title: Transcriptional activation of vascular cell adhesion molecule-1 gene in vivo and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock.
abstract: Polymorphonuclear leukocytes (neutrophils) can cause hepatic parenchymal cell injury during endotoxin (ET) shock. Because adhesion molecules are critical for inflammatory cell damage, the role of vascular cell adhesion molecule-1 (VCAM-1) was studied in the pathophysiology of ET shock. ET-sensitive mice (C3Heb/FeJ) were treated with 700 mg/kg galactosamine in combination with 100 microg/kg Salmonella abortus equi ET, 15 microg/kg TNF-alpha, or 13 to 23 microg/kg IL-1. VCAM-1 mRNA formation was strongly activated in animals treated with ET, TNF-alpha, or IL-1. In contrast, only TNF-alpha and IL-1, not ET, induced VCAM-1 gene transcription in livers of ET-resistant mice (C3H/HeJ). Immunohistochemistry and isolation of liver cells during endotoxemia indicated that VCAM-1 mRNA and protein were only formed in endothelial cells and Kupffer cells, not in hepatocytes. Galactosamine/ET induced neutrophil accumulation in sinusoids (515 +/- 30 neutrophils/50 high power fields) followed by transmigration at 7 h. At that time, severe liver injury was observed (necrosis, 53 +/- 5%). An anti-VCAM-1 Ab (3 mg/kg) attenuated the area of necrosis by 60%. The Ab reduced neutrophil transmigration by 84%, but had no effect on the total number of cells in the liver vasculature. Flow cytometric analysis identified the presence of very late Ag-4 on mouse peripheral neutrophils. Our data demonstrated cytokine-dependent VCAM-1 gene transcription and protein expression in the liver during endotoxemia. Neutrophils were able to use very late Ag-4/VCAM-1 interactions to transmigrate into liver parenchyma in vivo. Preventing transmigration by blocking VCAM-1 protected hepatocytes against neutrophil-induced injury.
authors.affiliation: Cardiovascular Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49007, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Essani
authors.forename: M L
authors.initials: ML
authors.lastname: Bajt
authors.forename: A
authors.initials: A
authors.lastname: Farhood
authors.forename: S L
authors.initials: SL
authors.lastname: Vonderfecht
authors.forename: H
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000818:Animals; D008099:Liver / Q000473:pathology; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis; D012772:Shock, Septic / Q000503:physiopathology*; D015533:Transcriptional Activation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1