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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-1
,
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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