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.
Highlights
Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al 2016), results in an estimated 5.3 million deaths worldwide annually (Fleischmann et al 2016)
These findings demonstrate that rhMFG-E8 can be developed as an effective therapy for sepsis associated with alcohol abuse
Results rhMFG-E8 attenuates serum levels of Tumor necrosis factor alpha (TNF-α), Interleukin 6 (IL-6), and endotoxin in cecal ligation and puncture (CLP) after acute alcohol exposure Serum levels of TNF-α and IL-6 are indicative of the immune system activation during sepsis
Summary
Sepsis, defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection (Singer et al 2016), results in an estimated 5.3 million deaths worldwide annually (Fleischmann et al 2016). Excessive alcohol drinking is a major risk factor for developing alcohol use disorders (AUD) (Vincent and Sakr 2019) In addition to their well-known adverse effects on the hepatic, nervous, and cardiovascular function, AUD is associated with increased morbidity and mortality due to infection (Trevejo-Nunez et al 2015; Probst et al 2018; Waldschmidt et al 2008; Bird and Kovacs 2008; Ness et al 2008; Aloman et al 2007; Cook 1998). 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
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