BEATRIZ MANGUEIRA SARAIVA RAMANHOLO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina
LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina
13 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 13
- Comparison of the Effects of Aerobic Conditioning Before and After Pulmonary Allergic Inflammation(2015) SILVA, Ronaldo Aparecido da; ALMEIDA, Francine Maria; OLIVO, Clarice Rosa; SARAIVA-ROMANHOLO, Beatriz Mangueira; PERINI, Adenir; MARTINS, Milton Arruda; CARVALHO, Celso Ricardo FernandesThe aim of this study is to compare the effects of aerobic conditioning (AC) before (ACBS) and after (ACAS) allergic sensitization. BALB/c mice were divided into two main groups: ACBS and ACAS. Each groups was divided into subgroups: control (nonsensitized/nontrained), AC (nonsensitized/trained), ovalbumin (OVA) (sensitized/nontrained), AC + OVA (trained/sensitized), and OVA + AC (sensitized/trained). Sensitization was induced using OVA and AC performed in treadmill (moderate intensity). We examined IgE and IgG(1) levels, eosinophil counting, expression of Th1 (interleukin (IL)-2, IFN-alpha) and Th2 cytokines (IL-4, IL-5, IL-13), IL-10, vascular endothelial growth factor (VEGF), and airway remodeling. IgE and IgG(1) were decreased only when exercise was performed before sensitization (ACBS); however, there was a decrease of eosinophils, Th2 cytokines, VEGF, and airway remodeling and increase in IL-10 in either ACBS or ACAS groups. Our results demonstrate that aerobic conditioning reduces Th2 response before and after sensitization by increasing IL-10 while the production of anaphylactic antibodies is reduced only when exercise is performed before sensitization.
- Impairment on Cardiopulmonary Function after Marathon: Role of Exhaled Nitric Oxide(2019) SIERRA, Ana Paula; OLIVEIRA-JUNIOR, Manoel Carneiro; ALMEIDA, Francine Maria; BENETTI, Marino; OLIVEIRA, Rodrigo; FELIX, Soraia Nogueira; GENARO, Isabella Santos; ROMANHOLO, Beatriz Mangueira Saraiva; GHORAYEB, Nabil; KISS, Maria Augusta Peduti Dal Molin; CURY-BOAVENTURA, Maria Fernanda; PESQUERO, Joao Bosco; VIEIRA, Rodolfo PaulaBackground. The endurance exercise is capable of inducing skeletal muscle, heart, and respiratory fatigue, evidenced by morphofunctional cardiac changes, release of myocardial injury biomarkers, and reduction of maximal voluntary ventilation and oxygen consumption (VO2) at peak exercise. Purpose. The aim of this study was to investigate whether marathoners present cardiac fatigue after marathon and whether it correlates with pulmonary levels of exhaled nitric oxide (eNO) and pulmonary inflammation. Methods. 31 male marathoners, age 39 +/- 9 years, were evaluated by cardiopulmonary exercise test three weeks before and between three and 15 days after a marathon; eNO analysis and spirometry were evaluated before, immediately after, and 24 and 72 hours after the marathon, and sputum cellularity and cytokine level were assessed before and after the marathon. Results. Marathon induced an increase in the percentage of macrophages, neutrophils (from 0.65% to 4.28% and 6.79% to 14.11%, respectively), and epithelial cells and a decrease in cytokines in induced sputum, followed by an increase in eNO concentration (20 +/- 11 to 35 +/- 19 ppb), which presented a significant reduction 24 and 72 hours after marathon (9 +/- 12 e 12 +/- 9 ppb, p < 0.05). We observed a decrease in the spirometry parameters in all time points assessed after the marathon (p < 0.05) as well as in cardiopulmonary capacity, evidenced by a reduction in VO2 and ventilation peaks (57 +/- 6 to 55 +/- 6 mL.min(-1).Kg(-1 )and 134 +/- 19 to 132 +/- 18 Lpm, respectively, p < 0.05). Finally, we observed a negative correlation between the decrease in forced expiratory volume and decrease in eNO 24 and 72 hours after marathon (r = -0.4, p = 0.05). Conclusion. Reduction in eNO bioavailability after marathon prevents the reduction in cardiopulmonary capacity induced by acute inflammatory pattern after marathon.
