transforming-growth-factor-alpha and Short-Bowel-Syndrome

Recently, glucagon-like peptide 2 has emerged as a potent stimulator of epithelial growth, joining insulin-like growth factor I, hepatocyte growth factor and keratinocyte growth factor as potential treatment modalities for intestinal disorders associated with loss of mucosal mass, such as short bowel syndrome. Investigations into other members of the expanded epidermal growth factor peptide family, the development of more potent peptide analogues, and advances in the development of enterally administered bioactive growth factor formulations further expands the repertoire of epithelial growth factors applicable to conditions associated with epithelial insufficiency.

Topics: Adaptation, Physiological; Epidermal Growth Factor; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Glucagon-Like Peptide 2; Glucagon-Like Peptides; Growth Substances; Hepatocyte Growth Factor; Humans; Intestinal Diseases; Intestinal Mucosa; Mucins; Muscle Proteins; Neuropeptides; Peptides; Regeneration; Short Bowel Syndrome; Somatomedins; Transforming Growth Factor alpha; Trefoil Factor-2; Trefoil Factor-3

Recent evidence suggests that transforming growth factor alpha (TGF-alpha) enhances enterocyte proliferation and stimulates intestinal adaptation after massive bowel resection. In the present study, we evaluated the effects of TGF-alpha on enterocyte turnover and correlated it with epidermal-growth factor (EGF) receptor expression along the villus-crypt axis in a rat model of short bowel syndrome (SBS). Male rats were divided into three groups, sham rats underwent bowel transection (group A); SBS rats underwent a 75% bowel resection (group B); and SBS/TGF-alpha rats underwent bowel resection and were treated with TGF-alpha (75 microg/kg) (group C) from the seventh postoperative day. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined on day 15. Villus tips, lateral villi and crypts were separated using laser capture microdissection. EGF receptor expression for each compartment was assessed by quantitative real-time PCR (Taqman). Statistical analysis was performed using one-way ANOVA test, with P < 0.05 considered statistically significant. Treatment with TGF-alpha resulted in a significant increase in all parameters of intestinal adaptation. EGF receptor expression in crypts significantly increased in SBS rats (vs sham rats) (0.035 +/- 0.013 vs 0.010 +/- 0.002 Log ng Total RNA/18 s) and was accompanied by a significant increase in enterocyte proliferation (169 +/- 8 vs 138 +/- 5 BrdU positive cells/per 10 crypts, P < 0.05) and decreased apoptosis following TGF-alpha administration (group C). A significant decrease in EGF receptor expression at the tip of the villus (0.005 +/- 0.002 vs 0.029 +/- 0.014 Log ng Total RNA/18 s) and in the lateral villus (0.003 +/- 0.001 vs 0.028 +/- 0.006 Log ng Total RNA/18 s) in SBS (group B) rats (vs sham, group A) was accompanied by increased cell apoptosis in these compartments following treatment with TGF-alpha (group C). In a rat model of SBS, TGF-alpha increased enterocyte proliferation and stimulated intestinal adaptation. The effect of TGF-alpha on enterocyte turnover is correlated with EGF receptor expression along the villus-crypt axis.

Topics: Animals; Apoptosis; Caspase 3; Cell Proliferation; Disease Models, Animal; Enterocytes; ErbB Receptors; Follow-Up Studies; Gene Expression; Immunohistochemistry; Male; Microscopy, Confocal; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Short Bowel Syndrome; Transforming Growth Factor alpha

TGF-alpha has recently been shown to stimulate enterocyte proliferation. In the present study we investigated the effect of TGF-alpha on enterocyte proliferation and loss via apoptosis and its effects on intestinal adaptation in a rat following massive bowel resection.. Male Sprague-Dawley rats underwent bowel transection and reanastomosis (sham group) or 75% small bowel resection and anastomosis (SBS group) and were treated with intraperitoneal TGF-alpha (75 microg/kg) from the ninth postoperative day (SBS-TGF-alpha group). Parameters of intestinal adaptation (overall bowel and mucosal weight, mucosal DNA and protein, villus height, and crypt depth), enterocyte proliferation, and apoptosis were determined on day 15. Statistical significance was determined by ANOVA with a P < 0.05 considered significant.. SBS-TGF-alpha rats demonstrated a significant increase (vs SBS) in duodenal, jejunal, and ileal overall bowel and mucosal weights; ileal mucosal DNA and protein; and jejunal and ileal villus height. SBS-TGF-alpha rats also showed an increased cell proliferation index in jejunum (704 +/- 43 vs 499 +/- 63 BrdU-positive cells/10 crypts, P < 0.05) and ileum (715 +/- 84 vs 529 +/- 40 BrdU-positive cells/10 crypts, P < 0.05) and decreased apoptotic index in ileum (8.7 +/- 1.1 vs 21.8 +/- 3.2 apoptotic cells/1,000 villus cells, P < 0.05) compared to SBS animals.. In a rat model of SBS, TGF-alpha enhances intestinal adaptation. Possible mechanisms may include increased cell proliferation and decreased enterocyte loss via apoptosis.

Topics: Adaptation, Physiological; Animals; Apoptosis; Body Weight; Cell Division; DNA; Intestinal Mucosa; Intestine, Small; Male; Organ Size; Proteins; Rats; Rats, Sprague-Dawley; Short Bowel Syndrome; Transforming Growth Factor alpha