RENATO FRAGA RIGHETTI
Projetos de Pesquisa
Unidades Organizacionais
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina
3 resultados
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- 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 Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress(2019) VASCONCELOS, Luiz Henrique Cesar; SILVA, Maria da Conceicao Correia; COSTA, Alana Cristina; OLIVEIRA, Giuliana Amanda de; SOUZA, Iara Leao Luna de; QUEIROGA, Fernando Ramos; ARAUJO, Layanne da Cunha; CARDOSO, Glebia Alexa; RIGHETTI, Renato Fraga; SILVA, Alexandre Sergio; SILVA, Patricia Mirella da; CARVALHO, Carla Roberta de Oliveira; VIEIRA, Giciane Carvalho; TIBERIO, Iolanda de Fatima Lopes Calvo; CAVALCANTE, Fabiana de Andrade; SILVA, Bagnolia Araujo daAsthma is a heterogeneous disease of the airways characterized by chronic inflammation associated with bronchial and smooth muscle hyperresponsiveness. Currently, different murine models for the study of asthma show poor bronchial hyperresponsiveness due to a scarcity of smooth muscle and large airways, resulting in a failure to reproduce smooth muscle hyperreactivity. Thus, we aimed to standardize a guinea pig model of chronic allergic lung inflammation mimicking airway smooth muscle hyperreactivity observed in asthmatics (Asth). Animals were randomly divided into a control group (Ctrl), which received saline (0.9% NaCl), and the Asth group, subjected to in vivo sensitization with ovalbumin (OVA) nebulization. Morphological analysis was performed by hematoxylin-eosin staining. Bronchial hyperresponsiveness was evaluated by nebulization time in the fifth, sixth, and seventh inhalations (NT5-7) and tracheal isometric contractions were assessed by force transducer. Total antioxidant capacity was measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and protein expression by Western blot. Histologically, the Asth group developed peribronchial cellular infiltrate, epithelial hyperplasia and smooth muscle thickening. After the fourth nebulization, the Asth group developed bronchial hyperreactivity. The trachea from the Asth group contracted after in vitro stimulation with OVA, differing from the Ctrl group, which showed no response. Additionally, airway smooth muscle hyperreactivity to carbachol and histamine was observed in the Asth group only in intact epithelium preparations, but not to KCl, and this effect was associated with an augmented production of reactive oxygen species. Moreover, lung inflammation impaired the relaxant potency of isoproterenol only in intact epithelium preparations, without interfering with nifedipine, and it was found to be produced by transforming growth factor-beta negative modulation of beta adrenergic receptors and, furthermore, big-conductance Ca2+-sensitive K+ channels. These effects were also associated with increased levels of phosphatidylinositol 3-kinases but not extracellular signal-regulated kinases 1/2 or phosphorylation, and augmented alpha-actin content as well, explaining the increased smooth muscle mass. Furthermore, pulmonary antioxidant capacity was impaired in the Asth group. Therefore, we developed a standardized and easy-touse, reproducible guinea pig model of lung inflammation that mimics airway smooth muscle hypercontractility, facilitating the investigation of the mechanisms of bronchial hyperresponsiveness in asthma and new therapeutic alternatives.