title: T-5224, a selective inhibitor of c-Fos/activator protein-1, improves survival by inhibiting serum high mobility group box-1 in lethal lipopolysaccharide-induced acute kidney injury model.
abstract: BACKGROUND
  Sepsis is a potentially fatal syndrome mediated by an early [e.g., tumor necrosis factor-alpha (TNF-α)] and late [high mobility group box-1 (HMGB-1)] proinflammatory cytokine response to infection. Sepsis-induced acute kidney injury (AKI) is associated with a high mortality. C-Fos/activator protein-1 (AP-1) controls the transactivation of proinflammatory cytokines via AP-1 binding in the promoter region. T-5224 is a de novo small molecule inhibitor of c-Fos/AP-1 that controls gene expression of multiple proinflammatory cytokines. We investigated whether T-5224, a selective inhibitor of c-Fos/AP-1, improves survival in lethal lipopolysaccharide (LPS)-induced AKI by inhibiting early (TNF-α) and late (HMGB-1) proinflammatory cytokine response.
  
  
  METHODS
  Mice were divided into four groups (control, LPS, LPS + T-5224, and T-5224 only). Control mice were administered polyvinylpyrrolidone (PVP) solution orally, immediately after intraperitoneal (i.p.) saline injection. LPS mice were administered PVP solution orally immediately after i.p. LPS (10 mg/kg) injection. LPS + T-5224 mice were administered T-5224 orally (300 mg/kg) immediately after i.p. LPS injection. T-5224 mice were administered T-5224 orally (300 mg/kg) after i.p. saline injection. Serum concentrations of TNF-α, HMBG-1, and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay (ELISA). Serum blood urea nitrogen (BUN) and creatinine concentrations were commercially analyzed. Finally, histological examination was performed on the kidney.
  
  
  RESULTS
  Treatment with T-5224 decreased serum TNF-α and HMGB-1 levels and increased survival after LPS injection. Furthermore, T-5224 treatment decreased serum BUN and creatinine concentrations but increased serum IL-10 concentration. LPS-induced pathological changes in kidney were attenuated by T-5224 treatment.
  
  
  CONCLUSIONS
  These results suggest that T-5224, a selective inhibitor of c-Fos/AP-1, inhibits expression of early and late proinflammatory cytokines, protecting mice from LPS-induced lethality. T-5224 is a potential approach for decreasing lethality in sepsis-induced AKI.
authors.affiliation: Department of Anesthesia, Hyogo Rehabilitation Centre Central Hospital, Kobe, Hyogo 651-2181 Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Division of Anesthesia, Nishiwaki Municipal Hospital, 652-1 Shimotoda, Nishiwaki, Hyogo 677-0043 Japan ; Department of Emergency and Critical Care Medicine, Kobe University Hospital, Kobe, Hyogo 650-0017 Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ueki
authors.affiliation: Department of Anesthesia, Higashiosaka City General Hospital, Osaka, 578-8588 Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Morishita
authors.affiliation: Department of Pathology and Host Defense, Faculty of Medicine, Kagawa University, Kagawa, 761-0793 Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Department of Internal Medicine, Kyushu University Beppu Hospital, Oita, 874-0838 Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Shiozawa
authors.affiliation: Division of Anesthesia, Nishiwaki Municipal Hospital, 652-1 Shimotoda, Nishiwaki, Hyogo 677-0043 Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Maekawa
keywords: C-Fos/activator protein-1; High mobility group box-1 (HMGB-1); Interleukin-10 (IL-10); Lipopolysaccharide (LPS); T-5224; Tumor necrosis factor-alpha (TNF-α)