- Effect of Anti-IL17 Antibody Treatment Alone and in Combination With Rho-Kinase Inhibitor in a Murine Model of Asthma(2018) SANTOS, Tabata M. dos; RIGHETTI, Renato F.; CAMARGO, Leandro do N.; SARAIVA-ROMANHOLO, Beatriz M.; ARISTOTELES, Luciana R. C. R. B.; SOUZA, Flavia C. R. de; FUKUZAKI, Silvia; ALONSO-VALE, Maria I. C.; CRUZ, Maysa M.; PRADO, Carla M.; LEICK, Edna A.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.Background: Interleukin-17 (IL-17) and Rho-kinase (ROCK) play an important role in regulating the expression of inflammatory mediators, immune cell recruitment, hyper-responsiveness, tissue remodeling, and oxidative stress. Modulation of IL-17 and ROCK proteins may represent a promising approach for the treatment of this disease. Objective: To study the effects of an anti-IL17 neutralizing antibody and ROCK inhibitor treatments, separately and in combination, in a murine model of chronic allergy-induced lung inflammation. Methods: Sixty-four BALBc mice, were divided into eight groups (n = 8): SAL (saline-instilled); OVA (exposed-ovalbumin); SAL-RHOi (saline and ROCK inhibitor), OVA-RHOi (exposed-ovalbumin and ROCK inhibitor); SAL-anti-IL17 (saline and anti-IL17); OVA-anti-IL1 7 (exposed-ovalbumin and anti-IL1 7); SAL-RHOi-anti-IL17 (saline, ROCK inhibitor and anti-IL17); and OVA-RHOi-anti-IL17 (exposed-ovalbumin, anti-IL17, and ROCK inhibitor). A 28-day protocol of albumin treatment was used for sensitization and induction of pulmonary inflammation. The anti-IL17A neutralizing antibody (7.5 mu g per treatment) was administered by intraperitoneal injection and ROCK inhibitor (Y-27632) intranasally (10 mg/kg), 1 h prior to each ovalbumin challenge (days 22, 24, 26, and 28). Results: Treatment with the anti-IL17 neutralizing antibody and ROCK inhibitor attenuated the percentage of maximal increase of respiratory system resistance and respiratory system elastance after challenge with methacholine and the inflammatory response markers evaluated (CD4(+), CD8(+), ROCK1, ROCK2, IL-4, IL-5, IL-6, IL-10 IL-13, IL-17, TNF-alpha, TGF-beta, NF-kappa B, dendritic cells, iNOS, MMP-9, MMP-12, TIMP-1, FOXP3, isoprostane, biglycan, decorin, fibronectin, collagen fibers content and gene expression of IL-17, VAChT, and arginase) compared to the OVA group (p < 0.05). Treatment with anti-IL17 and the ROCK inhibitor together resulted in potentiation in decreasing the percentage of resistance increase after challenge with methacholine, decreased the number of IL-5 positive cells in the airway, and reduced, IL-5, TGF beta, FOXP3, ROCK1 and ROCK2 positive cells in the alveolar septa compared to the OVA-RHOi and OVA-anti-IL17 groups (p < 0.05). Conclusion: Anti-IL17 treatment alone or in conjunction with the ROCK inhibitor, modulates airway responsiveness, inflammation, tissue remodeling, and oxidative stress in mice with chronic allergic lung inflammation.
- 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.
- Inflammatory and functional responses after (bio)diesel exhaust exposure in allergic sensitized mice. A comparison between diesel and biodiesel(2019) TIMMERMAN, Tirza; BRITO, Jose Mara de; ALMEIDA, Natalia Madureira de; ALMEIDA, Francine Maria de; ARANTES-COSTA, Fernanda Magalhaes; GUIMARAES, Eliane Tigre; LICHTENFELS, Ana Julia Faria Coimbra; RIVERO, Dolores Helena Rodriguez Ferreira; OLIVEIRA, Regiani Carvalho de; LACERDA, Joao Paulo Amorim de; MORAES, Jamille Moreira; PIMENTAL, Danilo Augusto; SARAIVA-ROMANHOLO, Beatriz Mangueira; SALDIVA, Paulo Hilario Nascimento; VIEIRA, Rodolfo de Paula; MAUAD, ThaisMany cities fail to meet air quality standards, which results in increased risk for pulmonary disorders, including asthma. Human and experimental studies have shown that diesel exhaust (DE) particles are associated with worsening of allergic asthma. Biodiesel (BD), a cleaner fuel from renewable sources, was introduced in the eighties. Because of the reduction in particulate matter (PM) emissions, BD was expected to cause fewer adverse pulmonary effects. However, only limited data on the effect of BD emissions in asthma are available. Objective: Determine whether BD exhaust exposure in allergic sensitized mice leads to different effects on inflammatory and functional responses compared to DE exposure. Methods: Balb/C mice were orotracheally sensitized with House Dust Mite (HDM) or a saline solution with 3 weekly instillations. From day 9 until day 17 after sensitization, they were exposed daily to filtered air (FA), DE and BD exhaust (concentration: 600 mu g/m(3) PM2.5). Lung function, bronchoalveolar lavage fluid (BALF) cell counts, cytokine levels (IL-2, IL-4, IL-5, IL-17, TNF-alpha, TSLP) in the BALF, peribronchiolar eosinophils and parenchymal macrophages were measured. Results: HDM-sensitized animals presented increased lung elastance (p = 0.046), IgG1 serum levels (p = 0.029), peribronchiolar eosinophils (p = 0.028), BALF levels of total cells (p = 0.020), eosinophils (p = 0.028), IL-5 levels (p = 0.002) and TSLP levels (p = 0.046) in BALF. DE exposure alone increased lung elastance (p = 0.000) and BALF IL-4 levels (p = 0.045), whereas BD exposure alone increased BALF TSLP levels (p = 0.004). BD exposure did not influence any parameters after HDM challenge, while DE exposed animals presented increased BALF levels of total cells (p = 0.019), lymphocytes (p = 0.000), neutrophils (p = 0.040), macrophages (p = 0.034), BALF IL-4 levels (p = 0.028), and macrophagic inflammation in the lung tissue (p = 0.037), as well as decreased IgG1 (p = 0.046) and lgG2 (p = 0.043) levels when compared to the HDM group. Conclusion: The results indicate more adverse pulmonary effects of DE compared to BD exposure in allergic sensitized animals.
- Low-dose chlorine exposure impairs lung function, inflammation and oxidative stress in mice(2021) GENARO, Isabella Santos de; ALMEIDA, Francine Maria de; LOPES, Fernanda Degobbi Tenorio Quirino dos Santos; KUNZLER, Deborah De Camargo Hizume; TRIPODE, Bruna Gabryela Busoletto; KURDEJAK, Adriana; CORDEIRO, Bruna Nakamura; PANDOLPHO, Renata; MACCHIONE, Mariangela; BRUGGEMANN, Thayse Regina; VIEIRA, Rodolfo Paula; MARTINS, Milton Arruda; TIBERIO, Iolanda de Fatima Lopes Calvo; SARAIVA-ROMANHOLO, Beatriz MangueiraAim: To explore the different consequences of acute and chronic exposure to chlorine gas (Cl-2) on the functional and histological parameters of health mice. Main methods: Firstly, male BALB/c mice were acute exposed to 3.3 or 33.3 or 70.5 mg/m(3) Cl-2. We analyzed the lung function, the inflammatory cells in the bronchoalveolar lavage, cell influx in the peribrochoalveolar space and mucus production. In a second phase, mice were chronic exposed to 70.5 mg/m(3) Cl-2. Besides the first phase analyses, we also evaluated the epithelial cells thickness, collagen deposition in the airways, immunohisto-chemistry stain for IL-1 beta, iNOS, IL-17 and ROCK-2 and the levels of IL-5, IL-13, IL-17, IL-1 beta and TNF-alpha in lung homogenate. Key findings: Acute exposure to chlorine impaired the lung function, increased the number of inflammatory cells in the BALF and in the airways, also increased the mucus production. Furthermore, when chlorine was exposed chronically, increased the airway remodeling with collagen deposition and epithelial cells thickness, positive cells for IL-1 beta, iNOS, IL-17 in the airways and in the alveolar walls and ROCK-2 in the alveolar walls, lung inflammation with increased levels of IL-5, IL-13, IL-1 beta and TNF-alpha in the lung homogenate, and also, induced the acid mucus production by the nasal epithelium. Significance: Acute and chronic exposure to low dose of chlorine gas worsens lung function, induces oxidative stress activation and mucus production and contributes to augmenting inflammation in health mice.
- Diphteria-tetanus-pertussis vaccine reduces specific IgE, inflammation and remodelling in an animal model of mite-induced respiratory allergy(2020) AUN, Marcelo Vivolo; ALMEIDA, Francine Maria de; SARAIVA-ROMANHOLO, Beatriz Mangueira; MARTINS, Milton de Arruda; KALIL, Jorge; ARANTES-COSTA, Fernanda Magalhaes; GIAVINA-BIANCHI, PedroBackground: Adjuvants, such as bacterial lipopolysaccharides, have been studied to improve the efficacy of allergen-specific immunotherapy. The Bordetella pertussis (Pw) vaccine has been shown to have a protective role in ovalbumin-induced asthma models. However, its role in allergy to mites is unknown. We evaluated the effects of the diphtheria-tetanus-pertussis (DTPw) vaccine on a murine model of respiratory allergy induced by Dermatophagoides pteronyssinus (Derp). Methods: In a 30-day protocol, BALB/c mice were immunized subcutaneously with saline or Derp, alone or in combination with diphtheria-tetanus (DT) or DTPw vaccines (days 0, 7 and 14). Subsequently, they underwent a daily intranasal challenge with saline or Derp (days 22-28) and were then sacrificed (day 29). We evaluated serum-specific immunoglobulins, bronchoalveolar lavage (BAL) cellularity, remodelling of the lower airways, density of polymorphonuclear leukocytes (PMNs) and acidic nasal mucus content. Results: The animals sensitized with Derp produced high levels of specific immunoglobulins, increased density of PMNs and nasal mucus content, and elevated BAL cellularity and remodelling. Vaccines led to a reduction in IgE levels, with the Derp-DTPw group being similar to the saline groups. The vaccinated groups had reductions of BAL cellularity and remodelling, with more expressive results in the Derp-DTPw group compared to the Derp-DT group. The DT and DTPw vaccines inhibited the nasal PMN infiltrate, and DTPw modulated the production of acidic nasal mucus. Conclusions: The DTPw vaccine reduced serum specific IgE, nasal and pulmonary inflammation and remodelling of the lower airways.
