Developmental endothelial locus-1 as a potential biomarker for the incidence of acute exacerbation in patients with chronic obstructive pulmonary disease

Abstract

Background Despite 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. Objective To elucidate the role of plasma DEL-1 as a biomarker of COPD in terms of pathogenesis and for predicting acute exacerbation. Methods Cigarette 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. Results In 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). Conclusion Low 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.

Del-1 Plays a Protective Role against COPD Development by Inhibiting Inflammation and Apoptosis

“…In our previous study, the protective effect of Del-1 in response to CSE was demonstrated through increased emphysema in Del-1 KO mice [11]. Consistent with this, Del-1 levels were found to be lower in lung homogenates from patients with COPD than those from smokers without COPD.…”

“…Previously, we have shown that plasma levels of Del-1 are lower in patients with COPD and that this reduced Del-1 level predicts the subsequent risk of AE-COPD [11]. These findings suggest that extracellular soluble Del-1 plays a protective role against the development of both COPD and AE-COPD.…”

“…We previously demonstrated that intratracheal instillation of CSE induced more severe emphysema in Del-1 KO mice than in WT mice [11]. In the lung tissues of Del-1 KO mice, the surrogate markers of oxidative stress (8-OHdG and 4-HNE) were increased (Supplementary Figure S1), suggesting the protective effects of Del-1 against COPD development via an anti-oxidative mechanism.…”

“…Macrophages are recognized as crucial inflammatory cells in the pathogenesis of COPD and AE-COPD during bacterial infections [11]. Changes in Del-1 levels were observed in immune cells, including macrophages, in the lung tissues of smoker/COPD patients and CSE-instilled mice.…”

Proteomic Networks and Related Genetic Variants Associated with Smoking and Chronic Obstructive Pulmonary Disease

“…EDIL3 (EGF-like repeat and discoidin I-like domain-containing protein 3) is an integrin ligand that promotes adhesion of endothelial cells and is involved in angiogenesis and vascular remodeling. Plasma levels of EDIL3 have been shown to be decreased in COPD patients and associated with increased risk of acute exacerbation [80]. CRLD2 (Cysteine-rich secretory protein LCCL domain-containing 2) [CRISPLD2] is a secreted protein that promotes matrix assembly and modulates airway branching and alveogenesis [81].…”