Interaction between sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-β/Smads pathways in experimental intestinal fibrosis. An in vivo immunohistochemical study

A concomitant action of multiple profibrotic mediators appears crucial in the development and progression of fibrosis. Sphingosine kinase/ sphingosine 1 phosphateand transforming growth factor-β/ Smadspathways are both involved in pathogenesis of fibrosisin several organs by controlling differentiation of fibroblasts to myofibroblastsand the epithelial to-mesenchymal transition. However, their direct involvement in chronic colitis-associated fibrosisit is not yet known. In this study we evaluated the immunohistochemical expression of some proteins implicated in sphingosine kinase/ sphingosine 1 phosphateand transforming growth factor-β/ Smadspathways in Dextrane Sodium Sulphate (DSS)-induced colorectal fibrosisin mice. Compared to control mice, DSS-induced chronic colitis mice developed a marked intestinal fibrosisassociated with a concomitant overexpression of TGF-β, p-Smad3, α-SMA, collagen I-III, SPHK1, RhoA, PI3K, Akt, p-Akt, p-mTOR. This study highlights the relationship between the two pathways and the possible role of SPHK1 in the intestinal fibrosis. These results, if confirmed by in vitro studies, may have important clinical implications in the development of new therapeutical approaches in inflammatory bowel disease.