Abstract
A patient’s recovery from lung inflammatory injury or development of multi-system organ failure is determined by the host’s ability to resolve inflammation and repair tissue damage, both of which require the clearance of apoptotic neutrophils by macrophages (efferocytosis). Here, we investigated the effects of isoflurane on macrophage efferocytosis and resolution of lung inflammatory injury. Treatment of murine bone marrow-derived macrophages (BMDMs) or alveolar macrophages with isoflurane dramatically enhanced phagocytosis of apoptotic neutrophils. Isoflurane significantly increased the surface expression of the receptor tyrosine kinase Mer in macrophages, but markedly decreased the levels of a soluble form of Mer protein in the medium. Isoflurane treatment also caused a decrease in a disintegrin and metalloproteinase 17 (ADAM17) on the cell surface and a concomitant increase in its cytoplasmic fraction. These responses induced by isoflurane were completely reversed by a pharmacological inhibitor or genetic deletion of AMP-activated protein kinase (AMPK). In a mouse model of lipopolysaccharide-induced lung injury, isoflurane accelerated the recovery of lung inflammation and injury that was coupled with an increase in the number of alveolar macrophages containing apoptotic bodies. In alveolar macrophage-depleted mice, administration of isoflurane-pretreated BMDMs facilitated resolution of lung inflammation following lipopolysaccharide challenge. Thus, isoflurane promoted resolution of lipopolysaccharide-induced lung inflammatory injury via enhancement of macrophage efferocytosis. Increased macrophage efferocytosis following isoflurane treatment correlates with upregulation of Mer surface expression through AMPK-mediated blockade of ADAM17 trafficking to the cell membrane.
Highlights
We identified that isoflurane promoted macrophage efferocytosis and subsequent resolution of lung inflammation in a model of sepsis with endotoxin and that these effects are closely associated with upregulation of receptor tyrosine kinase Mer surface expression in macrophages
These results demonstrate the ability of isoflurane to stimulate macrophage phagocytosis of apoptotic promotes efferocytosis neutrophil (PMN)
By transplanting bone marrow-derived macrophages (BMDMs) treated with vehicle or isoflurane into alveolar macrophage-depleted mice, we examined the effect of increased macrophage efferocytosis induced by isoflurane on resolution of LPS-induced lung inflammatory injury
Summary
Acute lung inflammation is an essential defense response to pathogenic or noninfectious insults and is characterized by exudation of intravascular fluid and increased polymorphonuclear. Isoflurane promotes efferocytosis neutrophil (PMN) infiltration into the lung interstitial and alveolar space. Recruited PMNs at sites of infection kill and clear invading microorganisms, which limits the inciting injury or infection [1, 2]. Uncontrolled and massive inflammatory response can result in lung injury that severely impairs gas exchange. Unresolved lung inflammation contributes directly to the development of acute respiratory distress syndrome (ARDS) [1, 3]. Successful resolution of lung inflammation, characterized by clearance of inflammatory cells and restoration of alveolar function, is critical for the return of respiratory homeostasis and recovery from acute lung injury [4, 5]
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