ALESSANDRA CHOQUETA DE TOLEDO ARRUDA
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LIM/20 - Laboratório de Terapêutica Experimental, Hospital das Clínicas, Faculdade de Medicina
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article 31 Citação(ões) na Scopus Short-term exposure of mice to cigarette smoke and/or residual oil fly ash produces proximal airspace enlargements and airway epithelium remodeling(2011) BISELLI, P. J. C.; LOPES, F. D. T. Q. S.; MORIYA, H. T.; RIVERO, D. H. R. F.; TOLEDO, A. C.; SALDIVA, P. H. N.; MAUAD, T.; MARTINS, A.Chronic obstructive pulmonary disease (COPD) is associated with inflammatory cell reactions, tissue destruction and lung remodeling. Many signaling pathways for these phenomena are still to be identified. We developed a mouse model of COPD to evaluate some pathophysiological mechanisms acting during the initial stage of the disease. Forty-seven 6- to 8-week-old female C57/BL6 mice (approximately 22 g) were exposed for 2 months to cigarette smoke and/or residual oil fly ash (ROFA), a concentrate of air pollution. We measured lung mechanics, airspace enlargement, airway wall thickness, epithelial cell profile, elastic and collagen fiber deposition, and by immunohistochemistry transforming growth factor-beta 1 (TGF-beta 1), macrophage elastase (MMP12), neutrophils and macrophages. We observed regional airspace enlargements near terminal bronchioles associated with the exposure to smoke or ROFA. There were also increases in airway resistance and thickening of airway walls in animals exposed to smoke. In the epithelium, we noted a decrease in the ciliated cell area of animals exposed to smoke and an increase in the total cell area associated with exposure to both smoke and ROFA. There was also an increase in the expression of TGF-beta 1 both in the airways and parenchyma of animals exposed to smoke. However, we could not detect inflammatory cell recruitment, increases in MMP12 or elastic and collagen fiber deposition. After 2 months of exposure to cigarette smoke and/or ROFA, mice developed regional airspace enlargements and airway epithelium remodeling, although no inflammation or increases in fiber deposition were detected. Some of these phenomena may have been mediated by TGF-beta 1.- Structure-Activity Association of Flavonoids in Lung Diseases(2014) LAGO, Joao Henrique G.; TOLEDO-ARRUDA, Alessandra C.; MERNAK, Marcia; BARROSA, Kaidu H.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.; PRADO, Carla M.Flavonoids are polyphenolic compounds classified into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins, and chalcones according to their chemical structures. They are abundantly found in Nature and over 8,000 flavonoids have from different sources, mainly plant materials, have been described. Recently reports have shown the valuable effects of flavonoids as antiviral, anti-allergic, antiplatelet, antitumor, antioxidant, and anti-inflammatory agents and interest in these compounds has been increasing since they can be helpful to human health. Several mechanisms of action are involved in the biological properties of flavonoids such as free radical scavenging, transition metal ion chelation, activation of survival genes and signaling pathways, regulation of mitochondrial function and modulation of inflammatory responses. The anti-inflammatory effects of flavonoids have been described in a number of studies in the literature, but not frequently associated to respiratory disease. Thus, this review aims to discuss the effects of different flavonoids in the control of lung inflammation in some disorders such as asthma, lung emphysema and acute respiratory distress syndrome and the possible mechanisms of action, as well as establish some structure-activity relationships between this biological potential and chemical profile of these compounds.
- Nasal Mucociliary Clearance in Subjects With COPD After Smoking Cessation(2015) ITO, Juliana T.; RAMOS, Dionei; LIMA, Fabiano F.; RODRIGUES, Fernanda M. M.; GOMES, Paulo R.; MOREIRA, Graciane L.; MACCHIONE, Mariangela; TOLEDO, Alessandra C.; RAMOS, Ercy M. C.BACKGROUND: Exposure to cigarette smoke causes significant impairment in mucociliary clearance (MCC), which predisposes patients to secretion retention and recurrent airway infections that play a role in exacerbations of COPD. To determine whether smoking cessation may influence MCC and frequency of exacerbations, the following groups were evaluated: ex-smokers with COPD, smokers with COPD, current smokers with normal lung function, and nonsmokers with normal lung function. METHODS: Ninety-three subjects were divided into 4 groups: ex-smokers with COPD (n = 23, 62.4 +/- 8.0 y, 13 males), smokers with COPD (n = 17, 58.2 +/- 8.0 y, 6 males), current smokers (n = 27, 61.5 +/- 6.4 y, 17 males), and nonsmokers (n = 26, 60.8 +/- 11.3 y, 7 males). MCC was evaluated using the saccharin transit time (STT) test, and the frequency of exacerbations in the last year was assessed by questionnaire. The Kruskal-Wallis test followed by Dunn's test were used to compare STT among groups, and the Goodman test was used to compare the frequency of exacerbations. RESULTS: STT of smokers with COPD (16.5 [11-28] min; median [interquartile range 25-75%]) and current smokers (15.9 110-271 min) was longer compared with ex-smokers with COPD (9.7 [6-12] min) and nonsmokers (8 [6-16] min) (P < .001). There was no difference in STT values between smokers with COPD and current smokers, and these values in ex-smokers with COPD were similar to the control group (P > .05). The frequency of exacerbations was lower in ex-smokers with COPD compared with smokers with COPD. CONCLUSIONS: One year after smoking cessation, subjects with COPD had improved mucociliary clearance.
- Plant Proteinase Inhibitor BbCI Modulates Lung Inflammatory Responses and Mechanic and Remodeling Alterations Induced by Elastase in Mice(2017) ALMEIDA-REIS, Rafael; THEODORO-JUNIOR, Osmar A.; OLIVEIRA, Bruno T. M.; OLIVA, Leandro V.; TOLEDO-ARRUDA, Alessandra C.; BONTURI, Camila R.; BRITO, Marlon V.; LOPES, Fernanda D. T. Q. S.; PRADO, Carla M.; FLORENCIO, Ariana C.; MARTINS, Milton A.; OWEN, Caroline A.; LEICK, Edna A.; OLIVA, Maria L. V.; TIBERIO, Iolanda F. L. C.Background. Proteinases play a key role in emphysema. Bauhinia bauhinioides cruzipain inhibitor (BbCI) is a serine-cysteine proteinase inhibitor. We evaluated BbCI treatment in elastase-induced pulmonary alterations. Methods. C57BL/6 mice received intratracheal elastase (ELA group) or saline (SAL group). One group of mice was treated with BbCI (days 1, 15, and 21 after elastase instillation, ELABC group). Controls received saline and BbCI (SALBC group). After 28 days, we evaluated respiratory mechanics, exhaled nitric oxide, and bronchoalveolar lavage fluid. In lung tissue we measured airspace enlargement, quantified neutrophils, TNF alpha-, MMP-9-, MMP-12-, TIMP-1-, iNOS-, and eNOS-positive cells, 8-iso-PGF2 alpha, collagen,and elastic fibers in alveolar septa and airways. MUC-5-positive cells were quantified only in airways. Results. BbCI reduced elastase-induced changes in pulmonary mechanics, airspace enlargement and elastase-induced increases in total cells, and neutrophils in BALF. BbCI reduced macrophages and neutrophils positive cells in alveolar septa and neutrophils and TNF alpha-positive cells in airways. BbCI attenuated elastic and collagen fibers, MMP-9- and MMP-12-positive cells, and isoprostane and iNOS-positive cells in alveolar septa and airways. BbCI reduced MUC5ac-positive cells in airways. Conclusions. BbCI improved lung mechanics and reduced lung inflammation and airspace enlargement and increased oxidative stress levels induced by elastase. BbCI may have therapeutic potential in chronic obstructive pulmonary disease.
