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
Journal of Immunology
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 μg/kg Salmonella abortus equi ET, 15 μg/kg TNF-α, or 13 to 23 μg/kg IL-1. VCAM-1 mRNA formation was strongly activated in animals treated with ET, TNF-α, or IL-1. In contrast, only TNF-α 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.
Essani, N., Bajt, M., Farhood, A., Vonderfecht, S., & Jaeschke, H. (1997). 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. Journal of Immunology, 158 (12). Retrieved from https://hsrc.himmelfarb.gwu.edu/smhs_path_facpubs/851