SB203580 inhibits epithelial-mesenchymal transition and pulmonary fibrosis in a rat silicosis model

To investigate the role of p38 MAPK in silicosis, we explored the effects of SB203580 as a specific inhibitor of p38 MAPK in the silicosis model in rats. Rats were exposed to 50mg/ml silica intratracheally. From the first day after instillation, rats were injected with SB2035801mg/kg/d. Rats were sacrificed at 7 and 15days after exposure of silica. The results demonstrated SB203580 could prevent the activation of p38. TGF-β1 in bronchoalveolar lavage fluid, the expression of vimentin and α-SMA in the lung tissue was down-regulated and E-cadherin was up-regulated after intervention with SB203580 at 7days and 15days. The percentage of the cells staining with SP-C and vimentin doubly was lower in SB203580 treated group than in silica group at 7days and 15days. SB203580 also inhibited the increase of ZEB-1, ZEB-2 and Twist at 7days. Histopathologic examination showed the decrease in the number of nodules and the blue areas of collagen fibers in the lung after SB203580 treatment. The content of hydroxyproline and the expression of collagen I and III decreased in SB203580 treated group than in silica group. These results suggested that p38 MAPK/ZEB-1 (ZEB-2, Twist) pathway was involved at 7days after silica instillation and p38 MAPK was pivotal for EMT in silicosis fibrosis in rats.

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S1076 SB203580 SB203580 is a p38 MAPK inhibitor with IC50 of 0.3-0.5 μM in THP-1 cells, 10-fold less sensitive to SAPK3(106T) and SAPK4(106T) and blocks PKB phosphorylation with IC50 of 3-5 μM. SB203580 induces mitophagy and autophagy. (422) (6)

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