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Recombinant human milk fat globule-EGF factor 8 produces dose-dependent benefits in sepsis

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Abstract

Purpose

Animal milk fat globule-EGF factor 8 (MFG-E8) has been shown to be beneficial in attenuating the inflammatory response in sepsis. In this study, we examined the effect of recombinant human MFG-E8 (rhMFG-E8) in an animal model of sepsis in an effort to develop it as a potential therapy against sepsis in humans.

Methods

Rats were subjected to sepsis by cecal ligation and puncture (CLP), and at 5 h post-CLP, they were given different doses of rhMFG-E8 (20, 40, 80, 160 μg/kg BW) in normal saline. At 20 h post-CLP, samples were collected for further analysis. A 10-day survival study was also performed.

Results

At 20 h after CLP, organ injury indicators, serum IL-6 and TNF-α, and plasma HMGB-1 levels were significantly increased as compared to sham-operated animals. Treatment with 20 μg/kg rhMFG-E8 significantly reduced these levels. With higher doses, further reductions in AST and ALT (59–62%), creatinine (65–68%), and lactate (46–57%), and serum IL-6 and TNF-α were obtained. The 160 μg/kg dose produced the greatest reduction in serum TNF-α. With treatment with 20 μg/kg rhMFG-E8, HMGB-1 levels decreased by 80%, returning back to sham values. In a 10-day survival study, vehicle-treated animals produced a 36% survival rate, while rhMFG-E8 significantly improved the survival rate to 68–72%. Treatment with increasing doses of rhMFG-E8 significantly reduced the number of apoptotic cells detected and markedly attenuated the tissue damages observed in the lungs.

Conclusions

These data suggest that recombinant human MFG-E8 is beneficial in ameliorating sepsis in an animal model of sepsis.

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Acknowledgments

This study was supported by the National Institutes of Health (NIH) grants, R01GM057468 and R01GM053008 (P.W.).

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Corresponding author

Correspondence to Ping Wang.

Additional information

One of the authors (P. Wang) is an inventor of the pending PCT application no. WO/2006/122327: “Milk fat globule epidermal growth factor-factor VIII and sepsis” and PCT application no. WO/2009/064448: “Prevention and treatment of inflammation and organ injury after ischemia/reperfusion using MFG-E8.” These patent applications cover the fundamental concept of using MFG-E8 for the treatment of sepsis and ischemia/reperfusion injury. The other authors report no financial conflicts of interest.

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Shah, K.G., Wu, R., Jacob, A. et al. Recombinant human milk fat globule-EGF factor 8 produces dose-dependent benefits in sepsis. Intensive Care Med 38, 128–136 (2012). https://doi.org/10.1007/s00134-011-2353-7

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  • DOI: https://doi.org/10.1007/s00134-011-2353-7

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