RESUMO
BACKGROUND & AIMS: We recently identified a novel member of the human fibroblast growth factor (FGF) family of signaling molecules, designated FGF-20. In the present study, we examined the activity of this protein in 2 animal models of acute intestinal inflammation and in mechanistic studies in vitro. METHODS: In vivo experiments consisted of a murine dextran sulfate sodium (DSS) model of colitis and a rat indomethacin model of small intestinal ulceration/inflammation. Cell growth, restitution, gene expression (cyclooxygenase-2 [COX-2] and intestinal trefoil factor [ITF]), and prostaglandin E2 (PGE2) levels were examined in vitro. RESULTS: In the DSS-colitis model, prophylactic administration of FGF-20 significantly reduced the severity and extent of mucosal damage as indicated by a 55%-93% reduction in luminal blood loss, distal colonic edema, histologic inflammation, and epithelial cell loss relative to animals administered vehicle control. No toxicity was noted during administration of FGF-20 to normal controls. In addition, therapeutic administration of FGF-20 enhanced survival in this model. In the indomethacin-small bowel ulceration/inflammation model, administration of FGF-20 reduced small intestinal weight gain, necrosis, inflammation, and weight loss (36%-53% relative to vehicle control). In vitro studies demonstrated that FGF-20 stimulates growth, restitution, mRNA expression of COX-2 and ITF, and PGE2 levels in human intestinal epithelial cells and enhances the growth of human intestinal fibroblasts. CONCLUSIONS: FGF-20, having demonstrated therapeutic activity in 2 experimental models of intestinal inflammation, represents a promising new candidate for the treatment of human inflammatory bowel disease.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/farmacologia , Mucinas , Proteínas Musculares , Neuropeptídeos , Células 3T3 , Sequência de Aminoácidos , Animais , Anti-Inflamatórios não Esteroides , Anticoagulantes , Divisão Celular/efeitos dos fármacos , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/mortalidade , Colite Ulcerativa/prevenção & controle , Doença de Crohn/induzido quimicamente , Doença de Crohn/mortalidade , Doença de Crohn/prevenção & controle , Ciclo-Oxigenase 2 , Sulfato de Dextrana , Dinoprostona/metabolismo , Modelos Animais de Doenças , Feminino , Fatores de Crescimento de Fibroblastos/genética , Expressão Gênica , Substâncias de Crescimento/genética , Humanos , Indometacina , Intestino Delgado/citologia , Intestino Delgado/enzimologia , Isoenzimas/genética , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Peptídeos/genética , Prostaglandina-Endoperóxido Sintases/genética , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Taxa de Sobrevida , Fator Trefoil-2 , Fator Trefoil-3RESUMO
The angiopoietins comprise a family of proteins that have pro or antiangiogenic activities. Through a proprietary technology designed to identify transcripts of all expressed genes, we isolated a cDNA encoding an angiopoietin-related protein that we designate angioarrestin. The mRNA expression profile of angioarrestin was striking in that it was down-regulated in many tumor tissues when compared with adjacent nontumor tissue, suggesting a role for this protein in tumor inhibition. To test this hypothesis, we ectopically expressed angioarrestin in HT1080 tumor cells and measured pulmonary tumor nodule formation in nude mice. HT1080 cells expressing angioarrestin showed a marked reduction in the number and size of tumor nodules. In vitro, the recombinant protein was systematically tested in a number of endothelial cell assays and found to block critical processes involved in the angiogenic cascade, such as vascular endothelial growth factor/basic fibroblast growth factor-mediated endothelial cell proliferation, migration, tubular network formation, and adhesion to extracellular matrix proteins. These findings reveal a novel function for angioarrestin as an angiogenesis inhibitor and indicate that the molecule may be a potential cancer therapeutic.
