PMID- 26507263 OWN - NLM STAT- MEDLINE DCOM- 20160630 LR - 20220310 IS - 1466-609X (Electronic) IS - 1364-8535 (Print) IS - 1364-8535 (Linking) VI - 19 DP - 2015 Oct 28 TI - Milk fat globule epidermal growth factor-factor 8-derived peptide attenuates organ injury and improves survival in sepsis. PG - 375 LID - 10.1186/s13054-015-1094-3 [doi] LID - 375 AB - INTRODUCTION: Sepsis involves overwhelming inflammatory responses with subsequent immune-suppression that can lead to multiple organ dysfunction and ultimately death. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory protein found to have multiple biological activities against autoimmune and inflammatory diseases. MFG-E8 contains an Arg-Gly-Asp (RGD) motif involved in cell-cell and cell-matrix interactions. In sepsis, excessive neutrophils migration through endothelial cells and matrix to sites of inflammation results in organ damage. We hypothesized that MFG-E8-derived short peptides (MSP) flanking its RGD motif could provide protection against organ injury in sepsis. METHODS: The differentiated human neutrophil-like HL-60 cells (dHL60) were incubated with a series of peptides flanking the RGD motif of human MFG-E8 for a cell adhesion assay to fibronectin or human pulmonary artery endothelial cells (PAECs). For the induction of sepsis, male C57BL/6 mice (20-25 g) were subjected to cecal ligation and puncture (CLP). Peptide MSP68 (1 mg/kg body weight) or normal saline (vehicle) was injected intravenously at 2 h after CLP. Blood and tissue samples were collected at 20 h after CLP for various measurements. RESULTS: After screening, peptide MSP68 (VRGDV) had the highest inhibition of dHL-60 cell adhesion to fibronectin by 55.8 % and to PAEC by 67.7 %. MSP68 treatment significantly decreased plasma levels of organ injury marker AST by 37.1 % and the proinflammatory cytokines IL-6 and TNF-alpha by 61.9 % and 22.1 %, respectively after CLP. MSP68 improved the integrity of microscopic architectures, decreased IL-6 levels in the lungs by 85.1 %, and reduced apoptosis. MSP68 treatment also significantly reduced the total number of neutrophil infiltration by 61.9 % and 48.3 % as well as MPO activity by 40.8 % and 47.3 % in the lungs and liver, respectively, after CLP. Moreover, the number of bacteria translocated to mesenteric lymph nodes was decreased by 57 % with MSP68 treatment. Finally, the 10-day survival rate was increased from 26 % in the vehicle group to 58 % in the MSP68-treated group. CONCLUSIONS: MSP68 effectively inhibits excessive neutrophils infiltrating to organs, leading to moderate attenuation of organ injury and significantly improved survival in septic mice. Thus, MSP68 may be a potential therapeutic agent for treating sepsis. FAU - Yang, Weng-Lang AU - Yang WL AD - Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, 11030, USA. wlyang@nshs.edu. AD - Center for Translational Research, The Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA. wlyang@nshs.edu. FAU - Sharma, Archna AU - Sharma A AD - Center for Translational Research, The Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA. asharma11@nshs.edu. FAU - Zhang, Fangming AU - Zhang F AD - Center for Translational Research, The Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA. fzhang1@nshs.edu. FAU - Matsuo, Shingo AU - Matsuo S AD - Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, 11030, USA. Shingo.matsuo123@gmail.com. AD - Present address: Department of Surgery II, Tokyo Women's Medical University, Tokyo, Japan. Shingo.matsuo123@gmail.com. FAU - Wang, Zhimin AU - Wang Z AD - Center for Translational Research, The Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA. zwang@nshs.edu. FAU - Wang, Haichao AU - Wang H AD - Laboratory for Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, NY, 11030, USA. hwang@nshs.edu. FAU - Wang, Ping AU - Wang P AD - Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, 11030, USA. pwang@nshs.edu. AD - Center for Translational Research, The Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY, 11030, USA. pwang@nshs.edu. LA - eng GR - GM053008/GM/NIGMS NIH HHS/United States GR - R01 GM057468/GM/NIGMS NIH HHS/United States GR - GM057468/GM/NIGMS NIH HHS/United States GR - R01 GM053008/GM/NIGMS NIH HHS/United States GR - R29 GM053008/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20151028 PL - England TA - Crit Care JT - Critical care (London, England) JID - 9801902 RN - 0 (Antigens, Surface) RN - 0 (MFGE8 protein, human) RN - 0 (Milk Proteins) SB - IM MH - Animals MH - Antigens, Surface/administration & dosage/*therapeutic use MH - Disease Models, Animal MH - HL-60 Cells MH - Humans MH - Injections, Intravenous MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Milk Proteins/administration & dosage/*therapeutic use MH - Multiple Organ Failure/etiology/*prevention & control MH - Neutrophil Infiltration/drug effects MH - Sepsis/*drug therapy/mortality/physiopathology PMC - PMC4624601 EDAT- 2015/10/29 06:00 MHDA- 2016/07/01 06:00 PMCR- 2015/10/28 CRDT- 2015/10/29 06:00 PHST- 2015/07/02 00:00 [received] PHST- 2015/10/07 00:00 [accepted] PHST- 2015/10/29 06:00 [entrez] PHST- 2015/10/29 06:00 [pubmed] PHST- 2016/07/01 06:00 [medline] PHST- 2015/10/28 00:00 [pmc-release] AID - 10.1186/s13054-015-1094-3 [pii] AID - 1094 [pii] AID - 10.1186/s13054-015-1094-3 [doi] PST - epublish SO - Crit Care. 2015 Oct 28;19:375. doi: 10.1186/s13054-015-1094-3.