Amelioration of Excess Collagen IαI, Fibrosis, and Smooth Muscle Growth in TNBS-induced Colitis in IGF-I(±) Mice

作者：Mahavadi, Sunila; Flynn, Robert S.; Grider, John R.; Qiao, Li-Ya; Murthy, Karnam S.; Hazelgrove, Krystina B.; Kuemmerle, John F.^*

来源：Inflammatory Bowel Diseases, 2011, 17(3): 711-719.

DOI：10.1002/ibd.21437

• stricture
• colitis
• Crohn's disease
• smooth muscle

Background: Strictures occur in of patients with Crohn's disease (CD) and are characterized by intestinal smooth muscle hyperplasia, hypertrophy, and fibrosis due to excess extracellular matrix production including collagen. Insulin-like growth factor-I (IGF-I) expression is increased in smooth muscle cells of the muscularis propria in CD and in animal models of CD, including trinitrobenzene sulfonic acid (TNBS)-induced colitis. While upregulated IGF-I is conjectured to cause smooth muscle cell growth and collagen production in the inflamed intestine, its role in the development of fibrosis has not been directly demonstrated. @@@ Methods: Colitis was induced in IGF-I(+/-) or wildtype C57BL/6J mice by rectal administration of TNBS or ethanol vehicle. After 7 days, colonic smooth muscle cells were isolated and used to prepare RNA or protein lysates. Transcript levels of IGF-IEa, IGF binding protein (IGFBP)-3, IGFBP-5, TGF-beta 1, and collagen fat were measured by quantitative reverse-transcription polymerase chain reaction (RT-PCR). Corresponding protein levels were measured by Western blot or enzyme-linked immunosorbent assay (ELISA). Fibrosis was measured using digital image analysis of Masson's trichrome-stained histologic sections. @@@ Results: In IGF-I(+/-) mice, which express significantly lower levels of IGF-I than wildtype, the response to TNBS-induced colitis: upregulation of IGF-I, IGFBP-3, IGFBP-5 muscle growth, and collagen I alpha I expression, the resulting collagen deposition, and fibrosis are all significantly diminished compared to C57BL/6J wildtype controls. TGF-beta 1 expression and its increase following TNBS administration are not altered in IGF-I(+/-) mice compared to wildtype. @@@ Conclusions: The findings indicate that IGF-I is a key regulator in intestinal smooth muscle hyperplasia and excess collagen production that leads to fibrosis and long term to stricture formation.

• 出版日期2011-3