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| Author(s): |
Paulo José Basso
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2015-08-20 |
| Examining board members: |
Cristina Ribeiro de Barros Cardoso;
Alexandre Salgado Basso;
Jose Joaquim Ribeiro da Rocha
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| Advisor: | Cristina Ribeiro de Barros Cardoso |
| Abstract | |
Crohn\'s disease (CD) and Ulcerative colitis (UC) are the main conditions that comprise the Inflammatory Bowel Diseases (IBD). The conventional drug therapies for IBD aim to attenuate the uncontrolled inflammation in the intestinal mucosa, to treat the complications and to extend clinical remission. However, all available drugs have unpredictable or limited effects. Glucocorticoids (GCs) are commonly anti-inflammatory drugs, which are associated to refractoriness and/or dependence in over half of IBD patients. On the other hand, statins have pleiotropic properties and the concomitant use with GCs has shown good prospects in several autoimmune and inflammatory diseases, including IBD. Despite the putative clinical improvement after combined use of GCs and statins in IBD, there is a lack of data indicating their additive effects on the immune system. Therefore, the purpose of this study was to evaluate the immune modulatory effects of the concomitant use of statins and GCs in experimental colitis induced by dextran sulfate sodium (DSS). The results showed that long-term use of GCs (dexamethasone - DX), alone or associated to statins (atorvastatin - ATO), did not improve the clinical signs and increased the death rates of C57BL/6 mice exposed to DSS, while the opposite was observed after treatment with statins alone. Short-term use of ATO (3 doses), alone or associated to DX, improved the clinical signs and histological parameters in DSS-exposed mice, decreased the number of white blood cells (mainly monocytes), the number of mononuclear cells in the lamina propria (LP), the frequency of CD11b+ cells in the LP, the frequency of CD11b+CD11c+ and CD11b-CD11c+ dendritic cells (DCs) in the spleen and the frequency of IFN--producing CD4+ T cells in the mesenteric lymph nodes (MLN). However, ATO alone or associated to DX lead to increased CD8+ T lymphocytes in the spleen and MLN. Moreover, both therapies containing ATO inhibited the proliferation of in vitro-treated splenocytes, besides decreasing IL-6 and increasing IL-10 synthesis. Differentially, the association of drugs led to a more pronounced effects over the changes mentioned above than the single use of statin and additionally decreased IL-1, IL-17 and IFN- mRNA expression levels at the intestinal tissue, the number of circulating lymphocytes, the number of leukocytes in spleen and MLN and the frequency of CD4+ T lymphocytes in the MLN. In addition, statins and GCs increased the frequency of CD11b-CD11c+ DCs in LP and the Fas-L concentrations in the large intestine. Considering the short-term use of ATO there was increased frequency of CD11b-CD11c+ DCs in MLN, increased frequency of natural killer (NK) cells in the spleen and decreased mRNA expression of PPAR- in the large intestine. The short-term use of DX improved the histology parameters, decreased the number of macrophages and IFN- levels in the colon, reduced the number of circulating leukocytes (mainly lymphocytes), and increased the frequency of CD11b+ cells in spleen and IL-10 synthesis by ex vivo splenocytes. Finally, since both regulatory T cells (Treg) frequency and the splenocytes susceptibility to regulatory signals have not been modified after the different treatments, our findings suggest that single use of statins preserved an efficient and controlled inflammatory response, while the combined use of GCs and statins led to immunosuppression, which probably contributed to long-term clinical complications of DSS-induced colitis. (AU) | |
| FAPESP's process: | 13/11042-6 - Evaluation of the immune modulatory effects of statins and glucocorticoids in experimental colitis |
| Grantee: | Paulo José Basso |
| Support Opportunities: | Scholarships in Brazil - Master |