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Early growth response-1 contributes to galactosamine/lipopolysaccharide-induced acute liver injury in mice

¹Department of Pathobiology and ²Department of Gastroenterology, Cleveland Clinic, Cleveland, Ohio; and ³Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky

Submitted 18 July 2007 ; accepted in final form 28 September 2007

Early growth response (Egr)-1 is a transcription factor that regulates genes involved in inflammation, innate and adaptive immunity, coagulation, and wound healing; however, little is known about the role of Egr-1 in acute liver injury. We tested the hypothesis that Egr-1 is involved in acute liver injury induced by galactosamine/lipopolysaccharide (GalN/LPS). GalN/LPS exposure biphasically increased hepatic egr-1 mRNA accumulation at 1 h and again at 4–5.5 h after treatment in wild-type mice. Within 4–5.5 h after GalN/LPS exposure, wild-type mice exhibited histological evidence of hepatocyte injury, cell death, and extensive areas of hemorrhage, as well as increased plasma alanine aminotransferase activities. In contrast, these parameters were largely attenuated in egr-1^–/– mice. The initial expression of tumor necrosis factor-, macrophage inflammatory protein-2, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1 mRNA or protein was equivalent between genotypes at 1 h after GalN/LPS administration. However, at subsequent time points, hepatic expression of these genes was decreased in egr-1^–/– compared with wild-type mice. In addition, neutrophil extravasation from hepatic sinusoids into the liver parenchyma was decreased in egr-1^–/– compared with wild-type mice 4 h after GalN/LPS. Whereas caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive nuclei were detected in wild-type mice at 4 and 5.5 h after GalN/LPS administration, respectively, these markers of apoptosis were delayed in egr-1^–/– mice. Delayed development of apoptosis was associated with an extension of survival by 1 h in egr-1^–/– compared with wild-type mice. These data demonstrate that Egr-1 plays an important role in acceleration of hepatic inflammation, apoptosis, and subsequent mortality in GalN/LPS-induced acute liver injury.

inflammation; neutrophils; apoptosis