log(DEL-1) (adjusted incidence rate ratio, 3.64; 95% confidence interval, 1.03–12.9).ConclusionLow DEL-1 levels are associated with COPD development and increased risk of subsequent COPD acute exacerbation. DEL-1 can be a useful biomarker in patients with COPD.
Highlights
Despite the high disease burden of chronic obstructive pulmonary disease (COPD) and risk of acute COPD exacerbation, few COPD biomarkers are available
Low developmental endothelial locus-1 (DEL-1) levels are associated with COPD development and increased risk of subsequent COPD acute exacerbation
In vivo study DEL‐1 deficiency resulted in emphysema development and augmented Cigarette smoke extract (CSE)‐induced emphysema in mice We first evaluated the role of DEL-1 in the development of emphysema in mice following CSE treatment
Summary
Despite the high disease burden of chronic obstructive pulmonary disease (COPD) and risk of acute COPD exacerbation, few COPD biomarkers are available. GOLD introduced ABCD system including COPD assessment test and prior history of acute exacerbation [10], and the needs for other biomarkers increased, which led to investigations of various biomarkers. A few blood biomarkers linked to systemic inflammation such as C-reactive protein (CRP), interleukins (ILs), fibrinogen and tumor necrosis factor (TNF)-α have been identified [12]. These biomarkers are associated with COPD outcomes including acute exacerbation [12], the relationship between airway inflammation, that is the key pathogenesis in acute exacerbation, and systemic inflammation is unclear [13, 14]. There are other blood biomarkers, including surfactant protein D (SP-D) [15] and club cell protein-16 (CC-16) [16], associated with acute exacerbation, those have limitations as reliable biomarkers due to conflicting results [17] and small size study [16]
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