Synthetic RGDS peptide attenuated lipopolysaccharide/D-galactosamine-induced fulminant hepatic failure in mice.
OBJECTIVE
Fulminant hepatic failure (FHF) is a serious clinic syndrome with extremely poor prognosis and no effective treatment except for liver transplantation. Synthetic RGDS peptide, an inhibitor of integrins, was proved to suppress integrin signals. In this study, we investigated the protection effects of RGDS peptide on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced FHF and the underlying molecular mechanisms.


METHODS
Synthetic RGDS peptide was given intraperitoneally 30 min before LPS/D-GalN injection. Liver function and the extent of liver injury were analyzed biochemically and pathologically respectively. Enzyme-linked immunosorbent assay, real-time polymerase chain reaction and Western blotting were used to detect effectors and signaling molecules.


RESULTS
Pretreatment with synthetic RGDS peptide significantly improved LPS/D-GalN-induced mortality, and liver injury as determined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, as well as pathological analysis. In addition, RGDS peptide significantly reduced tumor necrosis factor (TNF)-α and macrophage inflammatory protein (MIP)-2 production, and decreased myeloperoxidase (MPO) and NF-κB activity. Furthermore, Western blotting indicated that the levels of phospho-integrin β3, phospho-focal adhesion kinase (FAK) and phospho-p38 mitogen-activated protein kinases (MAPK) decreased with RGDS peptide pretreatment.


CONCLUSIONS
Together, these data suggest that synthetic RGDS peptide protect against LPS/D-GalN-induced FHF by inhibiting inflammatory cells migration and blocking the integrin αVβ3-FAK-p38 MAPK and NF-κB signaling.
Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China.
Xinru
X
Yin
Xia
X
Gong
Rong
R
Jiang
Li
L
Zhang
Bin
B
Wang
Ge
G
Xu
Changdong
C
Wang
Jingyuan
J
Wan
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005688:Galactosamine; D007274:Injections, Intraperitoneal; D016023:Integrins / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000008:administration & dosage* / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D015415:Biomarkers; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016023:Integrins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; C046617:arginyl-glycyl-aspartyl-serine; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
RGDS peptide; fulminant hepatic failure; integrin αVβ3; lipopolysaccharide