When clearance fails: the role of efferocytosis in COPD

Despite the enormous global burden associated with chronic obstructive pulmonary disease (COPD), its precise underlying mechanisms remain incompletely understood. A key feature of COPD is persistent, nonresolving inflammation, traditionally attributed to an exaggerated immune response, oxidative stress, protease-antiprotease imbalances and increased cell death. While excessive cell death in COPD is well described, emerging evidence highlights defects in the subsequent clearance process, known as efferocytosis. Effective removal of dead cells is essential to prevent further inflammation in order to maintain tissue homeostasis. In this article, we critically review the literature and highlight the significant impairment of efferocytosis in COPD, as alveolar macrophages from COPD patients show a reduced capacity to engulf apoptotic airway epithelial cells. This impairment appears to be irreversible once COPD has developed, even after smoking cessation. This raises the possibility that impaired efferocytosis may represent an additional pathogenetic mechanism in COPD. We further discuss recent literature on how dysregulation in each of the consecutive steps of efferocytosis, namely the "find-me", "eat-me", uptake and degradation phases, can contribute to COPD pathogenesis. Finally, we propose future directions for both basic and clinical research in COPD and highlight novel therapeutic opportunities aimed at targeting the underlying disease mechanisms, rather than merely addressing symptoms.