title: Simvastatin attenuates intestinal fibrosis independent of the anti-inflammatory effect by promoting fibroblast/myofibroblast apoptosis in the regeneration/healing process from TNBS-induced colitis.
abstract: BACKGROUND
  Intestinal deformity and stenosis are induced by fibrosis during the process healing of intestinal chronic inflammation in inflammatory bowel disease (IBD). Potent anti-inflammatory treatment of patients with Crohn's disease (CD) may induce fibrous stenosis, and this is often difficult to treat in clinical practice. Therefore, it is necessary to develop a treatment strategy that concomitantly exhibits repair/regenerative and anti-fibrotic effects, in addition to the current anti-inflammatory effect, for the treatment of inflammatory bowel diseases. However, the relationship between the course of inflammatory activity and the healing process and fibrogenesis has not been elucidated; although the complex involvement of various factors in the mechanism of biological fibrosis has been investigated. Simvastatin (SIMV), an HMG-CoA reductase inhibitor, exhibits anti-inflammatory and anti-fibrotic effects. The current study established a model of the regeneration/healing process from TNBS-induced colitis and investigated the anti-inflammatory and anti-fibrotic effects of SIMV.
  
  
  METHODS
  Four groups of TNBS-induced colitis model were prepared using male SJL/J mice: A: Normal control group, B: control group, and C and D: treatment groups. The mucosal healing process was classified into three phases (an early phase: inflammation period, a mid-phase: regeneration promoting period, and a late phase: regeneration-converging period), and inflammation, the expression of fibrosis-related growth factors, and induction of apoptosis of fibrosis-related cells were compared in each period.
  
  
  RESULTS
  (1) The clinical findings showed that SIMV showed anti-inflammatory effects with body weight gain and improvement of epithelial injury in the late phase. Histological (macroscopic/microscopic) improvement was noted in the mid- and late phases. The inflammatory cytokine (TNF-α) level significantly decreased in the mid- and late phases in the high-dose treatment group. (2) SIMV also had anti-fibrotic effects characterized by a dose-dependent decrease in the level of a fibrosis-related growth factor (CTGF) in the early and mid-phases, irrespective of inflammation or changes in the TGF-β(1) level. Dose-dependent induction of apoptosis was noted in both fibroblasts and myofibroblasts from a relatively early stage.
  
  
  CONCLUSIONS
  The results suggested that SIMV induces anti-fibrotic activity that is not directly involved in the anti-inflammatory effect from a relatively early stage the healing process of TNBS-induced colitis.
authors: 2nd Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan. y-abe@kg7.so-net.ne.jp
authors: Yosuke
authors: Y
authors: Abe
authors: Mitsuyuki
authors: M
authors: Murano
authors: Naoko
authors: N
authors: Murano
authors: Eijiro
authors: E
authors: Morita
authors: Takuya
authors: T
authors: Inoue
authors: Ken
authors: K
authors: Kawakami
authors: Kumi
authors: K
authors: Ishida
authors: Takanori
authors: T
authors: Kuramoto
authors: Kazuki
authors: K
authors: Kakimoto
authors: Toshihiko
authors: T
authors: Okada
authors: Ken
authors: K
authors: Narabayashi
authors: Eiji
authors: E
authors: Umegaki
authors: Kazuhide
authors: K
authors: Higuchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000502:physiology; D017439:Cicatrix, Hypertrophic / Q000503:physiopathology; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D058628:Myofibroblasts / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin