RESUMO
1. Inflammation-induced proliferation of cardiac fibroblasts plays an important role in cardiac remodelling. Pharmacological doses of exogenous glucocorticoids (GC) are the most effective therapy for inflammatory diseases. Similarly, physiological concentrations of endogenous GC have recently been shown to have anti-inflammatory effects. Therefore, the aim of the present study was to determine whether a physiological concentration of GC could inhibit pro-inflammatory cytokine-stimulated proliferation of cardiac fibroblasts and to explore the mechanisms involved. 2. Cardiac fibroblasts were isolated from adult male Sprague-Dawley rats and cell proliferation was measured using a CCK-8 kit. Western blotting was used to detect protein expression of extracellular-regulated kinase (ERK) 1/2 and nuclear factor (NF)-κB. 3. Cardiac fibroblast proliferation was significantly increased by tumour necrosis factor-α, interleukin (IL)-1ß and angiotensin II and was accompanied by upregulated protein expression of ERK1/2 and NF-κB. A physiological concentration of hydrocortisone (127 ng/mL) not only inhibited the proliferation of cardiac fibroblasts, but also suppressed activation of ERK1/2 and NF-κB. These effects of hydrocortisone were abrogated by the glucocorticoid receptor (GR) antagonist RU-486 (100 nmol/L). Furthermore, inflammation-induced cardiac fibroblast proliferation was also blocked by the mitogen-activated protein kinase kinase 1/2 inhibitor U0126 (100 nmol/L) and the NF-κB inhibitor pyrrolidine dithiocarbamate (1 µmol/L). Cytokine-induced ERK1/2 phosphorylation and cyclin D1 expression were attenuated by U0126, suggesting that the ERK1/2 and NF-κB signalling pathways were involved in cardiac fibroblast proliferation. 4. In conclusion, the results of the present study indicate that a physiological concentration of hydrocortisone can inhibit inflammation-induced proliferation of cardiac fibroblasts by preventing the activation of ERK1/2 and NF-κB.
Assuntos
Hidrocortisona/farmacologia , Mediadores da Inflamação/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miofibroblastos/metabolismo , NF-kappa B/metabolismo , Angiotensina II/metabolismo , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Células Cultivadas , Ciclina D1/genética , Ciclina D1/metabolismo , Hidrocortisona/fisiologia , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Miocárdio/citologia , Miocárdio/metabolismo , Miofibroblastos/citologia , Miofibroblastos/efeitos dos fármacos , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/genéticaRESUMO
The dipyrrolylquinoxaline (DPQ)-containing monomer and polymers were synthesized and employed as chromogenic and fluorescent chemosensors for inorganic anions. We have found that in the presence of fluoride or pyrophosphate, the receptors do not form hydrogen bonds between the pyrrole protons and anions. The colorimetric responses and fluorescence quenching in these chemosensors are indeed the result of deprotonation of the N-H proton. The anion selectivity is primarily determined by the relative basicity of anions. The sensitivity of DPQ-based chemosensor was found to display a 34-fold enhancement by incorporation into the conjugated polymer. The anion-induced deprotonation generates low-energy, non-fluorescent trapping sites and is responsible for the signal amplification where the quenching of the excited state occurs from the deprotonated DPQ site in the network by rapid exciton migration along the polymeric backbone.