RESUMEN
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.
Asunto(s)
Colitis Ulcerosa/tratamiento farmacológico , Enfermedad de Crohn/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/farmacología , Mucinas , Proteínas Musculares , Neuropéptidos , Células 3T3 , Secuencia de Aminoácidos , Animales , Antiinflamatorios no Esteroideos , Anticoagulantes , División Celular/efectos de los fármacos , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/mortalidad , Colitis Ulcerosa/prevención & control , Enfermedad de Crohn/inducido químicamente , Enfermedad de Crohn/mortalidad , Enfermedad de Crohn/prevención & control , Ciclooxigenasa 2 , Sulfato de Dextran , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Femenino , Factores de Crecimiento de Fibroblastos/genética , Expresión Génica , Sustancias de Crecimiento/genética , Humanos , Indometacina , Intestino Delgado/citología , Intestino Delgado/enzimología , Isoenzimas/genética , Proteínas de la Membrana , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Péptidos/genética , Prostaglandina-Endoperóxido Sintasas/genética , Ratas , Ratas Endogámicas Lew , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Tasa de Supervivencia , Factor Trefoil-2 , Factor Trefoil-3RESUMEN
Platelet-derived growth factor (PDGF) has been directly implicated in developmental and physiological processes, as well as in human cancer and other proliferative disorders. We have recently isolated and characterized a novel protease-activated member of the PDGF family, PDGF D. PDGF D has been shown to be proliferative for cells of mesenchymal origin, signaling through PDGF receptors. Comprehensive and systematic PDGF D transcript analysis revealed expression in many cell lines derived from ovarian, renal, and lung cancers, as well as from astrocytomas and medulloblastomas. beta PDGF receptor profiling further suggested autocrine signaling in several brain tumor cell lines. PDGF D transforming ability and tumor formation in SCID mice was further demonstrated. Exploiting a sensitive PDGF D sandwich ELISA using fully human monoclonal antibodies, PDGF D was detected at elevated levels in the sera of ovarian, renal, lung, and brain cancer patients. Immunohistochemical analysis confirmed PDGF D localization to ovarian and lung tumor tissues. Together, these data demonstrate that PDGF D plays a role in certain human cancers.
