RENATO FRAGA RIGHETTI
Projetos de Pesquisa
Unidades Organizacionais
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina
19 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 19
- Treatment with proteinase inhibitor from Enterolobium contortisiliquum in mice with asthma-COPD(2020) BARBOSA, Jessica Anastacia Silva; SILVA, Luana Laura Sales Da; JOAO, Juliana Morelli Lopes Goncalves; SANTOS, Tabata Maruyama Dos; CAMARGO, Leandro Nascimento; CAMPOS, Elaine Cristina De; GALLI, Thiago Tafarel; SARAIVA-ROMANHOLO, Beatriz Mangueira; BEZERRA, Suellen Karoline Moreira; HAMAGUCHI, Sara Sumie Sobral; LEICK, Edna Aparecida; PRADO, Carla Maximo; MARTINS, Milton De Arruda; OLIVO, Maria Luiza Vilela; RIGHETTI, Renato Fraga; TIBERIO, Iolanda De Fatima Lopes Calvo
- iNOS Inhibition Reduces Lung Mechanical Alterations and Remodeling Induced by Particulate Matter in Mice(2019) PRADO, Carla Maximo; RIGHETTI, Renato Fraga; LOPES, Fernanda Degobbi Tenorio Quirino dos Santos; LEICK, Edna Aparecida; ARANTES-COSTA, Fernanda Magalhaes; ALMEIDA, Francine Maria de; SALDIVA, Paulo Hilario Nascimento; MAUAD, Thais; TIBERIO, Iolanda de Fatima Lopes Calvo; MARTINS, Milton de ArrudaBackground. The epidemiologic association between pulmonary exposure to ambient particulate matter (PM) and acute lung damage is well known. However, the mechanism involved in the effects of repeated exposures of PM in the lung injury is poorly documented. This study tested the hypotheses that chronic nasal instillation of residual oil fly ash (ROFA) induced not only distal lung and airway inflammation but also remodeling. In addition, we evaluated the effects of inducible nitric oxide inhibition in these responses. For this purpose, airway and lung parenchyma were evaluated by quantitative analysis of collagen and elastic fibers, immunohistochemistry for macrophages, neutrophils, inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), and alveolar septa 8-iso prostaglandin F2 (8-iso-PGF-2) detection. Anesthetized in vivo (airway resistance, elastance, H, G, and Raw) respiratory mechanics were also analyzed. C57BL6 mice received daily 60ul of ROFA (intranasal) for five (ROFA-5d) or fifteen days (ROFA-15d). Controls have received saline (SAL). Part of the animals has received 1400W (SAL+1400W and ROFA-15d+1400W), an iNOS inhibitor, for four days before the end of the protocol. A marked neutrophil and macrophage infiltration and an increase in the iNOS, nNOS, and 8-iso-PGF2 expression was observed in peribronchiolar and alveolar wall both in ROFA-5d and in ROFA-15d groups. There was an increment of the collagen and elastic fibers in alveolar and airway walls in ROFA-15d group. The iNOS inhibition reduced all alterations induced by ROFA, except for the 8-iso-PGF2 expression. In conclusion, repeated particulate matter exposures induce extracellular matrix remodeling of airway and alveolar walls, which could contribute to the pulmonary mechanical changes observed. The mechanism involved is, at least, dependent on the inducible nitric oxide activation.
- Effects of Anti-IL-17 on Inflammation, Remodeling, and Oxidative Stress in an Experimental Model of Asthma Exacerbated by LPS(2018) CAMARGO, Leandro do Nascimento; RIGHETTI, Renato Fraga; ARISTOTELES, Luciana Ritha de Cassia Rolim Barbosa; SANTOS, Tabata Maruyama dos; SOUZA, Flavia Castro Ribas de; FUKUZAKI, Silvia; CRUZ, Maysa Mariana; ALONSO-VALE, Maria Isabel Cardoso; SARAIVA-ROMANHOLO, Beatriz Mangueira; PRADO, Carla Maximo; MARTINS, Milton de Arruda; LEICK, Aparecida; TIBERIO, Iolanda de Fatima Lopes CalvoInflammation plays a central role in the development of asthma, which is considered an allergic disease with a classic Th2 inflammatory profile. However, cytokine IL-17 has been examined to better understand the pathophysiology of this disease. Severe asthmatic patients experience frequent exacerbations, leading to infection, and subsequently show altered levels of inflammation that are unlikely to be due to the Th2 immune response alone. This study estimates the effects of anti-IL-17 therapy in the pulmonary parenchyma in a murine asthma model exacerbated by LPS. BALB/c mice were sensitized with intraperitoneal ovalbumin and repeatedly exposed to inhalation with ovalbumin, followed by treatment with or without anti-IL-17. Twenty-four hours prior to the end of the 29-day experimental protocol, the two groups received LPS (0.1 mg/ml intratracheal OVA-LPS and OVA-LPS IL-17). We subsequently evaluated bronchoalveolar lavage fluid, performed a lung tissue morphometric analysis, and measured IL-6 gene expression. OVA-LPS-treated animals treated with anti-IL-17 showed decreased pulmonary inflammation, edema, oxidative stress, and extracellular matrix remodeling compared to the non-treated OVA and OVA-LPS groups (p < 0.05). The anti-IL-17 treatment also decreased the numbers of dendritic cells, FOXP3, NF-kappa B, and Rho kinase 1-and 2-positive cells compared to the non-treated OVA and OVA-LPS groups (p < 0.05). In conclusion, these data suggest that inhibition of IL-17 is a promising therapeutic avenue, even in exacerbated asthmatic patients, and significantly contributes to the control of Th1/Th2/Th17 inflammation, chemokine expression, extracellular matrix remodeling, and oxidative stress in a murine experimental asthma model exacerbated by LPS.
