Laura W Hansen1, Weng Lang Yang2, Alexandra C Bolognese1, Asha Jacob2, Tracy Chen3, Jose M Prince2, Jeffrey M Nicastro1, Gene F Coppa1, Ping Wang4. 1. Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY. 2. Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY. 3. Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY. 4. Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY. Electronic address: pwang@northwell.edu.
Abstract
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.
BACKGROUND:Sepsis remains one of the leading causes of infantdeath 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 murineinjury models by improving the clearance of dying cells. We hypothesized that exogenous administration of recombinant mouseMFG-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 mouseMFG-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 mouseMFG-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 mouseMFG-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 mouseMFG-E8 treatment. Lung neutrophil infiltration as observed by Gr-1 staining and, TUNEL-positive cells were also significantly reduced with recombinant mouseMFG-E8 treatment. CONCLUSION: Treatment with recombinant mouseMFG-E8attenuated inflammation and lung injury in murineneonatal sepsis. Thus, MFG-E8 could be developed as a possible therapy for neonatal sepsis.
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