Frank Procaccino

Protective effect of epidermal growth factor in an experimental model of colitis in rats

BACKGROUND/AIMS The role of epidermal growth factor (EGF) in the maintenance of mucosal integrity in the lower gastrointestinal tract is unknown. The aim of this study was to determine the effect of EGF in experimental colitis. METHODS Colitis was induced with 2,4,6-trinitrobenzenesulfonic acid/ethanol enemas. Rats were pretreated with intraperitoneal administration of recombinant human EGF (600 micrograms/kg) or vehicle 1 hour before induction of colitis and daily thereafter until killed at 8 hours, 48 hours, and 1 week. A separate group received an identical dosage and administration of EGF or vehicle for 1 week with treatment initiated 24 hours after the induction of colitis. Colonic tissue was evaluated macroscopically, histologically, and for myeloperoxidase activity. RESULTS Pretreatment with EGF reduced microscopic erosions at 8 and 48 hours by 74% and 54%, respectively (P < 0.05). At 1 week, microscopic ulcerations and myeloperoxidase activity were reduced by 65% in the EGF-pretreated group (P < 0.05). No significant difference in macroscopic injury, histological damage, or myeloperoxidase activity was noted when EGF treatment was initiated after the induction of colitis. CONCLUSIONS Systemic EGF administration reduces mucosal damage and inflammation in a trinitrobenzenesulfonic acid/ethanol model of colitis in rats through a mechanism involving mucosal protection.

Mice lacking transforming growth factor alpha have an increased susceptibility to dextran sulfate-induced colitis.

BACKGROUND & AIMS There is indirect evidence that transforming growth factor alpha (TGF-alpha) is an important mediator of mucosal defense and repair. TGF-alpha knockout mice and TGF-alpha-deficient mice (wa-1) provide novel approaches to evaluate the role of TGF-alpha in preserving the integrity of the colon. METHODS Colitis was induced by oral administration of dextran sodium sulfate (DSS, 5 g/dL) to knockout mice, their genetic controls (GC), wa-1 mice, and BALB/c mice. TGF-alpha was also administered intraperitoneally to wa-1 mice to evaluate the effect of exogenous TGF-alpha in DSS colitis. RESULTS In response to DSS, nearly 60% of the entire colonic mucosa was destroyed in knockout and wa-1 mice, compared with 22% in GC mice and 16% in BALB/ c mice. Body weight loss was doubled in knockout (28%) and wa-1 mice (23%) compared with GC (11%) and Balb/c mice (12%). TGF-alpha application to wa-1 mice reduced the severity of mucosal injury by almost 70% compared with controls. CONCLUSIONS The marked susceptibility of TGF-alpha knockout and wa-1 mice to DSS and the obvious amelioration of the colonic injury by exogenous TGF-alpha application in wa-1 mice suggest that TGF-alpha is a mediator of protection and/or healing mechanisms in the colon.

Keratinocyte growth factor promotes healing of left-sided colon anastomoses

BACKGROUND Inadequate healing and consequent leakage from bowel anastomoses are a significant cause of postoperative morbidity and mortality. Systemic application of keratinocyte growth factor (KGF) has been shown to promote mucosal healing in models of colitis in rats and mice. The aim of the present study was to evaluate the effect of systemic KGF administration on healing of colonic anastomoses in rats. METHODS Rats underwent laparotomy, division of the left colon, and sigmoido-sigmoidostomy. KGF (5 mg/kg) or vehicle were administered intraperitoneally in two groups (n = 30 per group) 12 hours prior to surgery, and then once daily until sacrifice (6 animals per group; 2, 4, 7, 12, and 21 days after surgery). Bursting pressure measurements, histologic evaluation, morphometric analysis, mucin and collagen staining, and hydroxyproline measurements of the anastomotic site were performed. RESULTS Administration of KGF significantly increased anastomotic bursting pressure on postoperative days 2, 4, and 7 by 34%, 49%, and 19%, respectively. Histology, mucin staining, and measurements of the colonic crypt depth showed markedly less extended inflammation with an increased acidic mucin content and a significantly thickened mucosal layer in the KGF treated group when compared with vehicle-treated animals. CONCLUSIONS KGF promotes healing of colonic anastomoses in rats during a 1-week postoperative period following large bowel surgery. KGF may be acting to accelerate host reparative processes as well as to enhance protection of the anastomotic wound bed by increased colonic epithelium proliferation, increased mucus production, and reduction of the inflammatory activity at the anastomotic site.

Keratinocyte Growth Factor Ameliorates Dextran Sodium Sulfate Colitis in Mice

Keratinocyte growth factor (KGF) is emerging asan important mediator of mucosal defense and repair inthe colon. The aim of the present study was to evaluateand further characterize the effects of exogenous KGF administration utilizing the dextran sodiumsulfate (DSS) model of colitis in mice. Colitis wasinduced via oral administration of DSS (5 g/100 ml) toBalb/c mice for eight days. Intraperitonealadministration of KGF (5 mg/kg, once daily) or vehicle (VEH)was initiated 1 hr prior to the induction of the colitis(N = 10, each group). Mucosal injury of the entire colonwas histologically assessed and graded. An approximately fourfold reduction in the cryptdamage score was noted in the KGF group when compared tocontrols (VEH) (2.8 ± 1.03 and 11.4 ±0.78, respectively). The significant reduction ofmucosal injury in KGF treated mice confirms that KGF isa key mediator maintaining the integrity of the colonicmucosa.