Research Article: Isoflurane promotes phagocytosis of apoptotic neutrophils through AMPK-mediated ADAM17/Mer signaling

Date Published: July 3, 2017

Publisher: Public Library of Science

Author(s): Xueke Du, Chunling Jiang, Yang Lv, Randal O. Dull, You-Yang Zhao, David E. Schwartz, Guochang Hu, Bernhard Ryffel.


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.

Partial Text

Acute lung inflammation is an essential defense response to pathogenic or noninfectious insults and is characterized by exudation of intravascular fluid and increased polymorphonuclear neutrophil (PMN) infiltration into the lung interstitial and alveolar space. Recruited PMNs at sites of infection kill and ultimately clear invading microorganisms, which limits the inciting injury or infection [1, 2]. However, uncontrolled and massive inflammatory response can result in lung injury that severely impairs gas exchange. Unresolved lung inflammation also contributes directly to the development of acute respiratory distress syndrome (ARDS) [1, 3]. Thus, 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].

The findings in this study highlight the therapeutic potential of the volatile anesthetic isoflurane as a novel candidate for promoting resolution of lung inflammation during the perioperative period. We have shown that isoflurane facilitated the clearance of apoptotic PMNs both in vitro and in vivo and markedly stimulated the release of anti-inflammatory cytokines and accelerated recovery of lung inflammatory injury. Furthermore, we provide a comprehensive mechanistic framework for how isoflurane up-regulates the ability of macrophages to phagocytose apoptotic PMNs, including a crucial role for AMPK activation, decreased ADAM17 trafficking to the cell membrane and increased Mer surface expression.




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