TY - JOUR
T1 - Milk fat globule epidermal growth factor-factor 8 mitigates inflammation and tissue injury after hemorrhagic shock in experimental animals
AU - Zhang, Fangming
AU - Shah, Kavin G.
AU - Qi, Lei
AU - Wu, Rongqian
AU - Barrera, Rafael
AU - Nicastro, Jeffrey
AU - Coppa, Gene F.
AU - Wang, Ping
PY - 2012/4
Y1 - 2012/4
N2 - BACKGROUND: Insufficient clearance of apoptotic cells leads to increased inflammation and exaggerated organ injury. The opsonizing protein, milk fat globule epidermal growth factor-factor 8 (MFG-E8), upregulates apoptotic cell clearance. The purpose of this study was to determine the degree of apoptotic cell clearance, and whether inflammation, organ injury, and survival are improved after treatment with recombinant human MFG-E8 (rhMFG-E8) after hemorrhagic shock. METHODS: Male mice underwent a pressure-controlled (25 mm Hg ± 5 mm Hg) model of hemorrhagic shock for 90 minutes. They were resuscitated with normal saline with or without recombinant human MFG-E8 (rhMFG-E8) over 30 minutes. At 3.5-hour postresuscitation, blood and tissue were collected. MFG-E8 levels in the plasma, lungs, and spleen were measured. Apoptotic cell clearance was measured by cleaved caspase-3 levels and TUNEL staining. Neutrophil infiltration was assessed using myeloperoxidase activity in the lungs and spleen. Plasma and tissue levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured by ELISA. Finally, a seven-day survival study was also conducted. RESULTS: MFG-E8 levels in the plasma, lungs, and spleen significantly decreased by 33%, 44%, and 55%, respectively, at 3.5 hour after hemorrhage and resuscitation with rhMFG-E8. Treatment with rhMFG-E8 significantly improved apoptosis, by reducing TUNEL+ cells after treatment and restoring cleaved caspase-3 expression back to baseline. Neutrophil infiltration was blunted by 29% and 41% in the lungs and spleen, respectively. Cytokine expression was also reduced significantly, by 64% to 73% in plasma, 24% to 58% in the lungs, and 49% to 76% in the spleen. Finally, animals demonstrated a superior survival rate over 7 days after treatment with rhMFG-E8. CONCLUSION: The administration of rhMFG-E8 is a potent treatment in animals after hemorrhagic shock.
AB - BACKGROUND: Insufficient clearance of apoptotic cells leads to increased inflammation and exaggerated organ injury. The opsonizing protein, milk fat globule epidermal growth factor-factor 8 (MFG-E8), upregulates apoptotic cell clearance. The purpose of this study was to determine the degree of apoptotic cell clearance, and whether inflammation, organ injury, and survival are improved after treatment with recombinant human MFG-E8 (rhMFG-E8) after hemorrhagic shock. METHODS: Male mice underwent a pressure-controlled (25 mm Hg ± 5 mm Hg) model of hemorrhagic shock for 90 minutes. They were resuscitated with normal saline with or without recombinant human MFG-E8 (rhMFG-E8) over 30 minutes. At 3.5-hour postresuscitation, blood and tissue were collected. MFG-E8 levels in the plasma, lungs, and spleen were measured. Apoptotic cell clearance was measured by cleaved caspase-3 levels and TUNEL staining. Neutrophil infiltration was assessed using myeloperoxidase activity in the lungs and spleen. Plasma and tissue levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were measured by ELISA. Finally, a seven-day survival study was also conducted. RESULTS: MFG-E8 levels in the plasma, lungs, and spleen significantly decreased by 33%, 44%, and 55%, respectively, at 3.5 hour after hemorrhage and resuscitation with rhMFG-E8. Treatment with rhMFG-E8 significantly improved apoptosis, by reducing TUNEL+ cells after treatment and restoring cleaved caspase-3 expression back to baseline. Neutrophil infiltration was blunted by 29% and 41% in the lungs and spleen, respectively. Cytokine expression was also reduced significantly, by 64% to 73% in plasma, 24% to 58% in the lungs, and 49% to 76% in the spleen. Finally, animals demonstrated a superior survival rate over 7 days after treatment with rhMFG-E8. CONCLUSION: The administration of rhMFG-E8 is a potent treatment in animals after hemorrhagic shock.
KW - Apoptosis
KW - Hemorrhage
KW - Inflammatory cytokines
KW - Resuscitation
KW - RhMFG-E8
KW - Shock
UR - https://www.scopus.com/pages/publications/84862726870
U2 - 10.1097/TA.0b013e318249a97c
DO - 10.1097/TA.0b013e318249a97c
M3 - 文章
C2 - 22491597
AN - SCOPUS:84862726870
SN - 2163-0755
VL - 72
SP - 861
EP - 869
JO - Journal of Trauma and Acute Care Surgery
JF - Journal of Trauma and Acute Care Surgery
IS - 4
ER -