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A Controlled Mouse Model for Neonatal Polymicrobial Sepsis
Published on: January 27, 2019
Treatment with milk fat globule epidermal growth factor-factor 8 (MFG-E8) reduces inflammation and lung injury in
Laura W Hansen1, Weng Lang Yang2, Alexandra C Bolognese1
1Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY.
Insights
Milk fat globule epidermal growth factor-8 (MFG-E8) treatment reduced inflammation and lung injury in a neonatal sepsis mouse model. This suggests MFG-E8 may be a potential therapy for infant sepsis.
Area of Science:
- Neonatal immunology
- Inflammatory disease research
- Biomedical research
Background:
- Sepsis is a leading cause of infant mortality, characterized by uncontrolled inflammatory responses to bacterial infection.
- Current treatments lack specific therapies for the dysregulated inflammation in neonatal sepsis.
- Milk fat globule epidermal growth factor-8 (MFG-E8) is a glycoprotein that suppresses inflammation by enhancing the clearance of dying cells.
Purpose of the Study:
- To investigate the potential of exogenous recombinant mouse MFG-E8 as a therapy for neonatal sepsis.
- To assess the efficacy of MFG-E8 in mitigating exaggerated inflammatory responses and lung injury in a murine model of neonatal sepsis.
Main Methods:
- Neonatal sepsis was induced in 5- to 7-day-old mice via intraperitoneal injection of cecal slurry.
- Recombinant mouse MFG-E8 or vehicle was administered 1 hour after sepsis induction.
- Blood and lung tissues were collected 10 hours post-induction for analysis of inflammatory markers and lung injury.
Main Results:
- MFG-E8 treatment significantly reduced serum lactate dehydrogenase, IL-1β, and IL-6 levels.
- Lung injury scores improved by 48% in MFG-E8 treated mice compared to vehicle controls.
- MFG-E8 treatment decreased lung IL-6 and MIP-2 protein levels, neutrophil infiltration, and the number of TUNEL-positive cells.
Conclusions:
- Recombinant mouse MFG-E8 administration attenuated inflammation and lung injury in a murine model of neonatal sepsis.
- MFG-E8 demonstrates potential as a therapeutic agent for neonatal sepsis.
Background:
Sepsis remains one of the leading causes of infant death worldwide. It is characterized by 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 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- to 7-day-old male and female C57BL6 mice using an intraperitoneal injection of cecal slurry. At 1 hour after sepsis induction, a single dose of 40 μg/kg recombinant mouse MFG-E8 or vehicle was administered via retro-orbital injection. All neonates were returned to their mothers as a group. At 10 hours after cecal slurry injection, pups were killed and blood and lung tissues were collected. Control mice underwent a similar procedure with the exception of cecal slurry intraperitoneal injection.
Results:
Serum lactate dehydrogenase, IL-1β, and IL-6 were significantly increased 10 hours after cecal slurry injection. Treatment with recombinant mouse MFG-E8 decreased these levels by 30%, 56%, and 37%, respectively. Lung morphology was significantly compromised in the vehicle group after cecal slurry injection, whereas the recombinant mouse MFG-E8-treated groups demonstrated a 48% improvement in the lung injury score. Lung IL-6 and MIP-2 protein levels were significantly reduced with recombinant mouse MFG-E8 treatment. Lung neutrophil infiltration as observed by Gr-1 staining and, TUNEL-positive cells were also significantly reduced with recombinant mouse MFG-E8 treatment.
Conclusion:
Treatment with recombinant mouse MFG-E8 attenuated inflammation and lung injury in murine neonatal sepsis. Thus, MFG-E8 could be developed as a possible therapy for neonatal sepsis.
