Role of alveolar macrophages in chronic obstructive pulmonary disease

Abstract

Alveolar macrophages (AMs) represent a unique leukocyte population that responds to airborne irritants and microbes. This distinct microenvironment coordinates the maturation of long-lived AMs, which originate from fetal blood monocytes and self-renew through mechanisms dependent on GM-CSF and CSF-1 signaling. Peripheral blood monocytes can also replenish lung macrophages; however, this appears to occur in a stimuli specific manner. In addition to mounting an appropriate immune response during infection and injury, AMs actively coordinate the resolution of inflammation through efferocytosis of apoptotic cells. Any perturbation of this process can lead to deleterious responses. In chronic obstructive pulmonary disease (COPD), there is an accumulation of airway macrophages that do not conform to the classic M1/M2 dichotomy. There is also a skewed transcriptome profile that favors expression of wound-healing M2 markers, which is reflective of a deficiency to resolve inflammation. Endogenous mediators that can promote an imbalance in inhibitory M1 vs. healing M2 macrophages are discussed, as they are the plausible mechanisms underlying why AMs fail to effectively resolve inflammation and restore normal lung homeostasis in COPD.

Keywords: alveolar macrophage; chronic obstructive pulmonary disease; efferocytosis; lung inflammation; oxidative stress; resolution.

Figure 1

COPD alveolar macrophage. Cigarette smoke, oxidative stress, and the airway inflammatory microenvironment have a direct effect on alveolar macrophage (AM) phenotype in COPD that leads to the emergence of M1 and M2 populations. The ratio of these macrophages will govern the pathological processes in COPD. M1 macrophages will further drive inflammation and oxidative stress. Excessive oxidative stress impairs resolution mechanisms including macrophage-mediated phagocytosis and efferocytosis, which leads to colonization and exacerbations in COPD. In addition, the emergence of M2 macrophages can contribute to deleterious lung remodeling/damage through increased expression of M2-related genes and excessive protease (MMP-9, -12) production.