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Coexposure of mice to trovafloxacin and lipopolysaccharide results in a unique gene expression profile and liver injury dependent on early growth response‐1 transcription factor activation
Author(s) -
Shaw Patrick,
Ditewig Amy,
Waring Jeff,
Liguori Michael,
Blomme Eric,
Copple Bryan,
Ganey Patricia,
Roth Robert
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.709.8
Subject(s) - lipopolysaccharide , tumor necrosis factor alpha , liver injury , gene expression , activator (genetics) , pharmacology , trovafloxacin , inflammation , chemistry , biology , endocrinology , gene , immunology , antibiotics , biochemistry , antibacterial agent
Trovafloxacin (TVX), a fluoroquinolone antibiotic, has been linked to several cases of severe idiosyncratic hepatotoxicity in people. Previously, we showed that a modest inflammatory stress induced by lipopolysaccharide (LPS) renders mice sensitive to nonhepatotoxic doses of TVX, producing midzonal hepatic coagulative necrosis and increased plasma ALT activity. Hierarchical cluster analysis and principal component analysis of hepatic gene expression data from mice taken at 3 h after LPS, a time before the onset of liver injury, revealed treatment‐related clustering. One gene identified from gene expression analysis was the transcription factor early growth response‐1 (egr‐1). Egr‐1 mRNA was selectively increased in TVX/LPS‐treated mice at 3 h. In addition, the nuclear accumulation of egr was selectively increased in the livers of TVX/LPS‐treated mice at 3 h. The selective increase in egr‐1 was corroborated by the selective increase of two specific egr‐1 activation products, nab2 and dscr‐1. In addition, the expression of tumor necrosis factor α and plasminogen activator inhibitor 1, both of which are expressed upon egr‐1 activation and involved in the development of TVX/LPS‐induced liver injury, were selectively increased in TVX/LPS‐treated mice (Supported by NIH grants DK061315 and GM075865.)