Treatment with milk fat globule epidermal growth factor-factor 8 (MFG-E8) reduces inflammation and lung injury in neonatal sepsis

Abstract

Introduction Sepsis remains one of the leading causes of infant death worldwide. It is characterized as uncontrolled inflammatory responses due to proven bacterial infection. Despite improvement in supportive care and the availability of effective antibiotics, no specific therapy targeting the dysregulated inflammatory response is available for neonatal sepsis. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory glycoprotein abundantly present in human milk. MFG-E8 suppresses the systemic inflammatory responses in adult murine injury models by improving the clearance of dying cells. We hypothesized that exogenous administration of recombinant mouse (rm) MFG-E8 could inhibit the exaggerated inflammatory response and lung injury in a murine model of neonatal sepsis. Methods Neonatal sepsis was induced in 5–7 day old male and female C57BL6 mice using an intraperitoneal injection of cecal slurry (CS). At 1h after sepsis induction, a single dose of 40 μg/kg rmMFG-E8 or vehicle was administered via retro-orbital injection. All neonates were returned to their mothers as a group. At 10 h after CS injection, pups were euthanized and blood and lung tissues were collected. Control mice underwent similar procedure with the exception of CS IP injection. Results Serum LDH, IL-1β and IL-6 were significantly increased 10 h after CS injection. Treatment with rmMFG-E8 decreased these levels by 30%, 56% and 37%, respectively. Lung morphology was significantly compromised in the vehicle group after CS injection whereas the rmMFG-E8 treated groups demonstrated a 48% improvement in the lung injury score. Lung IL-6 and MIP-2 protein levels were significantly reduced with rmMFG-E8 treatment. Lung neutrophil infiltration as observed by Gr-1 staining and, TUNEL positive cells were also significantly reduced with rmMFG-E8 treatment. Conclusion Treatment with rmMFG-E8 attenuated inflammation and lung injury in murine neonatal sepsis. Thus, MFG-E8 could be developed as a possible therapy for neonatal sepsis.

MFG-E8 Plays an Important Role in Attenuating Cerulein-Induced Acute Pancreatitis in Mice

“…In addition to its protective role in intestinal tissues, MFG-E8 has been shown to regulate osteoclast homeostasis and protect against inflammatory bone loss [ 38 ]. Treatment with MFG-E8 reduces inflammation and lung injury [ 39 ], and MFG-E8/lactadherin was found to enhance neovascularization and promote wound healing [ 17 , 18 ]. In the present study, we found that Mfge8 expression is not only sustained in ductal epithelial cells but activated in acinar cells as well as endothelial cells of interlobular blood vessels during acute pancreatitis.…”

Neonatal intestinal dysbiosis in necrotizing enterocolitis

“…Breast milk contains immunoglobulins, cytokines, lactoferrin, and growth factors (Torrazza and Neu 2013 ). Breast milk also contains glycoproteins that have been shown to decrease organ injury and inflammation in sepsis in mouse models (Hansen et al 2017b ). In addition human milk contains human milk oligosaccharides (HMO) that stimulates the growth of “healthy” bacteria- Bifidobacteria and Bacteroides species both possess the proper enzymes to digest HMOs and metabolize them for energy.…”

Berberine Prevents Cognitive Disorders Induced by Sepsis by Regulating the Inflammatory Cytokines, Oxidative Stress and Neuronal Apoptosis in Rat Brain

“…Excessive inflammation and oxidative stress were recognized as the underlying mechanism in cognitive impairments caused by sepsis [22,23]. After that, severe acute kidney injury [24,25], lung injury [26], liver failure [27] as well as cognitive impairments were all detrimental to sepsis patients. Early research reported that BBR combination with yohimbine was helpful in the early phase of sepsis in which drugs were administered 2 h after CLP surgery [15].…”