B75-21 Adverse Impact of Bacterial Pneumonia on Efferocytosis Compliance

Rationale Acute respiratory distress syndrome (ARDS) is a complex and heterogeneous condition, often triggered by severe bacterial lung infections. ARDS is characterized by initial robust activation of immune responses and significant apoptosis of alveolar epithelial cells (AECs), followed by hypo-inflammatory phase and immune exhaustion. Efferocytosis, the process by which apoptotic cells are cleared by macrophages, is a crucial step in terminating the pro-inflammatory phase and enabling effective recovery from organ injury. However, how macrophage-dependent efferocytosis is impaired in ARDS remain poorly understood. Methods In mice, bacterial pneumonia-induced acute lung injury was induced by oropharyngeal (o.ph.) administration of Pseudomonas aeruginosa strain K (PAK). Hematoxylin and eosin (H&E) staining and fluorescence microscopy of lung sections were used to assess the severity of acute lung injury (ALI) and quantify the expression of efferocytosis-suppressing mediators, CD47 and CD24, on AECs and in bronchoalveolar lavage (BAL) fluid. Efferocytosis indices were determined using flow cytometry. Additional confirmatory data were obtained from BAL fluid of ARDS patients (n=12) and healthy control group (n=8). Soluble CD47 and CD24 were determined by ELISA. Results We demonstrate that soluble CD47 and CD24 mediators, in BAL fluid from mice subjected to PAK infection and among patients with ARDS, effectively suppress macrophage-dependent efferocytosis. The mechanistic studies revealed that alveolar epithelial cells are the primary source of soluble CD24 and CD47 mediators, as evidenced in a pre-clinical murine model of bacterial pneumonia. Notably, efferocytosis suppression was reversible upon neutralization of these mediators in BAL fluids (ARDS). Conclusions Our findings suggest that soluble CD47 and CD24 mediators play a significant role in the suppression of efferocytosis in ARDS. Soluble CD47 and CD24 mediators may serve as prognostic markers for assessing the severity of lung injury and the recovery process from bacterial lung infections. This abstract is funded by: 2R01HL139617; HT9425-24-1-0304