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Inflamm Bowel Dis. 2011 Mar;17(3):711-9. doi: 10.1002/ibd.21437. Epub 2010 Aug 18.

Amelioration of excess collagen IαI, fibrosis, and smooth muscle growth in TNBS-induced colitis in IGF-I(+/-) mice.

Author information

1
Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0341, USA.

Abstract

BACKGROUND:

Strictures occur in ≈ 30% 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-β1, and collagen IαI 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 IαI expression, the resulting collagen deposition, and fibrosis are all significantly diminished compared to C57BL/6J wildtype controls. TGF-β1 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.

PMID:
20722057
PMCID:
PMC2990779
DOI:
10.1002/ibd.21437
[Indexed for MEDLINE]
Free PMC Article

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