A Murine Model of Chronic Inflammation-Induced Intestinal Fibrosis Down-Regulated by Antisense NF-κB

Ian C. Lawrance, Feng Wu, André Z A Leite, Joseph Willis, Gail A. West, Claudio Fiocchi, Shukti Chakravarti

Research output: Contribution to journalArticlepeer-review

178 Scopus citations


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 κ B (NF-κB) 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 α [TNF-α], interferon γ [IFN-γ], transforming growth factor β1 [TGF-β1], 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-α and IFN-γ. Results: Colons of TNBS-treated mice contained acute and chronic inflammatory infiltrates, increased collagen, fibrogenic tissue architecture, and increased expression of TNF-α, TGF-β1, 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-γ, treatment. Fibrosis persisted for 2-4 weeks after cessation of the TNBS treatment. In mice given NF-κB 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-κB.

Original languageEnglish (US)
Pages (from-to)1750-1761
Number of pages12
Issue number6
StatePublished - Dec 2003

ASJC Scopus subject areas

  • Gastroenterology


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