Anti-TNF-α Therapy Exerts Intestinal Anti-inflammatory and Anti-apoptotic Effects After Massive Bowel Resection in a Rat.

OBJECTIVES

The aim of this study was to examine the effect of massive small bowel resection on proinflammatory cytokine intestinal expression and the effect of anti-TNF-α antibodies (ATA) on intestinal inflammation, epithelial cell turnover, and intestinal adaptation after bowel resection in rats.

METHODS

Male Sprague-Dawley rats were divided into 4 experimental groups: Sham-rats underwent bowel transection; Sham-ATA rats underwent bowel transection and were treated with ATA; SBS-animals underwent 75% bowel resection; and SBS-ATA rats underwent bowel resection and were treated with ATA similarly to Group B. Parameters of intestinal adaptation, enterocyte proliferation, and apoptosis were determined at sacrifice. TNF-α and apoptosis-related gene and protein levels were determined by Illumina's Digital Gene Expression (DGE) analysis, Real Time PCR, Western blotting, and immunohistochemistry.

RESULTS

From 25 genes related to TNF-α signalling that were investigated, 8 genes in the jejunum and 10 genes in the ileum were found to be up-regulated in resected versus sham animals. SBS rats demonstrated a significant increase in tissue and plasma TNF-α, IL-6 levels, intestinal mucosal TNF-α related gene expression, and microscopic parameters of inflammation. Treatment of resected animals with ATA resulted in a significant decrease in TNF-α levels, intestinal mucosal TNF-α-related gene expression, decreased number of intraepithelial lymphocytes and macrophages, and lower apoptotic index compared with SBS animals.

CONCLUSIONS

In a rat model of SBS, ATA decreased plasma and tissue TNF-α levels, diminished mucosal inflammation, and inhibited cell apoptosis. Anti-apoptotic effects of ATA appear to be associated with an inhibited extrinsic apoptotic pathway.