RESUMEN
OBJECTIVE: Tissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor beta (TGFbeta) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGFbeta/Smad signaling through the activation of nuclear translocation of Y-box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc. METHODS: Human dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGFbeta, and levels of collagen or fibronectin expression were determined. HSc025 (15 mg/kg/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin-induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model. RESULTS: Pretreatment with HSc025 prevented Smad-dependent promoter activation, in a dose-dependent manner; however, HSc025 had no effect on TGFbeta-induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGFbeta-induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin-treated mice. CONCLUSION: These results demonstrate that HSc025 is a novel inhibitor of TGFbeta/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc.
Asunto(s)
Extractos Vegetales/farmacología , Esclerodermia Sistémica/patología , Piel/patología , Proteínas Smad/antagonistas & inhibidores , Proteínas Smad/genética , Activación Transcripcional/efectos de los fármacos , Zanthoxylum , Alcadienos/farmacología , Alcadienos/uso terapéutico , Animales , Bleomicina/efectos adversos , Células Cultivadas , Colágeno/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibronectinas/metabolismo , Fibrosis , Humanos , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/uso terapéutico , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Esclerodermia Sistémica/tratamiento farmacológico , Esclerodermia Sistémica/metabolismo , Transducción de Señal/efectos de los fármacos , Piel/metabolismo , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Graft-versus-host disease (GVHD) is a frequent complication occurring after allogenic hematopoietic stem cell transplantation and is divided into acute and chronic type. Cutaneous involvement is the most frequent manifestation of acute GVHD, with maculopapular exanthema and perifollicular papular lesions. We describe the first case to develop acute cutaneous GVHD mimicking psoriasis vulgaris shortly after allogenic peripheral blood stem cell transplantation. The patient's rash resembled psoriasis vulgaris and showed histologic features of both psoriasis and acute GVHD. Despite various immunosuppressant therapies, the skin lesion was drug-resistant. Therefore, we administered psoralen-UVA (PUVA) therapy and achieved the desired therapeutic effect. As far as we know, this is the first case of psoriasiform skin eruption as a manifestation of acute GVHD.