- Time-course effects of aerobic physical training in the prevention of cigarette smoke-induced COPD(2017) TOLEDO-ARRUDA, Alessandra C.; VIEIRA, Rodolfo P.; GUARNIER, Flavia A.; SUEHIRO, Camila L.; CALEMAN-NETO, Agostinho; OLIVO, Clarice R.; ARANTES, Petra M. M.; ALMEIDA, Francine M.; LOPES, Fernanda D. T. Q. S.; RAMOS, Ercy M. C.; CECCHINI, Rubens; LIN, Chin Jia; MARTINS, Milton ArrudaA previous study by our group showed that regular exercise training (ET) attenuated pulmonary injury in an experimental model of chronic exposure to cigarette smoke (CS) in mice, but the time-course effects of the mechanisms involved in this protection remain poorly understood. We evaluated the temporal effects of regular ET in an experimental model of chronic CS exposure. Male C57BL/6 mice were divided into four groups: Control (sedentary + air), Exercise (aerobic training + air), Smoke (sedentary + smoke), and Smoke + Exercise (aerobic training + smoke). Mice were exposed to CS and ET for 4, 8, or 12 wk. Exercise protected mice exposed to CS from emphysema and reductions in tissue damping and tissue elastance after 12 wk (P < 0.01). The total number of inflammatory cells in the bronchoalveolar lavage increased in the Smoke group, mainly due to the recruitment of macrophages after 4 wk, neutrophils and lymphocytes after 8 wk, and lymphocytes and macrophages after 12 wk (P < 0.01). Exercise attenuated this increase in mice exposed to CS. The protection conferred by exercise was mainly observed after exercise adaptation. Exercise increased IL-6 and IL-10 in the quadriceps and lungs (P < 0.05) after 12 wk. Total antioxidant capacity and SOD was increased and TNF-alpha and oxidants decreased in lungs of mice exposed to CS after 12 wk (P < 0.05). The protective effects of exercise against lung injury induced by cigarette smoke exposure suggests that anti-inflammatory mediators and antioxidant enzymes play important roles in chronic obstructive pulmonary disease development mainly after the exercise adaptation. NEW & NOTEWORTHY These experiments investigated for the first time the temporal effects of regular moderate exercise training in cigarette smoke-induced chronic obstructive pulmonary disease. We demonstrate that aerobic conditioning had a protective effect in emphysema development induced by cigarette smoke exposure. This effect was most likely secondary to an effect of exercise on oxidant-antioxidant balance and anti-inflammatory mediators.
- Nasal and systemic inflammatory profile after short term smoking cessation(2014) RODRIGUES, Fernanda Maria Machado; RAMOS, Dionei; XAVIER, Rafaella Fagundes; ITO, Juliana Tiyaki; SOUZA, Alcirene Policarpo de; FERNANDES, Romulo Araujo; CECCHINI, Rubens; SILVA, Renata Calciolari Rossi e; MACCHIONE, Mariangela; TOLEDO-ARRUDA, Alessandra Choqueta de; GUARNIER, Flavia Alessandra; RAMOS, Ercy Mara CipuloIntroduction: Smoking cessation promotes health benefits and, despite cigarette smoking be an important pro inflammatory stimulus, there are few studies concerning the nasal and systemic inflammation; as well as the mucociliary clearance behavior in smokers after short period of smoking cessation. Aim: To evaluate the nasal and systemic inflammatory markers and mucociliary clearance behavior after 30 days of cigarette smoking abstinence. Methods: Twenty-five smokers were included and divided into two groups: abstinent smokers (n = 14) and current smokers (n = 11). Tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-10 were measured on nasal lavage and blood serum samples by ELISA at baseline and after 30 days. The mucociliary clearance, exhaled carbon monoxide (exCO) and carboxyhemoglobin (HbCO) were also measured at the same moments. Results: There was a decrease of TNF-alpha level only in blood serum at 30 days of abstinence compared to current smokers. The mucociliary clearance improved and there was a reduction in exCO and HbCO (p < 0.05 for all) after 30 days of smoking cessation. Conclusion: The short term smoking abstinence decreased systemic inflammation and improved nasal mucociliary clearance, despite not having changed the nasal inflammation.
