Efeito do inibidor de quinase da região NH2 terminal de c-Jun SP600125 sobre a resposta fibrótica pulmonar induzida por sílica em camundongos

• Autor(a) principal: Arantes, Ana Carolina Santos de
• Data de Publicação: 2009
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/7871
• topic: SP600125; JNK.Fibrosis; Silicosis; SP600125; JNK; Fibrose; Silicose; Silicose; Proteínas quinases; Fibrose pulmonar; Sílica; CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA

The silicosis is a dysfunction caused by inhalation of crystalline silica particles, characterized by intense inflammation and fibrosis, including the presence of granulomas dispersed in the lung parenchyma. Although silicosis is a serious disease there is no effective therapy until now. The JNK is an enzyme, member of the MAP kinases family, active signal transduction process by the phosphorylating the NH2 terminal region of the transcription factor c-Jun, and which was described to be implicated in chronic inflammatory diseases. In this study, we investigated the potential effect of the JNK inhibitor, SP 600125, on the fibrotic component of the experimental model of silicosis in mice. Swiss-Webster mice were injected intranasally with silica particles (10mg), and further, daily treated curatively with the inhibitor SP 600125 (2 and 5 mg/Kg, p.o), from day 21 to 27 after silica provocation. The analyses were performed 24 h after the last dose and consisted of: i) granuloma area (H&E staining) and collagen deposition (Sirius Red staining and quantification by Sircol technique); ii) pulmonary mechanics by invasive system (resistance and elastance); iii) quantification of cytokines and chemokines by ELISA; iv) quantification of phosphor-JNK levels by western blot. We verified that the curative treatment with the JNK SP 600125 (2 and 5 mg/Kg, p.o) markedly inhibited the lung inflammatory and fibrotic responses as attested by the decrease in leukocyte infiltration and granuloma area. A significant reduction of collagen deposition was evidenced by Picrus sirius staining and Sircol technique. Coherently, treatment with SP 600125 also inhibited the increase of lung resistance and elastance in silicotic animals. The generation of inflammatory and fibrotic mediators as well as increased labeling for macrophages and myofibroblasts in silicotic animals were significantly reduced by the treatment with SP 600125. At last, we noted that the increased levels of phosphor-JNK were sensitive to treatment with the compound. In conclusion, our results show that treatment with the JNK inhibitor SP 600125 effectively inhibited curatively the fibrotic response associated to the chronic phase of murine silicosis, indicating that the use of such pharmacological class of compounds seems to be a promising approach for the treatment of fibrotic diseases such as silicosis.