title: Hepatocyte growth factor inhibits lipopolysaccharide-induced oxidative stress via epithelial growth factor receptor degradation.
abstract: OBJECTIVE
  Lipopolysaccharide (LPS) triggers sepsis and systemic inflammatory response syndrome, which results in multiple organ failure. Our recent reports demonstrated that hepatocyte growth factor (HGF) attenuated angiotensin II-induced oxidative stress via epithelial growth factor receptor (EGFR) degradation in vascular smooth muscle cells. Here, we examined whether HGF can protect against systemic inflammatory response syndrome induced by LPS and investigated the mechanism.
  
  
  RESULTS
  HGF inhibited the increase in the expression of vascular cell adhesion molecule-1 and EGFR by LPS in vitro. HGF inhibited colocalization of EGFR and Src homology domain 2-containing inositol 5'-phosphatase 2. Furthermore, HGF inhibited reactive oxygen species production. We also injected LPS into HGF transgenic mice with increased HGF serum concentration and their littermates. HGF transgenic mice reduced LPS-induced vascular cell adhesion molecule-1 and reactive oxygen species compared with control, accompanied by significant EGFR degradation. Furthermore, HGF transgenic mice significantly improved survival in the LPS injection model.
  
  
  CONCLUSIONS
  The present study revealed inhibition of LPS-induced vascular cell adhesion molecule-1 expression by HGF via the degradation of EGFR. We demonstrated that HGF regulated Src homology domain 2-containing inositol 5'-phosphatase 2 recruitment to EGFR and inhibited LPS-induced inflammation via EGFR degradation. This effect of HGF may be useful for the treatment of inflammatory disease.
authors.affiliation: Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Shimizu
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwabayashi
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C066855:HGF protein, human; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C482199:lipopolysaccharide, E coli O55-B5; D017228:Hepatocyte Growth Factor; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases