Macrophage Engulfment of Apoptotic Neutrophils Contributes to the Resolution of Acute Pulmonary Inflammation In Vivo

Abstract

For resolution of inflammation to occur, it is necessary both to limit leukocyte influx and to clear now redundant cells from the tissues. Recent evidence from in vitro studies suggests that clearance may be an active process, accomplished in part by macrophage engulfment of intact cells that have undergone programmed cell death or apoptosis. However, the kinetics of these events and their association with the resolution of acute inflammatory responses in vivo remain to be elucidated. To investigate these events, we examined an animal model of acute, limited, neutrophilic pulmonary inflammation. Cells were obtained by bronchoalveolar lavage (BAL) of rats at various time points after intratracheal administration of lipopolysaccharide (LPS). Apoptotic neutrophils were rarely seen in BAL from control animals but were detected after neutrophil influx had occurred in response to LPS challenge. Macrophage engulfment of these cells was identified at light microscopy and confirmed at electron microscopy. The proportion of macrophages that had engulfed apoptotic neutrophils was maximal 24 h after LPS challenge and declined thereafter as total neutrophil numbers fell. During the resolution phase, the alveolar macrophages became positive for peroxidase, indicating the presence of neutrophil granule contents in their cytoplasm. These observations demonstrate that apoptosis of leukocytes indeed occurs during the course of an acute inflammatory response in vivo and that the emergence of apoptotic neutrophils and macrophage engulfment of these cells are temporally correlated with the resolution of acute inflammation.