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Simvastatin Attenuates Intestinal Fibrosis Independent of the Anti-Inflammatory Effect by Promoting Fibroblast/Myofibroblast Apoptosis in the Regeneration/Healing Process from TNBS-Induced Colitis

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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.

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-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-β1 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.

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Authors and Affiliations

  1. 2nd Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan

    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

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  1. Yosuke Abe
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  2. Mitsuyuki Murano
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  3. Naoko Murano
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Correspondence to Yosuke Abe.

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Abe, Y., Murano, M., Murano, N. et al. Simvastatin Attenuates Intestinal Fibrosis Independent of the Anti-Inflammatory Effect by Promoting Fibroblast/Myofibroblast Apoptosis in the Regeneration/Healing Process from TNBS-Induced Colitis. Dig Dis Sci 57, 335–344 (2012). https://doi.org/10.1007/s10620-011-1879-4

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