RESUMEN
PURPOSE: Rapamycin has antiproliferative and antifibrogenic effects in vitro and in vivo. The purpose of this study was to evaluate the effects of rapamycin on transforming growth factor (TGF) beta 1 induced myofibroblast differentiation (alpha smooth-muscle actin [SMA]), extracellular matrix production, and collagen contraction in nasal polyp-derived fibroblasts (NPDF). The underlying molecular mechanisms of rapamycin were also determined in NPDFs. METHODS: NPDFs were grown in culture and transformed into myofibroblasts by using TGF beta 1 (5 ng/mL). For cytotoxicity evaluation, a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay was used. Expression levels of alpha SMA, phosphorylated phosphatidylinositol 3-kinase (PI3K), and phosphorylated mammalian target of rapamycin (mTOR) were determined by using Western blot, reverse transcription-polymerase chain reaction, and immunofluorescence staining. The total amount of collagen was analyzed by using the Sircol collagen assay, and contractile activity was measured with a collagen gel contraction assay. Silencing mTOR with mTOR-specific small interference RNA was determined by using reverse transcription-polymerase chain reaction. RESULTS: Whereas rapamycin (range, 0-400 nM) had no significant cytotoxic effects on TGF beta 1 induced NPDFs, it significantly reduced the expression levels of alpha-SMA in TGF beta 1 induced NPDFs in a dose-dependent manner. TGF beta 1 induced collagen production and collagen contraction were significantly inhibited by rapamycin treatment. Rapamycin also attenuated the TGF beta 1 induced activation of PI3K and mTOR, and its inhibitory effects were similar to those of mTOR silencing and a specific PI3K inhibitor. CONCLUSIONS: Rapamycin inhibited TGF beta 1 induced myofibroblast differentiation, extracellular matrix production, and collagen contraction through the PI3K/mTOR signal pathways in NPDFs.
Asunto(s)
Fibroblastos/efectos de los fármacos , Inmunosupresores/farmacología , Miofibroblastos/efectos de los fármacos , Pólipos Nasales/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Actinas/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Células Cultivadas , Colágeno/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/fisiología , Humanos , Miofibroblastos/fisiología , Pólipos Nasales/metabolismo , Pólipos Nasales/patología , ARN Interferente Pequeño/genética , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The combined symptoms of vertigo, hearing loss, and facial palsy indicate the presence of lesions in the internal auditory canal (IAC). Differential diagnoses, such as inner/middle ear infections and IAC neoplasms, can make the definitive diagnosis of IAC lymphomas challenging. Lymphomas can infiltrate the central nervous system at various sites; however, IAC involvement in metastatic lymphomas is very rare. Herein we report the case of a patient with IAC lymphoma presenting with aural fullness of the left ear and intractable otalgia followed by symptoms of facial weakness, hearing loss, and vertigo within 48 h. The uncharacteristic clinical manifestations and concurrent middle ear infection meant that the conclusive diagnosis of IAC lymphoma was delayed.