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

Abstract

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, PGE(2), 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, PGE(2) 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 PGE(2) 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.

An Herbal Medicine Orengedokuto Prevents Indomethacin-Induced Enteropathy

“…Many agents have been found to have protective effects in the indomethacin-induced enteropathy model which results in relatively milder injury and little lethality. [26][27][28][29][30][31][32] So far, only human glucagon-like peptide 2 has been reported to be protective against indomethacin-induced lethality. 21) We also investigated the effect of OGT on intestinal PGE2 levels.…”

Pharmacologic and pharmacokinetic profile of repifermin (KGF-2) in monkeys and comparative pharmacokinetics in humans

“…13 Repifermin was found to be more effective than the vehicle control at closing the interstices of a human meshed skin graft explanted to athymic nude rats. 14 In light of this pharmacological profile, repifermin is being developed as a potential therapeutic agent for chemotherapy-or radiotherapyinduced mucositis, ulcerative colitis, and cutaneous wounds.…”

New Biologic Drugs for Ulcerative Colitis

“…In UC the inflammation is confined to the mucosa and epithelial cell damage is an important feature. Repifermin (KGF-2) has been shown to reduce inflammation in animal models of colitis (52)(53)(54). The effect of Repifermin were studied in a phase II, placebo controlled trial in 88 patients with active UC.…”