Mucosal healing and fibrosis after acute or chronic inflammation in wild type FVB-N mice and C57BL6 procollagen α1(I)-promoter-GFP reporter mice

PLoS One. 2012;7(8):e42568. doi: 10.1371/journal.pone.0042568. Epub 2012 Aug 3.

Abstract

Background: Injury and intestinal inflammation trigger wound healing responses that can restore mucosal architecture but if chronic, can promote intestinal fibrosis. Intestinal fibrosis is a major complication of Crohn's disease. The cellular and molecular basis of mucosal healing and intestinal fibrosis are not well defined and better understanding requires well characterized mouse models.

Methods: FVB-N wild type mice and C57BL6 procollagen α1(I)-GFP reporter mice were given one (DSS1) or two (DSS2) cycles of 3% DSS (5 days/cycle) followed by 7 days recovery. Histological scoring of inflammation and fibrosis were performed at DSS1, DSS1+3, DSS1+7, DSS2, DSS2+3, and DSS2+7. Procollagen α1(I)-GFP activation was assessed in DSS and also TNBS models by whole colon GFP imaging and fluorescence microscopy. Colocalization of GFP with α-smooth muscle actin (α-SMA) or vimentin was examined. GFP mRNA levels were tested for correlation with endogenous collagen α1(I) mRNA.

Results: Males were more susceptible to DSS-induced disease and mortality than females. In FVB-N mice one DSS cycle induced transient mucosal inflammation and fibrosis that resolved by 7 days of recovery. Two DSS cycles induced transmural inflammation and fibrosis in a subset of FVB-N mice but overall, did not yield more consistent, severe or sustained fibrosis. In C57BL6 mice, procollagen α1(I)-GFP reporter was activated at the end of DSS1 and through DSS+7 with more dramatic and transmural activation at DSS2 through DSS2+7, and in TNBS treated mice. In DSS and TNBS models GFP reporter expression localized to vimentin(+) cells and much fewer α-SMA(+) cells. GFP mRNA strongly correlated with collagen α1(I) mRNA.

Conclusions: One DSS cycle in FVB-N mice provides a model to study mucosal injury and subsequent mucosal healing. The procollagen α1(I)-GFP transgenic provides a useful model to study activation of a gene encoding a major extracellular matrix protein during acute or chronic experimental intestinal inflammation and fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antigens / metabolism
  • Chronic Disease
  • Collagen Type I / genetics*
  • Collagen Type I, alpha 1 Chain
  • Colon / pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Female
  • Fibrosis
  • Genes, Reporter*
  • Green Fluorescent Proteins / metabolism*
  • Inflammation / pathology*
  • Intestinal Mucosa / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Promoter Regions, Genetic / genetics*
  • Survival Analysis
  • Trinitrobenzenesulfonic Acid
  • Vimentin / metabolism
  • Weight Loss
  • Wound Healing*

Substances

  • Antigens
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Vimentin
  • Green Fluorescent Proteins
  • Trinitrobenzenesulfonic Acid
  • Dextran Sulfate