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

Polymorphonuclear leukocytes (neutrophils) can cause hepatic parenchym al 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 galac tosamine in combination with 100 mu g/kg Salmonella abortus equi ET, 1 5 mu g/kg TNF-alpha, or 13 to 23 mu g/kg IL-1, VCAM-1 mRNA formation w as 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 tran scription in livers of ET-resistant mice (C3H/HeJ). Immunohistochemist ry 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 accumul ation in sinusoids (515 +/- 30 neutrophils/50 high power fields) follo wed by transmigration at 7 h, At that time, severe liver injury was ob served (necrosis, 53 +/- 5%), An anti-VCAM-1 Ab (3 mg/kg) attenuated t he area of necrosis by 60%, The Ab reduced neutrophil transmigration b y 84%, but had no effect on the total number of cells in the liver vas culature, Flow cytometric analysis identified the presence of very lat e Ag-4 on mouse peripheral neutrophils, Our data demonstrated cytokine -dependent VCAM-1 gene transcription and protein expression in the liv er during endotoxemia, Neutrophils were able to use very rate Ag-4/VCA M-1 interactions to transmigrate into liver parenchyma in vivo, Preven ting transmigration by blocking VCAM-1 protected hepatocytes against n eutrophil-induced injury.