Recombinant human milk fat globule-EGF factor VIII (rhMFG-E8) as a therapy for sepsis after acute exposure to alcohol

Abstract

BackgroundAlcohol intake predisposes to infections and sepsis. Alcohol and sepsis inhibit the expression of milk fat globule epidermal growth factor-factor VIII (MFG-E8), a glycoprotein essential for optimal efferocytosis, resulting in the release of proinflammatory molecules and increased sepsis severity. We previously reported that recombinant mouse (rm) MFG-E8 attenuates sepsis-induced organ injury in rats with acute alcohol intoxication. In order to develop a therapy that can be safely used in humans, we have produced recombinant human (rh) MFG-E8 and evaluated its efficacy to ameliorate sepsis after acute exposure to alcohol.MethodsWe induced acute alcohol intoxication with a bolus injection of alcohol (1.75 g/kg BW) followed by an intravenous infusion of 300 mg/kg/h alcohol for 10 h. Sepsis was then induced by cecal ligation and puncture (CLP). At -10, 0, and 10 h relative to CLP, rats received MFG-E8 or vehicle (albumin) intravenously. Animals were euthanized at 20 h after CLP for blood and tissue collection. Additional groups of animals were used for a survival study.ResultsCompared to vehicle, rhMFG-E8 treatment ameliorated blood levels of proinflammatory cytokines (% improvement: TNF-α 49.8%, IL-6 34.7%) and endotoxin (61.7%), as well as of transaminases (AST 36.2%, ALT 40.1%) and lactate (18.4%). Rats treated with rhMFG-E8 also had a significant histological attenuation of the acute lung injury, as well as a reduction in the number of apoptotic cells in the thymus (43.4%) and cleaved caspase 3 (38.7%) in the spleen. In addition, rhMFG-E8 improved the 10-day sepsis survival rate from 45 to 80%ConclusionrhMFG-E8 significantly ameliorated sepsis in rats with acute alcohol exposure, demonstrating rhMFG-E8’s potential to be developed as an effective therapy for sepsis in alcohol abusers.

Gut Barrier in Critical States of the Body

“…Sepsis is a systemic inflammatory response to endotoxinemia and bacteremia most frequently complicating acute poisoning in alcohol dependent individuals (Chaung et al, 2019). In massive acute methanol poisoning, sepsis developed in 6.4% of victims (Kumar et al, 2019).…”

Secondary Dysfunction of the Intestinal Barrier in the Pathogenesis of Complications of Acute Poisoning

“…The issue of which specific substances are involved in endotoxemia formation under acute poisoning is of interest. One of them is endotoxin, whose increased blood level has been shown in severe acute poisoning with colchicine [ 97 ], verapamil [ 104 ], and ethanol [ 105 ]. Manifest endotoxemia accompanies patients’ preparation for hematopoietic stem cell transplantation, during which cytostatic drugs are administered at potentially lethal doses.…”

“…Sepsis is a systemic inflammatory response to endotoxemia and bacteremia, which most frequently complicate acute poisoning in alcohol addicts [ 105 ]. Sepsis developed in 6.4% of the methanol poisoning victims [ 136 ].…”