Severity of local inflammation does not impact development of fibrosis in mouse models of intestinal fibrosis

Intestinal fibrosis is thought to be a consequence of excessive tissue repair, and constitutes a common problem in patients with Crohn's disease (CD). While fibrosis seems to require inflammation as a prerequisite it is unclear whether the severity or persistence of inflammation influences the degree of fibrosis. Our aim was to investigate the role of sustained inflammation in fibrogenesis. For the initiation of fibrosis in vivo the models of ll10(-/-) spontaneous colitis, dextran sodium sulfate (DSS)induced chronic colitis and heterotopic transplantation were used. In ll10(-/-) mice, we determined a positive correlation between expression of pro-inflammatory factors (ll1 beta, Tnf, lfn gamma, Mcp1 and ll6). We also found a positive correlation between the expression of pro-fibrotic factors (Col3a1 Colla1, Tgf beta and alpha Sma). In contrast, no significant correlation was determined between the expression of pro-inflammatory Tnf and pro-fibrotic alpha Sma, Col1a1, Col3a1, collagen layer thickness and the hydroxyproline (HYP) content. Results from the DSS-induced chronic colitis model confirmed this finding. In the transplantation model for intestinal fibrosis a pronounced increase in Mcpl, inos and ll6 in ll10(-/-) as compared to WT grafts was observed, indicating more severe inflammation in ll10(-/-) grafts. However, the increase of collagen over time was virtually identical in both ll10(-/-) and WT grafts. Severity of inflammation during onset of fibrogenesis did not correlate with collagen deposition. Although inflammation might be a pre-requisite for the initiation of fibrosis our data suggest that it has a minor impact on the progression of fibrosis. Our results suggest that development of fibrosis and inflammation may be disconnected. This may be important for explaining the inefficacy of anti-inflammatory treatments agents in most cases of fibrotic inflammatory bowel diseases (IBD).