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    Efeito do infliximabe e da diacereína na via eruptiva de molares de ratos.
    (Universidade Federal de São Paulo (UNIFESP), 2019-06-27) Pizzol Junior, Jose Paulo De [UNIFESP]; Cerri, Paulo Sergio [UNIFESP]; Cerri, Estela Sasso [UNIFESP]; http://lattes.cnpq.br/4455630076841302; http://lattes.cnpq.br/3278495911207882; http://lattes.cnpq.br/3031753481292518; Universidade Federal de São Paulo (UNIFESP)
    During tooth eruption, a complex cascade of cellular and molecular events occurs to promote the degradation of the lamina propria and bone located in the eruptive pathway. Tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) are cytokines involved in osteoclastogenesis and activation of matrix metalloproteinases (MMPs). The purpose of this study was to evaluate whether infliximab (TNF-α blocker) and diacerein (IL-1 synthesis inhibitor) interfere in the eruptive process, and in the osteoclastogenesis as well as in the degradation of the lamina propria during the tooth eruption in rat. One hundred and eight rats at 6 and 12 days of age were distributed in 4 groups (n = 27 rats per group): CG (control group) – physiological saline; DIAG -100 mg/kg/day diacerein (anti-IL-1 - Artrodar® - TRB Pharma Industry Chemical and Pharmaceutical Ltd.); INFG - 5mg/kg/day of infliximab (anti-TNF-α - Remicade® - Janssen Biotec.); INF+DIAG - 5mg/kg/day of infliximab + 100mg/kg/day of diacerein. Rats at 6 days of age received treatment for 3 and 5 days; rats at 12 days of age were treated for 4 days. After 24 hours of the last dose, the rats were sacrificed. Fragments of the oral mucosa were frozen for detection of TNF-α and IL-1β by western blot. Fragments of maxilla containing the first molar were fixed, decalcified and embedded in paraffin for light microscopy. Sections containing the eruptive pathway of first molar were stained with HE for morphological analysis. Some sections were submitted to immunohistochemical reactions for detection of TNF-α, IL-1, IL-6, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), MMP-1 and MMP-9. The number of immunolabelled cells for IL-1, IL-6, MMP-1 and MMP-9 in the lamina propria was computed while the number of RANKL- and OPG-positive cells was obtained on the bone surface. Some sections were submitted to the histochemical reaction for tartrate-resistant acid phosphatase (TRAP), and the number of TRAP-positive osteoclasts on the bone surface was computed. Sections stained with picrosirius-red were used to estimate the birefringent collagen content in the lamina propria. The data were analysed using Two-way ANOVA with the Tukey's test (p≤0.05). Fragments of maxilla (n= 3/group) were fixed in formaldehyde/glutaraldehyde and processed for analysis under the transmission electron microscope. The upper first molars of animals with 9 and 11 days were in the intraosseous eruptive phase and at 16 days in the mucosal penetration phase. At all periods, immunolabelled cells for TNF-α, IL-1β, IL-6, MMP-1 and MMP-9 were observed in the lamina propria. In the eruptive pathway of CG animals, a significant increase in the immunoexpression of TNF-α was observed over time, while the peak of immunoexpression for IL-1β was detected at 11 days. In relation to the treated-rats, a significant reduction of TNF-α was detected in the eruptive pathway of rats from INF+DIAG at 16 days. The IL-1β immunoexpression was significantly lower in the DIAG and INF+DIAG groups at 11 days. At 16 days, a significant reduction in the immunolabelling for IL-1β was observed only in the INF+DIAG. From 9 to 11 days, the bone surface showed a significant increase in the number of osteoclasts in the CG whereas, in the treated groups, significant differences were not observed. At 9 and 11 days, significant differences in the number of RANKL- and OPG-immunolabelled cells between the treated groups and CG were not detected. Ultrastructural analysis of specimens from treated groups revealed osteoclasts exhibiting condensed chromatin, typical of cells undergoing xi apoptosis; ruffled border and clear zone were not observed in these altered osteoclasts. At 16 days, the collagen content was significantly higher in the lamina propria of DIAG and INFG groups than CG (p = 0.001 and p = 0.003, respectively). At all periods, significant differences between the groups were not detected in the number of MMP-1-, MMP-9- and IL-6-immunolabelled cells in the lamina propria. Over time, a significant increase in the number of MMP-1-, MMP-9- and IL-6-immunolabelled cells was observed in all groups, with exception of MMP-1 and IL-6 in the rats of INFG. Our results showed that the peak of IL-1β occurs in the intraosseous phase whereas the TNF-α occurs in the mucosal penetration phase. Although the treatment with diacerein and infliximab caused alterations in the immunoexpression of IL-1β and TNF-α in the lamina propria, they did not promote significant alterations in the eruptive process. Diacerein and infliximab did not interfere with osteoclastogenesis in the eruptive pathway; however, our results suggest that these drugs should promote apoptosis of osteoclasts.