- Bronchial Vascular Remodeling Is Attenuated by Anti-IL-17 in Asthmatic Responses Exacerbated by LPS(2020) CAMARGO, Leandro do Nascimento; SANTOS, Tabata Maruyama dos; ANDRADE, Felipp Costa Pinto de; FUKUZAKI, Silvia; LOPES, Fernanda Degobbi Tenorio Quirino dos Santos; MARTINS, Milton de Arruda; PRADO, Carla Maximo; LEICK, Edna Aparecida; RIGHETTI, Renato Fraga; TIBERIO, Iolanda de Fatima Lopes CalvoIntroduction Although the major alterations associated with asthma are related to the airways, there is also evidence of the importance of peribronchial vascular inflammation and remodeling in its pathophysiology. Objectives To determine the effects of anti-IL-17 therapy on peribronchial vessels of an asthma model exacerbated by lipopolysaccharide. Methods We evaluated several factors, including lung function, inflammation, oxidative stress, vascular remodeling, and signaling pathways present in the peribronchial vessels of 66 male BALB/c mice exposed to ovalbumin and treated (or not) treated with anti-IL-17. Twenty-four hours before the end of the experimental protocol, groups of sensitized animals (OVA-LPS and OVA-LPS anti-IL-17) also received LPS. Results The OVA-LPS-anti-IL-17 group presented a decrease in several factors [airway resistance and elastance, bronchoalveolar lavage fluid (BALF) cell counts, inflammatory response, eosinophils, TSLP, IL-33, TARC, TNF-alpha, CD4+, CD8+, IL-4, IL-6, IL-10, IL-17, and VEGF positive cells/10(4)mu m(2), peribronchovascular edema, and angiogenesis], including remodeling (MMP-9, MMP-12, TIMP-1 and TGF-beta positive cells and volume fraction of collagen fibers I, collagen fibers III, collagen fibers V, decorin, lumican, actin, biglycan, fibronectin, and integrin), oxidative stress (iNOS positive cells and volume fraction of PGF2 alpha), and signaling pathways (FoxP3), as well as dendritic cells, NF-kB, ROCK-1, ROCK-2, STAT-1, and phosphor-STAT1-positive cells compared to OVA-LPS (p < 0.05). Conclusions In this model of LPS-induced asthma exacerbation, IL-17 inhibition represents a promising therapeutic strategy, indicating the potential of bronchial vascular control of Th2 and Th17 responses and the activation of the remodeling and oxidative stress pathways, associated with the control of signaling pathways.
- Protective Effects of Anti-IL17 on Acute Lung Injury Induced by LPS in Mice(2018) RIGHETTI, Renato Fraga; SANTOS, Tabata Maruyama dos; CAMARGO, Leandro do Nascimento; ARISTOTELES, Luciana Ritha Cassia Rolim Barbosa; FUKUZAKI, Silvia; SOUZA, Flavia Castro Ribas de; SANTANA, Fernanda Paula Roncon; AGRELA, Marcus Vinicius Rodrigues de; CRUZ, Maysa Mariana; ALONSO-VALE, Maria Isabel Cardoso; GENARO, Isabella Santos; SARAIVA-ROMANHOLO, Beatriz Mangueira; LEICK, Edna Aparecida; MARTINS, Milton de Arruda; PRADO, Carla Maximo; TIBERIO, Iolanda de Fatima Lopes CalvoIntroduction: T helper 17 (Th17) has been implicated in a variety of inflammatory lung and immune system diseases. However, little is known about the expression and biological role of IL-17 in acute lung injury (ALI).We investigated the mechanisms involved in the effect of anti-IL17 in a model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Methods: Mice were pre-treated with anti-IL17, 1h before saline/LPS intratracheal administration alongside non-treated controls and levels of exhaled nitric oxide (eNO), cytokine expression, extracellular matrix remodeling and oxidative stress, as well as immune cell counts in bronchoalveolar lavage fluid (BALF), and respiratory mechanics were assessed in lung tissue. Results: LPS instillation led to an increase in multiple cytokines, proteases, nuclear factor-kappa B, and Forkhead box P3 (FOXP3), eNO and regulators of the actomyosin cytoskeleton, the number of CD4+ and iNOS-positive cells as well as the number of neutrophils and macrophages in BALF, resistance and elastance of the respiratory system, ARG-1 gene expression, collagen fibers, and actin and 8-iso-PGF2 alpha volume fractions. Pre-treatment with anti-IL17 led to a significant reduction in the level of all assessed factors. Conclusions: Anti-IL17 can protect the lungs from the inflammatory effects of LPS-induced ALI, primarily mediated by the reduced expression of cytokines and oxidative stress. This suggests that further studies using anti-IL17 in a treatment regime would be highly worthwhile.
- A plant proteinase inhibitor from Enterolobium contortisiliquum attenuates airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma(2019) RODRIGUES, Adriana Palmeira Dias; BORTOLOZZO, Anelize Sartori Santos; ARANTES-COSTA, Fernanda Magalhaes; SARAIVA-ROMANHOLO, Beatriz Mangueira; SOUZA, Flavia Castro Ribas de; BRUGGEMANNI, Thayse Regina; SANTANA, Fernanda Paula Roncon; BRITO, Marlon Vilela de; BONTURI, Camila Ramalho; NUNES, Natalia Neto dos Santos; PRADO, Carla Maximo; LEICK, Edna Aparecida; OLIVA, Maria Luiza Vilela; MARTINS, Milton de Arruda; RIGHETTI, Renato Fraga; TIBERIO, Iolanda de Fatima Lopes CalvoIntroduction. Proteinase inhibitors have been associated with anti-inflammatory and antioxidant activities and may represent a potential therapeutic treatment for asthma. Purpose. The aim of the present study was to evaluate the effects of Enterolobium contortisiliquum trypsin inhibitor (EcTI) on pulmonary mechanical function, eosinophilic recruitment, inflammatory cytokines, remodeling and oxidative stress in an experimental model of chronic allergic pulmonary inflammation. Methods. BALB/c mice were divided into 4 groups: C (saline i.p and inhalations with saline), OVA (ovalbumin i.p and inhalations with ovalbumin); C+EC (saline i.p, inhalations with s aline and treatment with EcTI); OVA+EC (ovalbumin i.p, inhalations with ovalbumin and treatment with EcTI). On day 29, we performed the following tests: resistance (Rrs) and elastance (Ers) of the respiratory system; (b) quantify eosinophils, 8-ISO-PGF2 alpha, collagen and elastic fiber volume fractions; (c) IFN-gamma, IL-4, IL-5, IL-13, MMP-9, TIMP-1,TGF-beta, iNOS and p65-NF kappa B-positive cells in the airway and alveolar walls. Results. In OVA+EC group, there was an attenuation of the Rrs and Ers, reduction of eosinophils, IL-4, IL-5, IL-13, IFN-gamma, iNOS and p65-NF kappa B-positive cells compared to OVA group. The 8-ISO-PGF2 alpha, elastic and collagen fibers volume fractions as well as the positive cells for MMP-9, TIMP-1 and TGF-beta positive cells were decreased in OVA+EC compared to the OVA group. Conclusion. EcTI attenuates bronchial hyperresponsiveness, inflammation, remodeling and oxidative stress activation in this experimental mouse model of asthma.
- The Plant Proteinase Inhibitor CrataBL Plays a Role in Controlling Asthma Response in Mice(2018) BORTOLOZZO, Anelize Sartori Santos; RODRIGUES, Adriana Palmeira Dias; ARANTES-COSTA, Fernanda Magalhaes; SARAIVA-ROMANHOLO, Beatriz Mangueira; SOUZA, Flavia Castro Ribas de; BRUGGEMANN, Thayse Regina; BRITO, Marlon Vilela de; FERREIRA, Rodrigo da Silva; CORREIA, Maria Tereza dos Santos; PAIVA, Patricia Maria Guedes; PRADO, Carla Maximo; LEICK, Edna Aparecida; OLIVA, Maria Luiza Vilela; MARTINS, Milton de Arruda; RUIZ-SCHUTZ, Viviane Christina; RIGHETTI, Renato Fraga; TIBERIO, Iolanda de Fatima Lopes CalvoBackground. CrataBL is a protein isolated from Crataeva tapia bark. It has been shown to exhibit several biological properties, including anti-inflammatory, analgesic, antitumor, and insecticidal activities. There are no studies evaluating the role of CrataBL in experimental asthma models. Aim. To evaluate the effects of CrataBL on lung mechanics, inflammation, remodeling, and oxidative stress activation of mice with allergic pulmonary inflammation. Materials and Methods. BALB/c mice (6-7 weeks old, 25-30g) were divided into four groups: nonsensitized and nontreated mice (C group, n=8); ovalbumin- (OVA-) sensitized and nontreated mice (OVA group, n=8); nonsensitized and CrataBL-treated mice (C+CR group, n=8); OVA-sensitized and CrataBL-treated mice (OVA+CR group, n=8). We evaluated hyperresponsiveness to methacholine, bronchoalveolar lavage fluid (BALF), pulmonary inflammation, extracellular matrix remodeling, and oxidative stress markers. Results. CrataBL treatment in OVA- sensitized mice (OVA+CR group) attenuated the following variables compared to OVA- sensitized mice without treatment (OVA group) (all p<0.05): (1) respiratory system resistance (Rrs) and elastance (Ers) after methacholine challenge; (2) total cells, macrophages, polymorphonuclear cells, and lymphocytes in BALF; (3) eosinophils and volume fraction of collagen and elastic fibers in the airway and alveolar wall according to histopathological and morphometry analysis; (4) IL-4-, IL-5-, IL-13-, IL-17-, IFN-gamma-, MMP-9-, TIMP-1-, TGF-beta-, iNOS-, and NF-kB-positive cells and volume of 8-iso-PGF2 in airway and alveolar septa according to immunohistochemistry; and (5) IL-4, IL-5, and IFN-according to an ELISA. Conclusion. CrataBL contributes to the control of hyperresponsiveness, pulmonary inflammation, extracellular matrix remodeling, and oxidative stress responses in an animal model of chronic allergic pulmonary inflammation.
- 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.
- The Plant-Derived Bauhinia bauhinioides Kallikrein Proteinase Inhibitor (rBbKI) Attenuates Elastase-Induced Emphysema in Mice(2016) MARTINS-OLIVERA, Bruno Tadeu; ALMEIDA-REIS, Rafael; THEODORO-JUNIOR, Osmar Aparecido; OLIVA, Leandro Vilela; NUNES, Natalia Neto dos Santos; OLIVO, Clarice Rosa; BRITO, Marlon Vilela de; PRADO, Carla Maximo; LEICK, Edna Aparecida; MARTINS, Milton de Arruda; OLIVA, Maria Luiza Vilela; RIGHETTI, Renato Fraga; TIBERIO, Iolanda de Fatima Lopes CalvoBackground. Elastase mediates important oxidative actions during the development of chronic obstructive pulmonary disease (COPD). However, few resources for the inhibition of elastase have been investigated. Our study evaluated the ability of the recombinant plant derived Bauhinia bauhinioides Kallikrein proteinase Inhibitor (rBbKI) to modulate elastase-induced pulmonary inflammation. Methods. C57Bl/6 mice were given intratracheal elastase (ELA group) or saline (SAL group) and were treated intraperitoneally with rBbKI (ELA-rBbKI and SAL-rBbKI groups). At day 28, the following analyses were performed: (I) lung mechanics, (II) exhaled nitric oxide (ENO), (III) bronchoalveolar lavage fluid (BALF), and (IV) lung immunohistochemical staining. Results. In addition to decreasing mechanical alterations and alveolar septum disruption, rBbKI reduced the number of cells in the BALF and decreased the cellular expression of TNF-alpha, MMP-9, MMP-12, TIMP-1, eNOS, and iNOS in airways and alveolar walls compared with the ELA group. rBbKI decreased the volume proportion of 8-iso-PGF2 alpha, collagen, and elastic fibers in the airways and alveolar walls compared with the ELA group. A reduction in the number of MUC-5-positive cells in the airway walls was also observed. Conclusion. rBbKI reduced elastase-induced pulmonary inflammation and extracellular matrix remodeling. rBbKI may be a potential pharmacological tool for COPD treatment.
- 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.