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

Keratinocyte growth factor-2 (KGF-2, repifermin) is a homolog of KGF-1 with epithelial mitogenic activities. We investigated the therapeutic role of K GF-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 ulc eration by indomethacin (Indo) in prevention and treatment protocols. In ac ute 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 da ily beginning before or 7 days after Indo. Injury was evaluated by blinded macroscopic and microscopic inflammatory scores, epithelial BrdU staining, tissue IL-1 beta, PGE(2), and hydroxyproline concentrations, and collagen t ype I RNA expression. In vitro effects of KGF-2 were evaluated by epithelia l cellular proliferation, restitution of wounded monolayers, PGE(2) secreti on, and expression of COX-2 and collagen mRNA. Intravenous KGF-2 significan tly decreased acute intestinal injury by all parameters and significantly d ecreased chronic ulceration. Pretreatment, daily infusion, and delayed trea tment were effective. KGF-2 promoted in vitro epithelial restitution with o nly modest effects on epithelial cell proliferation, stimulated COX-2 expre ssion in cultured epithelial cells, and upregulated in vitro and in vivo PG E(2) production. KGF-2 did not affect in vivo fibrosis, although it induced collagen expression in cultured intestinal myofibroblasts. These results s uggest that KGF-2 inhibits intestinal inflammation by stimulating epithelia l restitution and protective PGs.