- Chronic exposure of diesel exhaust particles induces alveolar enlargement in mice(2015) YOSHIZAKI, Kelly; BRITO, Jose Mara; MORIYA, Henrique T.; TOLEDO, Alessandra C.; FERZILAN, Sandra; OLIVEIRA, Ana Paula Ligeiro de; MACHADO, Isabel D.; FARSKY, Sandra H. P.; SILVA, Luiz F. F.; MARTINS, Milton A.; SALDIVA, Paulo H. N.; MAUAD, Thais; MACCHIONE, MariangelaBackground: Diesel exhaust particles (DEPs) are deposited into the respiratory tract and are thought to be a risk factor for the development of diseases of the respiratory system. In healthy individuals, the timing and mechanisms of respiratory tract injuries caused by chronic exposure to air pollution remain to be clarified. Methods: We evaluated the effects of chronic exposure to DEP at doses below those found in a typical bus corridor in Sao Paulo (150 mu g/m(3)). Male BALB/c mice were divided into mice receiving a nasal instillation: saline (saline; n = 30) and 30 mu g/10 mu L of DEP (DEP; n = 30). Nasal instillations were performed five days a week, over a period of 90 days. Bronchoalveolar lavage (BAL) was performed, and the concentrations of interleukin (IL)-4, IL-10, IL-13 and interferon-gamma (INF-gamma) were determined by ELISA-immunoassay. Assessment of respiratory mechanics was performed. The gene expression of Muc5ac in lung was evaluated by RT-PCR. The presence of IL-13, MAC2+ macrophages, CD3+, CD4+, CD8+ T cells and CD20+ B cells in tissues was analysed by immunohistochemistry. Bronchial thickness and the collagen/elastic fibers density were evaluated by morphometry. We measured the mean linear intercept (Lm), a measure of alveolar distension, and the mean airspace diameter (D0) and statistical distribution (D2). Results: DEP decreased IFN-gamma levels in BAL (p = 0.03), but did not significantly alter IL-4, IL-10 and IL-13 levels. MAC2+ macrophage, CD4+ T cell and CD20+ B cell numbers were not altered; however, numbers of CD3+ T cells (p <= 0.001) and CD8+ T cells (p <= 0.001) increased in the parenchyma. Although IL-13 (p = 0.008) expression decreased in the bronchiolar epithelium, Muc5ac gene expression was not altered in the lung of DEP-exposed animals. Although respiratory mechanics, elastic and collagen density were not modified, the mean linear intercept (Lm) was increased in the DEP-exposed animals (p <= 0.001), and the index D2 was statistically different (p = 0.038) from the control animals. Conclusion: Our data suggest that nasal instillation of low doses of DEP over a period of 90 days results in alveolar enlargement in the pulmonary parenchyma of healthy mice.
- A flavanone from Baccharis retusa (Asteraceae) prevents elastase-induced emphysema in mice by regulating NF-kappa B, oxidative stress and metalloproteinases(2015) TAGUCHI, Laura; PINHEIRO, Nathalia M.; OLIVO, Clarice R.; CHOQUETA-TOLEDO, Alessandra; GRECCO, Simone S.; LOPES, Fernanda D. T. Q. S.; CAPERUTO, Luciana C.; MARTINS, Milton A.; TIBERIO, Iolanda F. L. C.; CAMARA, Niels O.; LAGO, Joao Henrique G.; PRADO, Carla M.Background: Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative stress imbalance and lung remodeling, resulting in reduced lung function and a lower quality of life. Flavonoids are plant compounds with potential anti-inflammatory and antioxidant effects that have been used in folk medicine. Our aim was to determine whether treatment with sakuranetin, a flavonoid extracted from the aerial parts of Baccharis retusa, interferes with the development of lung emphysema. Methods: Intranasal saline or elastase was administered to mice; the animals were then treated with sakuranetin or vehicle 2 h later and again on days 7, 14 and 28. We evaluated lung function and the inflammatory profile in bronchoalveolar lavage fluid (BALF). The lungs were removed to evaluate alveolar enlargement, extracellular matrix fibers and the expression of MMP-9, MMP-12, TIMP-1, 8-iso-PGF-2 and p65-NF-kappa B in the fixed tissues as well as to evaluate cytokine levels and p65-NF-kappa B protein expression. Results: In the elastase-treated animals, sakuranetin treatment reduced the alveolar enlargement, collagen and elastic fiber deposition and the number of MMP-9- and MMP-12-positive cells but increased TIMP-1 expression. In addition, sakuranetin treatment decreased the inflammation and the levels of TNF-alpha, IL-1 beta and M-CSF in the BALF as well as the levels of NF-kappa B and 8-iso-PGF-2 alpha in the lungs of the elastase-treated animals. However, this treatment did not affect the changes in lung function. Conclusion: These data emphasize the importance of oxidative stress and metalloproteinase imbalance in the development of emphysema and suggest that sakuranetin is a potent candidate that should be further investigated as an emphysema treatment. This compound may be useful for counteracting lung remodeling and oxidative stress and thus attenuating the development of emphysema.
