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 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.
Han
D S
DS
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Li
F
F
Holt
L
L
Connolly
K
K
Hubert
M
M
Miceli
R
R
Okoye
Z
Z
Santiago
G
G
Windle
K
K
Wong
E
E
Sartor
R B
RB
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018938:Caco-2 Cells; D002455:Cell Division / Q000187:drug effects; D002908:Chronic Disease; D003094:Collagen / Q000235:genetics; D015232:Dinoprostone / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005260:Female; D051526:Fibroblast Growth Factor 10; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D007213:Indomethacin; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D007375:Interleukin-1 / Q000032:analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D013047:Specific Pathogen-Free Organisms; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; C496463:FGF10 protein, human; C496453:FGF7 protein, human; C496465:Fgf10 protein, rat; C496455:Fgf7 protein, rat; D051526:Fibroblast Growth Factor 10; D006133:Growth Substances; D007375:Interleukin-1; D012333:RNA, Messenger; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D003094:Collagen; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D006909:Hydroxyproline; D007213:Indomethacin