- Cigarette smoke dissociates inflammation and lung remodeling in OVA-sensitized and challenged mice(2012) HIZUME, Deborah C.; TOLEDO, Alessandra C.; MORIYA, Henrique T.; SARAIVA-ROMANHOLO, Beatriz M.; ALMEIDA, Francine M.; ARANTES-COSTA, Fernanda M.; VIEIRA, Rodolfo P.; DOLHNIKOFF, Marisa; KASAHARA, David Itiro; MARTINS, Milton A.We evaluated the effects of cigarette smoke (CS) on lung inflammation and remodeling in a model of ovalbumin (OVA)-sensitized and OVA-challenged mice. Male BALB/c mice were divided into 4 groups: non-sensitized and air-exposed (control); non-sensitized and exposed to cigarette smoke (CS), sensitized and air-exposed (OVA) (50 mu g + OVA 1% 3 times/week for 3 weeks) and sensitized and cigarette smoke exposed mice (OVA + CS). IgE levels were not affected by CS exposure. The increases in total bronchoalveolar fluid cells in the OVA group were attenuated by co-exposure to CS, as were the changes in IL-4, IL-5, and eotaxin levels as well as tissue elastance (p < 0.05). In contrast, only the OVA + CS group showed a significant increase in the protein expression of IFN-gamma, VEGF, GM-CSF and collagen fiber content (p < 0.05). In our study, exposure to cigarette smoke in OVA-challenged mice resulted in an attenuation of pulmonary inflammation but led to an increase in pulmonary remodeling and resulted in the dissociation of airway inflammation from lung remodeling.
- Effects of the serine protease inhibitor rBmTI-A in an experimental mouse model of chronic allergic pulmonary inflammation(2019) FLORENCIO, Adana Correa; ALMEIDA, Robson S. de; ARANTES-COSTA, Fernanda M.; SARAIVA-ROMANHOLO, Beatriz M.; DURAN, Adriana F.; SASAKI, Sergio D.; MARTINS, Milton A.; LOPES, Fernanda D. T. Q. S.; TIBERIO, Iolanda F. L. C.; LEICK, Edna A.To evaluate whether a recombinant serine protease inhibitor (rBmTI-A) modulates inflammation in an experimental model of chronic allergic lung inflammation. Balb/c mice were divided into four groups: SAL (saline), OVA (sensitized with ovalbumin), SAL + rBmTI-A (control treated with rBmTI-A) and OVA + rBmTI-A (sensitized with ovalbumin and treated with rBmTI-A). The animals received an intraperitoneal injection of saline or ovalbumin, according to the group. The groups received inhalation with saline or ovalbumin and were treated with rBmTI-A or saline by nasal instillation. After 29 days, we evaluated the respiratory mechanics; bronchoalveolar lavage fluid (BALF); cytokines; MMP-9, TIMP-1; eosinophils; collagen and elastic fibre expression in the airways; and the trypsin-like, MMP-1, and MMP-9 lung tissue proteolytic activity. Treatment with rBmTI-A reduced the trypsin-like proteolytic activity, the elastance and resistance maximum response, the polymorphonuclear cells, IL-5, IL-10, IL-13 and IL-17A in the BALF, the expression of IL-5, IL-13, IL-17, CD4+, MMP-9, TIM P-1, eosinophils, collagen and elastic fibres in the airways of the OVA + rBmTI-A group compared to the OVA group (p < 0.05). rBmTI-A attenuated bronchial hyperresponsiveness, inflammation and remodelling in this experimental model of chronic allergic pulmonary inflammation. This inhibitor may serve as a potential therapeutic tool for asthma treatment.
- 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.