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Simvastatin Attenuates Intestinal Fibrosis Independent of the Anti-Inflammatory Effect by Promoting Fibroblast/Myofibroblast Apoptosis
Update time:2012-03-12 10:55:42   【 Font: Large  Medium Small

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. Subjects and 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-a) level significantly decreased in the midand late phases in the high-dose treatment group. (2) SIMV also had anti-fibrotic effects characterized by a dosedependent 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-b1 level. Dosedependent 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 antiinflammatory effect from a relatively early stage the healing process of TNBS-induced colitis.

Source:Dig Dis Sci     by Yosuke Abe ,Mitsuyuki Murano , Naoko Murano , Eijiro Morita , Takuya Inoue , Ken Kawakami , Kumi Ishida , Takanori Kuramoto , Kazuki Kakimoto , Toshihiko Okada , Ken Narabayashi , Eiji Umegaki , Kazuhide Higuchi