Abstract
Despite advances in the pathophysiology of chronic obstructive pulmonary disease (COPD), there is a distinct lack of biochemical markers to aid clinical management. Microvesicles (MVs) have been implicated in the pathophysiology of inflammatory diseases including COPD, but their association to COPD disease severity remains unknown. We analyzed different MV populations in plasma and bronchoalveolar lavage fluid (BALF) taken from 62 patients with mild to very severe COPD (51% male; mean age: 65.9 yr). These patients underwent comprehensive clinical evaluation (symptom scores, lung function, and exercise testing), and the capacity of MVs to be clinical markers of disease severity was assessed. We successfully identified various MV subtype populations within BALF [leukocyte, polymorphonuclear leukocyte (PMN; i.e., neutrophil), monocyte, epithelial, and platelet MVs] and plasma (leukocyte, PMN, monocyte, and endothelial MVs) and compared each MV population to disease severity. BALF neutrophil MVs were the only population to significantly correlate with the clinical evaluation scores including forced expiratory volume in 1 s, modified Medical Research Council dyspnea score, 6-min walk test, hyperinflation, and gas transfer. BALF neutrophil MVs, but not neutrophil cell numbers, also strongly correlated with BODE index. We have undertaken, for the first time, a comprehensive evaluation of MV profiles within BALF/plasma of COPD patients. We demonstrate that BALF levels of neutrophil-derived MVs are unique in correlating with a number of key functional and clinically relevant disease severity indexes. Our results show the potential of BALF neutrophil MVs for a COPD biomarker that tightly links a key pathophysiological mechanism of COPD (intra-alveolar neutrophil activation) with clinical severity/outcome.
Highlights
Chronic obstructive pulmonary disease (COPD) is a heterogeneous chronic inflammatory disease, defined by persistent airflow limitation that is not fully reversible and is characterized by a mixture of small airways disease and parenchymal destruction [1]
We demonstrated that polymorphonuclear leukocyte (PMN; i.e., neutrophil)-derived MVs are actively released within bronchoalveolar lavage fluid (BALF) in these patients and importantly their levels highly correlate with a number of vital physiological markers of COPD severity
We investigated a number of different MV subtype populations in patient BALF samples (Fig. 1) and demonstrated the presence of leukocyte derived-MVs (CD45 þ ), PMN MVs (CD66b þ /CD11b þ ), and monocyte MVs (CD45 þ /CD14 þ ), as previously described [23, 28, 29]
Summary
Chronic obstructive pulmonary disease (COPD) is a heterogeneous chronic inflammatory disease, defined by persistent airflow limitation that is not fully reversible and is characterized by a mixture of small airways disease and parenchymal destruction [1]. MICROVESICLES AND COPD SEVERITY are derived from eukaryotic cells following direct cell activation or injury They are increased in numerous pathophysiological states and have been proposed as potential biomarkers in many inflammatory diseases [6, 7]. Several studies have reported elevated levels of circulating endothelial-derived MVs in patients with COPD [8, 9], while a recent publication demonstrated that extracellular vesicles originating from neutrophils play a vital role in the pathophysiology of COPD [10]. Despite these studies, the biomarker potential of MVs, those originating in the intraalveolar space, remains largely unknown. Our results show the exciting potential of BALF neutrophil MVs for a COPD biomarker that tightly links, for the first time, a key pathophysiological mechanism of COPD (intra-alveolar neutrophil activation) with clinical severity/ outcome
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