Impaired Alveolar Macrophage Efferocytosis in ARDS causes accumulation of apoptotic neutrophils & prolonged inflammation

Abstract

Dysregulated alveolar inflammation is characteristic of ARDS, however the role of alveolar macrophages (AMs) in pathogenesis is unclear. We investigated whether AM efferocytic function is impaired in ARDS, and if this correlates with alveolar accumulation of apoptotic neutrophils. Methods: Bronchoalveolar lavage (BAL) was performed on ventilated ICU patients with ARDS (n=8) or Sepsis (n=10, control group at risk of ARDS). BAL neutrophils were assessed for apoptosis & viability using flow cytometry. BAL AMs were isolated for use in efferocytosis and phagocytosis assays, using labelled apoptotic neutrophils or pHrodo bioparticles (E. Coli & S. Aureus) respectively. Results: A greater proportion of BAL neutrophils were apoptotic in ARDS compared to Sepsis patients (39.2% vs 19%, p=0.04). AM efferocytic index was significantly impaired in ARDS compared to Sepsis patients (Fig 1, median 4.9% vs 23.5%, p=0.001). No significant difference in AM phagocytic index was seen between ARDS & Sepsis patients. Conclusions: The onset of ARDS is associated with impaired AM efferocytosis, which contributes to the accumulation of apoptotic neutrophils within alveoli. These persistent apoptotic neutrophils likely undergo secondary necrosis, causing the prolonged inflammation seen in ARDS. Therapeutic strategies to enhance AM efferocytosis may thereby aid resolution of inflammation in ARDS.