A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-kappa B

Gastroenterology. 2003 Dec;125(6):1750-61. doi: 10.1053/j.gastro.2003.08.027.


Background & aims: To elucidate extracellular matrix (ECM) changes underlying intestinal fibrosis, a frequent complication of inflammatory bowel disease, we developed a murine model of chronic colitis associated with intestinal fibrosis.

Methods: Chronic inflammation was established by weekly intrarectal administration of trinitrobenzene sulfonic acid (TNBS). In 2 variations of the model an antisense oligonucleotide for nuclear factor kappa B (NF-kappa B) p65 was given prophylactically or therapeutically to block chronic inflammation-associated fibrosis. Colonic inflammation and fibrosis were determined by histology. Total collagen level was estimated by hydroxyproline quantification. Colonic expression of collagens (Col1a2, Col3a2), ECM remodeling genes (matrix metalloproteinase [MMP]-1, -3, and tissue inhibitor of matrix metalloproteinase [TIMP]-1), and inflammation-modulating cytokines (tumor necrosis factor alpha [TNF-alpha], interferon gamma [IFN-gamma], transforming growth factor beta 1 [TGF-beta 1], and insulin-like growth factor 1 [IGF-1]) were assessed by semiquantitative reverse-transcription polymerase chain reaction. Control and TNBS-treated colonic mesenchymal cells were characterized by morphology, phenotype, and functional response to TNF-alpha and IFN-gamma.

Results: Colons of TNBS-treated mice contained acute and chronic inflammatory infiltrates, increased collagen, fibrogenic tissue architecture, and increased expression of TNF-alpha, TGF-beta 1, IGF-1, Col1a2, MMP-1, and TIMP-1. Colonic mesenchymal cells from TNBS-treated mice were also morphologically distinct from those of the control mice, with increased TIMP-1 expression in response to IFN-gamma treatment. Fibrosis persisted for 2-4 weeks after cessation of the TNBS treatment. In mice given NF-kappa B antisense prophylactically, 67% were fibrosis-free, whereas of those treated after establishing chronic inflammation, 43% were free of fibrosis.

Conclusions: Extended TNBS treatment of mice yielded chronic intestinal inflammation-associated fibrosis with extensive fibrogenic ECM changes that could be counteracted by specific blockade of NF-kappa B.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chronic Disease
  • Colitis / metabolism
  • Colitis / pathology
  • Colitis / therapy*
  • Collagen / analysis
  • Colon / pathology*
  • Disease Models, Animal*
  • Female
  • Fibrosis
  • Interferon-gamma / genetics
  • Interferon-gamma / pharmacology
  • Matrix Metalloproteinase 1 / genetics
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B / antagonists & inhibitors*
  • Oligonucleotides, Antisense / therapeutic use*
  • RNA, Messenger / analysis
  • Transcription Factor RelA
  • Transforming Growth Factor beta / genetics
  • Trinitrobenzenesulfonic Acid
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / pharmacology


  • NF-kappa B
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Transcription Factor RelA
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Trinitrobenzenesulfonic Acid
  • Collagen
  • Matrix Metalloproteinase 1