Milk Fat Globule-EGF Factor VIII in Sepsis and Ischemia-Reperfusion Injury

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.

Roles of Milk Fat Globule-Epidermal Growth Factor 8 in Intestinal Inflammation

“…Consistent with these findings, in the majority of stress-induced disease conditions, e.g. renal I/R, alcohol-intoxicated septic animals, and human atherosclerosis plaques, MFG-E8 expression has been found to be abruptly decreased [4,8,27]. …”

“…In addition to its scavenging function, MFG-E8 was shown to be effective in attenuating inflammation, by controlling epithelial integrity and healing of injured mucosa in the intestinal tract [7,8]. Those functions have been suggested to be dependent not only on enhanced clearance of apoptotic cells, but also on various novel molecular mechanisms.…”

Review: milk fat globule-EGF factor 8 expression, function and plausible signal transduction in resolving inflammation

“…Mesenteric I/R caused severe widespread injury and inflammation of the small intestines and remote organs, and thereby decreased MFG-E8 levels in the spleen and lung tissues [4,28]. Similarly, in mouse and rat models of renal and hepatic I/R, MFG-E8 levels were down-regulated in the spleen, kidney and liver as compared to sham [6,7]. On the other hand, although acute alcohol intoxication did not affect the production of MFG-E8 in the spleen, however the levels of MFG-E8 gene expression in pre-alcohol exposed septic animals were even significantly lower than those in sepsis alone animals, suggesting that alcohol possesses the priming effect that sensitizes the animal more susceptible to the second hit caused by sepsis [29].…”

“…2a). Riding on these mechanistic tools, exogenously treated rMFG-E8 attenuated inflammation by reducing pro-inflammatory cytokines, TNF-a, IL-6 and IL-1b in sepsis as well as renal, hepatic and intestinal I/R conditions where LPS-TLR4 signaling is predominant [6,53]. Moreover, the recovery from tissue/organ injury induced by those distresses was attained by rMFG-E8 via reducing myeloperoxidase levels and preventing cellular apoptosis through caspase three inhibitions [29].…”

“…To date, MFG-E8 research has been promulgated into the various sectors of molecular medicine and innate immune fields to exhibit its potential beneficial roles in several animal models of inflammatory diseases, e.g., colitis, renal, hepatic and intestinal ischemia/reperfusion (I/R) [5][6][7]. Some of those reports have delineated the signal transduction events towards implementing its functional outcome.…”