Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune effector cells that identify, engulf, and destroy pathogens and process inhaled particles, including cigarette smoke and particulate matter (PM), the main environmental triggers for COPD. The number of LMs in lung tissues and airspaces is increased in COPD, suggesting a potential key role for LMs in initiating and perpetuating the chronic inflammatory response that underpins the progressive nature of COPD. The purpose of this brief review is to discuss the origins of LMs, their functional properties (chemotaxis, recruitment, mediator production, phagocytosis and apoptosis) and changes in these properties due to exposure to cigarette smoke, ambient particulate and pathogens, as well as their persistent altered functional properties in subjects with established COPD. We also explore the potential to therapeutically modulate and restore LMs functional properties, to improve impaired immune system, prevent the progression of lung tissue destruction, and improve both morbidity and mortality related to COPD.

Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD)

“…We also showed that the proportion of these non-polarized macrophages increases with increasing COPD severity, suggesting that these macrophages could contribute to the progression of disease, though additional studies will be required to establish causality. Previous studies have shown that lung macrophages in COPD have reduced phagocytic ability [ 17 , 21 , 22 ], and here we showed that these non-polarized macrophages predominantly contribute to this impaired phagocytic activity. This reduced phagocytic activity of non-polarized macrophages was also related to the severity of the underlying COPD.…”

“…The clinical relevance of this observation, however, is unclear, although this phenotypic shift of macrophages in COPD supports the notion that these non-polarized macrophages contribute to the persistent inflammatory responses in lung tissues of COPD [ 6 , 7 ]. A few studies have previously addressed the issue of macrophage phenotypes shifts in COPD [ 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Kunz and coworkers, for example, used induced sputum samples (which represents mostly macrophages from the larger airways) to evaluate M1 and M2 phenotypes [ 15 ], while Eapen and co-workers [ 12 ], using macrophages harvested from BAL fluids, evaluated different phenotypes of macrophages and found that the percentage of non-polarized macrophage increased in COPD subjects; results that were similar to the findings of the present study.…”

“…We suspect that this macrophage plasticity is predominantly influenced by the local microenvironment [ 24 ]. The chronic and persistent inflammatory milieu in COPD lung tissue (or induced by inhalation of CS or PM) may recruit monocytes from the peripheral circulation into the lung tissue and/or airspaces [ 8 , 25 ] where they differentiate and become macrophages; these monocyte-derived macrophages may be initially non-polarized [ 17 ]. One potential source of non-polarized macrophages could be these “newly” recruited cells.…”

“…One potential source of non-polarized macrophages could be these “newly” recruited cells. Alternatively, these non-polarized macrophages could be macrophages that have lost their M1 or M2 characteristics (markers) over time and are destined for apoptosis and removal [ 17 , 25 ]. Leukocyte kinetic studies are necessary to address this issue.…”

“…Bazzan and co-workers described the presence of non-polarized macrophages (i.e., macrophages that are negative for both traditional M1 and M2 markers) [ 11 ], and Eapen and co-workers reported on dual-polarized macrophages, which express both M1 and M2 markers [ 12 ]. Preliminary studies from our laboratory confirmed the presence of these sub-populations of alveolar macrophages [ 16 ], but little is known about their functional properties or gene expression profiles in COPD [ 16 , 17 ]. The goal of this study was to quantify the distribution of these different macrophage subpopulations (M1, M2, double-polarized, and non-polarized macrophage) across the severity of COPD using macrophages harvested from broncho-alveolar lavage (BAL) fluid and characterize their functional properties in COPD patients.…”