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Abstract
Sepsis and ischemia-reperfusion (I/R) injury are among the leading causes of death in critically ill patients at the surgical intensive care unit setting. Both conditions are marked by the excessive inflammatory response which leads to a lethal disease complex such as acute lung injury, systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Despite the advances in the understanding of the pathophysiology of those conditions, very little progress has been made toward therapeutic interventions. One of the key aspects of these conditions is the accumulation of apoptotic cells that have the potential to release toxic and proinflammatory contents due to secondary necrosis without appropriate clearance by phagocytes. Along with the prevention of apoptosis, that is reported to be beneficial in sepsis and I/R injury, thwarting the development of secondary necrosis through the active removal of apoptotic cells via phagocytosis may offer a novel therapy. Milk fat globule-EGF factor VIII (MFG-E8), which is mainly produced by macrophages and dendritic cells, is an opsonin for apoptotic cells and acts as a bridging protein between apoptotic cells and phagocytes. Recently, we have shown that MFG-E8 expression is decreased in experimental sepsis and I/R injury models. Exogenous administration of MFG-E8 attenuated the inflammatory response as well as tissue injury and mortality through the promotion of phagocytosis of apoptotic cells. In this review, we describe novel information available about the involvement of MFG-E8 in the pathophysiology of sepsis and I/R injury, and the therapeutic potential of exogenous MFG-E8 treatment for those conditions.
Highlights
The critically ill patient frequently develops a complex disease spectrum that may include acute lung injury (ALI), systemic inflammatory response syndrome (SIRS), sepsis and/or septic shock [1]
We have shown that mature resident peritoneal macrophages (RPMs) which are major sources of inflammatory cytokines, while losing their efficacy for phagocytosis of apoptotic cells, express lower MFG-E8 levels and show higher tumor necrosis factor-α (TNF-α) response to LPS compared with immature thioglycolate-elicited peritoneal macrophages (TGPM) [60]
Asano et al [26] reported that a dominant-negative form of MFG-E8, designated as D89E, carrying a point mutation in an RGD motif, inhibited the phagocytosis of apoptotic cells by a wide variety of phagocytes, and inhibited the enhanced production of IL-10 by TGPM phagocytizing apoptotic cells. These results indicate that MFG-E8 plays a pivotal role in controlling excess inflammatory responses through the inhibition of apoptotic cell accumulation, which otherwise results in subsequent secondary necrosis, the antiinflammatory cytokine production and the inhibition of inflammatory cytokine production by activated phagocytes
Summary
The critically ill patient frequently develops a complex disease spectrum that may include acute lung injury (ALI), systemic inflammatory response syndrome (SIRS), sepsis and/or septic shock [1]. The functional roles of MFG-E8– associated tissue remodeling have been investigated widely, they include promoting removal of apoptotic lymphocytes by macrophages [13,14], clearance of mammary epithelial cells in involution [12], mediating sperm-egg bindings [11], maintenance of intestinal epithelium [10] and facilitating neovascularization as a downstream effector of vascular endothelial growth factor (VEGF) signaling [15].
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