RENATO FRAGA RIGHETTI
Projetos de Pesquisa
Unidades Organizacionais
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina
4 resultados
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- Y-27632 is associated with corticosteroid-potentiated control of pulmonary remodeling and inflammation in guinea pigs with chronic allergic inflammation(2015) PIGATI, Patricia Angeli; RIGHETTI, Renato Fraga; POSSA, Samantha Souza; ROMANHOLO, Beatriz Saraiva; RODRIGUES, Adriana Palmeira Dias; SANTOS, Anelize Sartori Alves dos; XISTO, Debora Gonalves; ANTUNES, Mariana Alves; PRADO, Carla Maximo; LEICK, Edna Aparecida; MARTINS, Milton de Arruda; ROCCO, Patrcia Rieken Macedo; TIBERIO, Iolanda de Fatima Lopes CalvoBackground: Previously, we showed that treatment with the Rho-kinase inhibitor Y-27632 was able to control airway responsiveness, inflammation, remodeling, and oxidative stress in an animal model of asthma, suggesting that this drug is beneficial in asthma. However, studies evaluating the effects of these inhibitors in conjunction with corticosteroids on chronic pulmonary inflammation have not been conducted. Therefore, we evaluated the effects of treatment with the Rho-kinase inhibitor Y-27632, with or without concurrent dexamethasone treatment, on airway and lung tissue mechanical responses, inflammation, extracellular matrix remodeling, and oxidative stress in guinea pigs with chronic allergic inflammation. Methods: The guinea pigs were subjected to seven ovalbumin or saline inhalation exposures. Treatment with Y-27632 (1 mM) and dexamethasone (2 mg/kg) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the pulmonary mechanics were evaluated and exhaled nitric oxide (E-NO) levels were determined. The lungs were removed and histological analysis was performed using morphometry. Results: The treatment of guinea pigs with the Rho-kinase inhibitor and dexamethasone (ORC group) decreased ENO, the maximal mechanical responses after antigen challenge, inflammation, extracellular matrix remodeling and oxidative stress in the lungs. This therapeutic strategy reduced the levels of collagen and IFN-gamma in the airway walls, as well as IL-2, IFN-gamma, 8-iso-PGF2 alpha and NF-kappa B in the distal parenchyma, when compared to isolated treatment with corticosteroid or Rho-kinase inhibitor (P < 0.05) and reduced the number of TIMP-1-positive cells and eosinophils in the alveolar septa compared to corticosteroid-treated animals (P < 0.05). The combined treatment with the Rho-kinase inhibitor and the corticosteroid provided maximal control over the remodeling response and inflammation in the airways and parenchyma. Conclusions: Rho-kinase inhibition, alone or in combination with corticosteroids, can be considered a future pharmacological tool for the control of asthma.
- Effects of Rho-kinase inhibition in lung tissue with chronic inflammation(2014) I, Renato Fraga Righett; PIGATI, Patricia Angeli da Silva; POSSA, Samantha Souza; HABRUM, Fabio Cetinic; XISTO, Debora Goncalves; ANTUNES, Mariana Alves; LEICK, Edna Aparecida; PRADO, Carla Maximo; MARTINS, Milton de Arruda; ROCCO, Patricia Rieken Macedo; TIBERIO, Iolanda de Fatima Lopes CalvoWe evaluated whether Rho-kinase inhibition (Y-27632) modulated distal lung responsiveness, inflammation, extracellular matrix remodeling and oxidative stress activation in guinea pigs (GPs) with chronic allergic inflammation. GPs were submitted to inhalation of ovalbumin (OVA-2x/week/4 weeks). From the 5th inhalation on, the Rho-kinase inhibitor group animals were submitted to Y-27632 inhalation 10 min before each inhalation of OVA. Seventy-two hours after the seventh inhalation, the oscillatory mechanics of the distal lung strips were assessed under the baseline condition and after the ovalbumin challenge. Subsequently, the lung slices were submitted to morphometry. Rho-kinase inhibition in the ovalbumin-exposed animals attenuated distal lung elastance and resistance, eosinophils, IL-2, IL-4, IL-5, IL-13, TIMP-1, MMP-9, TGF-beta, IFN-gamma, NF-kappa B and iNOS-positive cells and the volume fraction of 8-iso-PGF2 alpha, elastic, collagen and actin in alveolar walls compared with the OVA group (P < 0.05). Rho-kinase inhibition contributed to the control of distal lung responsiveness, eosinophilic and Th1/Th2 responses and extracellular matrix remodeling in an animal model of chronic allergic inflammation.
- Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation(2012) POSSA, Samantha Souza; CHARAFEDDINE, Homar Toledo; RIGHETTI, Renato Fraga; SILVA, Patricia Angeli da; ALMEIDA-REIS, Rafael; SARAIVA-ROMANHOLO, Beatriz Mangueira; PERINI, Adenir; PRADO, Carla Maximo; LEICK-MALDONADO, Edna Aparecida; MARTINS, Milton A.; TIBERIO, Iolanda de Fatima Lopes CalvoPossa SS, Charafeddine HT, Righetti RF, da Silva PA, Almeida-Reis R, Saraiva-Romanholo BM, Perini A, Prado CM, Leick-Maldonado EA, Martins MA, Tiberio ID. Rho-kinase inhibition attenuates airway responsiveness, inflammation, matrix remodeling, and oxidative stress activation induced by chronic inflammation. Am J Physiol Lung Cell Mol Physiol 303: L939-L952, 2012. First published September 21, 2012; doi:10.1152/ajplung.00034.2012.-Several studies have demonstrated the importance of Rho-kinase in the modulation of smooth muscle contraction, airway hyperresponsiveness, and inflammation. However, the effects of repeated treatment with a specific inhibitor of this pathway have not been previously investigated. We evaluated the effects of repeated treatment with Y-27632, a highly selective Rho-kinase inhibitor, on airway hyperresponsiveness, oxidative stress activation, extracellular matrix remodeling, eosinophilic inflammation, and cytokine expression in an animal model of chronic airway inflammation. Guinea pigs were subjected to seven ovalbumin or saline exposures. The treatment with Y-27632 (1 mM) started at the fifth inhalation. Seventy-two hours after the seventh inhalation, the animals' pulmonary mechanics were evaluated, and exhaled nitric oxide (E-NO) was collected. The lungs were removed, and histological analysis was performed using morphometry. Treatment with Y-27632 in sensitized animals reduced E-NO concentrations, maximal responses of resistance, elastance of the respiratory system, eosinophil counts, collagen and elastic fiber contents, the numbers of cells positive for IL-2, IL-4, IL-5, IL-13, inducible nitric oxide synthase, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, transforming growth factor-beta, NF-kappa B, IFN-gamma, and 8-iso-prostaglandin F2 alpha contents compared with the untreated group (P < 0.05). We observed positive correlations among the functional responses and inflammation, remodeling, and oxidative stress pathway activation markers evaluated. In conclusion, Rho-kinase pathway activation contributes to the potentiation of the hyperresponsiveness, inflammation, the extracellular matrix remodeling process, and oxidative stress activation. These results suggest that Rho-kinase inhibitors represent potential pharmacological tools for the control of asthma.
- Effect of anti-IL17 and/or Rho-kinase inhibitor treatments on vascular remodeling induced by chronic allergic pulmonary inflammation(2020) SANTOS, Tabata M. dos; RIGHETTI, Renato F.; REZENDE, Bianca G.; CAMPOS, Elaine C.; CAMARGO, Leandro do N.; SARAIVA-ROMANHOLO, Beatriz M.; FUKUZAKI, Silvia; PRADO, Carla M.; LEICK, Edna A.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.Background and aims: Expansion and morphological dysregulation of the bronchial vascular network occurs in asthmatic airways. Interleukin (IL) -17 and Rho-kinase (ROCK) are known to act in inflammation control and remodeling. Modulation of Rho-kinase proteins and IL-17 may be a promising approach for the treatment of asthma through the control of angiogenesis. Our objective was to analyze the effects of treatment with anti-IL17 and/or Rho-kinase inhibitor on vascular changes in mice with chronic allergic pulmonary inflammation. Methods: Sixty-four BALB/c mice, with pulmonary inflammation induced by ovalbumin were treated with anti-IL17A (7.5/mu g per dose, intraperitoneal) and/or Rho-kinase inhibitor (Y-27632-10 mg/kg, intranasal), 1 h before each ovalbumin challenge (22, 24, 26, and 28/days). Control animals were made to inhale saline. At the end of the protocol, lungs were removed, and morphometric analysis was performed to quantify vascular inflammatory, remodeling, and oxidative stress responses. Results: Anti-IL17 or Rho-kinase inhibitor reduced the number of CD4(+), CD8(+), dendritic cells, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, Rho-kinase 1 and 2, transforming growth factor (TGF-beta), vascular endothelial growth factor (VEGF), nuclear factor (NF)-KappaB, iNOS, metalloproteinase (MMP)-9, MMP-12, metalloproteinase inhibitor-1 (TIMP-1), FOXP-3, signal transducer and activator of transcription 1 (STAT1) and phospho-STAT1-positive cells, and actin, endothelin-1, isoprostane, biglycan, decorin, fibronectin and the collagen fibers volume fraction compared with the ovalbumin group (p < 0.05). The combination treatment, when compared with anti-IL17, resulted in potentiation of decrease in the number of IL1 beta- and dendritic cells-positive cells. When we compared the OVA-RHO inhibitor-anti-IL17 with OVA-RHO inhibitor we found a reduction in the number of CD8(+) and IL-17, TGF-beta, and phospho-STAT1-positive cells and endothelin-1 in the vessels (p < 0.05). There was an attenuation in the number of ROCK 2-positive cells in the group with the combined treatment when compared with anti-IL17 or Rho-kinase inhibitor-treated groups (p < 0.05). Conclusion: We observed no difference in angiogenesis after treatment with Rho-kinase inhibitor and anti-IL17. Although the treatments did not show differences in angiogenesis, they showed differences in the markers involved in the angiogenesis process contributing to inflammation control and vascular remodeling. The reviews of this paper are available via the supplemental material section.