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Inflammatory Phenotypes Associated with Chronic Obstructive Pulmonary Disease Increase Susceptibility to Exacerbation. Lessons from Single Cell Analysis of Lung Macrophages.

RATIONALE
Although it is well known that alveolar macrophages (AM) from individuals with chronic obstructive pulmonary disease (COPD) have reduced capacity to phagocytize pathogens or apoptotic cells compared with those of healthy individuals, the link between this defect and susceptibility to COPD exacerbation has not been established.


OBJECTIVES
To determine the molecular phenotype of AM associated with COPD exacerbation.


METHODS
AM from subjects with and without Global Initiative for Chronic Obstructive Lung Disease-defined (stage II-IV) COPD was collected by bronchoalveolar lavage (BAL) and were then used to perform functional assays including bacterial phagocytosis and apoptotic epithelial cell engulfment (efferocytosis) ex vivo. The phenotypes of AM were determined using a 44-marker mass cytometry panel developed in our laboratory and were analyzed to determine any association with subjects' clinical characteristics, including demographics, COPD severity, and exacerbation history.


RESULTS
We confirmed reduced phagocytosis and efferocytosis capability of AM in COPD and showed their association with severity of COPD (forced expiratory volume in 1 s), as previously described. However, we found no association between the frequency or severity of exacerbation and defects in phagocytosis or efferocytosis. Interestingly, subjects with a history of moderate or severe exacerbations had a relatively higher phagocytic response than an efferocytic response, suggesting a predominance of proinflammatory signals compared with those of resolution. We further examined AM with a 44-marker mass cytometry panel composed of 14 lineage markers, 16 activation or inhibitory markers, 8 adhesion or phagocytosis markers, and 6 chemokine markers, and found phenotypically distinct AM populations in subjects with COPD compared with healthy control subjects. A reduction in resolution phase markers including CD163 molecule, programmed cell death-1 ligand-1 (CD274), and programmed cell death-1 ligand-2 (PDL2) in AM from subjects with COPD was evident, confirming an imbalance in pro- versus antiinflammatory phenotypes.


CONCLUSIONS
An imbalance between proinflammatory and resolution phase responses may be associated with the exacerbation phenotype in COPD, as indicated by relative predominance of phagocytosis over efferocytosis and reduction in resolution phase markers in the BAL AM population, and could be explored for therapeutic strategies to decrease incidence of COPD exacerbation.