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Milk fat globule epidermal growth factor-factor 8-derived peptide attenuates organ injury and improves survival in sepsis.

Yang WL, Sharma A, Zhang F, Matsuo S, Wang Z, Wang H, Wang P - Crit Care (2015)

Bottom Line: MSP68 treatment significantly decreased plasma levels of organ injury marker AST by 37.1 % and the proinflammatory cytokines IL-6 and TNF-α 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 effectively inhibits excessive neutrophils infiltrating to organs, leading to moderate attenuation of organ injury and significantly improved survival in septic mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, 11030, USA. wlyang@nshs.edu.

ABSTRACT

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-α 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.

No MeSH data available.


Related in: MedlinePlus

MFG-E8-derived short peptide 6 (MSP68) improves the survival in cecal ligation and puncture (CLP)-induced sepsis. Mice were subjected to CLP followed by a single subcutaneous injection of 0.5 mg/kg antibiotic. At 2 h after CLP, mice were injected with normal saline as vehicle (n = 23) or 1 mg/kg of MSP68 (n = 24) through the jugular vein and survival was recorded for 10 days. The survival rate was estimated by the Kaplan–Meier method and compared using the log-rank test; *P = 0.05 versus vehicle
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Fig9: MFG-E8-derived short peptide 6 (MSP68) improves the survival in cecal ligation and puncture (CLP)-induced sepsis. Mice were subjected to CLP followed by a single subcutaneous injection of 0.5 mg/kg antibiotic. At 2 h after CLP, mice were injected with normal saline as vehicle (n = 23) or 1 mg/kg of MSP68 (n = 24) through the jugular vein and survival was recorded for 10 days. The survival rate was estimated by the Kaplan–Meier method and compared using the log-rank test; *P = 0.05 versus vehicle

Mentions: To explore the long-term effect of MSP68 treatment on the septic mice, we performed a 10-day survival study on mice injected with vehicle or 1 mg/kg BW of MSP68 at 2 h after CLP. As shown in Fig. 9, the survival rate after CLP in vehicle-treated animals was 56.5 % on day 2, and gradually decreased to 26 % on days 6–10. Administration of MSP68 significantly improved the 10-day survival rate increasing it to 54 % with improvement in survival starting as early as day 2 (Fig. 9).Fig. 9


Milk fat globule epidermal growth factor-factor 8-derived peptide attenuates organ injury and improves survival in sepsis.

Yang WL, Sharma A, Zhang F, Matsuo S, Wang Z, Wang H, Wang P - Crit Care (2015)

MFG-E8-derived short peptide 6 (MSP68) improves the survival in cecal ligation and puncture (CLP)-induced sepsis. Mice were subjected to CLP followed by a single subcutaneous injection of 0.5 mg/kg antibiotic. At 2 h after CLP, mice were injected with normal saline as vehicle (n = 23) or 1 mg/kg of MSP68 (n = 24) through the jugular vein and survival was recorded for 10 days. The survival rate was estimated by the Kaplan–Meier method and compared using the log-rank test; *P = 0.05 versus vehicle
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4624601&req=5

Fig9: MFG-E8-derived short peptide 6 (MSP68) improves the survival in cecal ligation and puncture (CLP)-induced sepsis. Mice were subjected to CLP followed by a single subcutaneous injection of 0.5 mg/kg antibiotic. At 2 h after CLP, mice were injected with normal saline as vehicle (n = 23) or 1 mg/kg of MSP68 (n = 24) through the jugular vein and survival was recorded for 10 days. The survival rate was estimated by the Kaplan–Meier method and compared using the log-rank test; *P = 0.05 versus vehicle
Mentions: To explore the long-term effect of MSP68 treatment on the septic mice, we performed a 10-day survival study on mice injected with vehicle or 1 mg/kg BW of MSP68 at 2 h after CLP. As shown in Fig. 9, the survival rate after CLP in vehicle-treated animals was 56.5 % on day 2, and gradually decreased to 26 % on days 6–10. Administration of MSP68 significantly improved the 10-day survival rate increasing it to 54 % with improvement in survival starting as early as day 2 (Fig. 9).Fig. 9

Bottom Line: MSP68 treatment significantly decreased plasma levels of organ injury marker AST by 37.1 % and the proinflammatory cytokines IL-6 and TNF-α 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 effectively inhibits excessive neutrophils infiltrating to organs, leading to moderate attenuation of organ injury and significantly improved survival in septic mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, 11030, USA. wlyang@nshs.edu.

ABSTRACT

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-α 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.

No MeSH data available.


Related in: MedlinePlus