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Am J Physiol Gastrointest Liver Physiol 279: G1011-G1022, 2000;
0193-1857/00 $5.00
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Vol. 279, Issue 5, G1011-G1022, November 2000

Keratinocyte growth factor-2 (FGF-10) promotes healing of experimental small intestinal ulceration in rats

Dong Soo Han1, Fengling Li1, Lisa Holt1, Kevin Connolly2, Melissa Hubert2, Reneé Miceli2, Zebedee Okoye2, Gemma Santiago2, Kathleen Windle2, Eling Wong2, and R. Balfour Sartor1

1 Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina 27599; and 2 Human Genome Sciences, Incorporated, Rockville, Maryland 20850

Keratinocyte growth factor-2 (KGF-2, repifermin) is a homolog of KGF-1 with epithelial mitogenic activities. We investigated the therapeutic role of KGF-2 in intestinal ulceration and its mechanisms of protection. KGF-2 (0.3-5 mg/kg) was administered before or after induction of small intestinal ulceration by indomethacin (Indo) in prevention and treatment protocols. In acute studies, KGF-2 was injected for up to 7 days before or daily for 5 days after Indo. In a 15-day chronic study, KGF-2 was injected intravenously daily beginning before or 7 days after Indo. Injury was evaluated by blinded macroscopic and microscopic inflammatory scores, epithelial BrdU staining, tissue IL-1beta , PGE2, and hydroxyproline concentrations, and collagen type I RNA expression. In vitro effects of KGF-2 were evaluated by epithelial cellular proliferation, restitution of wounded monolayers, PGE2 secretion, and expression of COX-2 and collagen mRNA. Intravenous KGF-2 significantly decreased acute intestinal injury by all parameters and significantly decreased chronic ulceration. Pretreatment, daily infusion, and delayed treatment were effective. KGF-2 promoted in vitro epithelial restitution with only modest effects on epithelial cell proliferation, stimulated COX-2 expression in cultured epithelial cells, and upregulated in vitro and in vivo PGE2 production. KGF-2 did not affect in vivo fibrosis, although it induced collagen expression in cultured intestinal myofibroblasts. These results suggest that KGF-2 inhibits intestinal inflammation by stimulating epithelial restitution and protective PGs.

immunoregulation; inflammatory bowel disease; cytokines; prostaglandins


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