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

Abstract

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 Il10−/− spontaneous colitis, dextran sodium sulfate (DSS)-induced chronic colitis and heterotopic transplantation were used. In Il10−/− mice, we determined a positive correlation between expression of pro-inflammatory factors (Il1β, Tnf, Ifnγ, Mcp1 and Il6). We also found a positive correlation between the expression of pro-fibrotic factors (Col3a1 Col1a1, Tgfβ and αSma). In contrast, no significant correlation was determined between the expression of pro-inflammatory Tnf and pro-fibrotic αSma, 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 Mcp1, inos and Il6 in Il10−/− as compared to WT grafts was observed, indicating more severe inflammation in Il10−/− grafts. However, the increase of collagen over time was virtually identical in both Il10−/− 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).

Soluble Guanylate Cyclase Reduced the Gastrointestinal Fibrosis in Bleomycin-induced Mouse Model of Systemic Sclerosis.

“…The mice treated with BLM for 4 weeks exhibited signi cantly different patterns of esophageal brosis compared to those treated for 6 weeks. However, the severity of in ammation during the onset of brogenesis did not correlate with collagen deposition in the mouse model of intestinal brosis [17]. Lee et al previously reported that the lung brosis induced by BLM spontaneously decreased after more than 6 weeks [4].…”

“…In our experiments, the gene expression level of IL-6 in the esophagus of BLM-treated mice was signi cantly increased compared with those of NS-treated mice. This in ammation is a pre-requisite for the initiation of brotic lesions [17].…”

Soluble guanylate cyclase stimulator reduced the gastrointestinal fibrosis in bleomycin-induced mouse model of systemic sclerosis

“…In our experiments, the gene expression level of IL-6 in the esophagus of BLM-treated mice was significantly increased compared with those of NS-treated mice. This inflammation is a pre-requisite for the initiation of fibrotic lesions [ 19 ]. In this mouse model, BLM administration caused an increase in the thickness of gastrointestinal hyperproliferative and prefibrotic response and reduced peristaltic distance.…”

“…We showed that more severe esophageal hyperproliferative and prefibrotic response was observed in the mice sacrificed on day 42 compared to those sacrificed on day 28. However, the severity of inflammation during the onset of fibrogenesis did not correlate with collagen deposition in another model of intestinal fibrosis [ 19 ]. Lee et al previously reported that the lung fibrosis induced by BLM spontaneously decreased after more than 6 weeks [ 4 ].…”

NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation

“…Clinical observations support the view that inflammation is a prerequisite for the initiation of intestinal fibrosis, but neither inflammation alone nor the extent of inflammation seem to correlate well with the progression of fibrosis [ 54 , 55 ]. Once initiated, intestinal fibrogenesis may become an independent, self-perpetuating process, which would explain why the advent of highly effective anti-inflammatory biological agents seems not to have significantly reduced the incidence of fibrotic CD [ 56 ].…”