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.

中文翻译：

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重组人乳脂肪球-EGF 因子 VIII (rhMFG-E8) 作为急性酒精暴露后脓毒症的治疗方法

背景酒精摄入易导致感染和败血症。酒精和败血症会抑制乳脂肪球表皮生长因子 VIII (MFG-E8) 的表达，这是一种对最佳胞吐作用必不可少的糖蛋白，导致促炎分子的释放和败血症的严重程度增加。我们之前曾报道重组小鼠 (rm) MFG-E8 可减轻急性酒精中毒大鼠败血症引起的器官损伤。为了开发一种可安全用于人类的疗法，我们生产了重组人 (rh) MFG-E8 并评估了其在急性酒精暴露后改善败血症的功效。 1.75 g/kg BW)，然后静脉输注 300 mg/kg/h 酒精 10 小时。然后通过盲肠结扎和穿刺（CLP）诱导脓毒症。在相对于 CLP 的 -10、0 和 10 小时，大鼠静脉内接受 MFG-E8 或载体（白蛋白）。在 CLP 后 20 小时对动物实施安乐死以收集血液和组织。额外的动物组用于生存研究。 结果与载体相比，rhMFG-E8 治疗改善了促炎细胞因子的血液水平（改善百分比：TNF-α 49.8%，IL-6 34.7%）和内毒素（61.7%），以及转氨酶（AST 36.2%，ALT 40.1%）和乳酸（18.4%）。用rhMFG-E8 治疗的大鼠的急性肺损伤也有显着的组织学衰减，以及胸腺中的凋亡细胞数量（43.4%）和脾脏中裂解的 caspase 3（38.7%）数量减少。此外，