- Correlation between heart rate variability indexes and aerobic physiological variables in patients with COPD(2015) LEITE, Marceli R.; RAMOS, Ercy Mara C.; KALVA-FILHO, Carlos A.; RODRIGUES, Fernanda Maria M.; FREIRE, Ana Paula C. F.; TACAO, Guilherme Y.; TOLEDO, Alessandra C. de; CECILIO, Michel J.; VANDERLEI, Luiz Carlos M.; RAMOS, DioneiBackground and objectivePrevious studies have shown a relationship between the level of physical fitness and autonomic variables. However, these relationships have not been investigated in patients with chronic obstructive pulmonary disease (COPD). The objective of this study was to correlate the resting heart rate variability (HRV) indexes with aerobic physiological variables obtained at a maximal exercise test in patients with COPD. MethodsThirty-seven patients with COPD (63 (59-70) years; 46 (35.4-63.7) forced expiratory volume in 1 s (FEV1)%) underwent assessment of autonomic modulation at rest for 20min to determine the HRV indexes in time and frequency domains. Soon after that, the patients performed an incremental exercise test to determine the anaerobic threshold (GET), the peak oxygen uptake (VO2PEAK) and the velocity corresponding to VO2PEAK (vVO(2PEAK)). ResultsThe indexes that express parasympathetic component as RMSSD (11.4 [7.5-23.8], HF (ms(2)) (35 [17-195] and SD1 (8.1 [5.3-16.8]), correlated with GET (r=0.39; r=0.43; r=0.39 respectively). The indexes that represent the overall variability, SDNN (19.5 [13.9-28.8]), LF (ms(2)) (111 [38-229]), and SD2 (26.8 [18.6-35.4]) correlated with vVO(2PEAK) (r=0.37; r=0.38; r=0.37; r=0.44; r=0.43; r=0.46 respectively). Likewise, the indexes LF (ms(2)), LF (nu) (63.2 [46-77,9]), HF (nu) (36.8 [22.1-54]), and LF/HF (1.7 [0.9-3.5]) correlated with VO2PEAK (r=0.35; r=0.35; r=-0.35; r=0.40 respectively). ConclusionsThis study demonstrated that HRV indexes at rest may become a predictive tool for aerobic capacity in COPD patients after the development of more consistent methods. This study aimed to investigate whether the HRV indexes correlate with aerobic physiological variables obtained in cardiopulmonary exercise testing of patients with COPD. Such correlation would have important clinical implications as it would allow, prior to the realization of the maximal exercise testing, to infer the patient's aerobic capacity.
- Exercise Inhibits the Effects of Smoke-Induced COPD Involving Modulation of STAT3(2017) BRANDAO-RANGEL, Maysa Alves Rodrigues; BACHI, Andre Luis Lacerda; OLIVEIRA-JUNIOR, Manoel Carneiro; ABBASI, Asghar; SILVA-RENNO, Adriano; BRITO, Aurileia Aparecida de; OLIVEIRA, Ana Paula Ligeiro de; TOLEDO-ARRUDA, Alessandra Choqueta; BELVISI, Maria Gabriela; VIEIRA, Rodolfo PaulaPurpose. Evaluate the participation of STAT3 in the effects of aerobic exercise (AE) in a model of smoke-induced COPD. Methods. C57Bl/6 male mice were divided into control, Exe, COPD, and COPD+ Exe groups. Smoke were administered during 90 days. Treadmill aerobic training begun on day 61 until day 90. Pulmonary inflammation, systemic inflammation, the level of lung emphysema, and the airway remodeling were evaluated. Analysis of integral and phosphorylated expression of STAT3 by airway epithelial cells, peribronchial leukocytes, and parenchymal leukocytes was performed. Results. AE inhibited smoke-induced accumulation of total cells (p < 0 001), lymphocytes (p < 0 001), and neutrophils (p < 0 001) in BAL, as well as BAL levels of IL-1 beta (p < 0 001), CXCL1 (p < 0 001), IL-17 (p < 0 001), and TNF-alpha (p < 0 05), while increased the levels of IL-10 (p < 0 001). AE also inhibited smoke-induced increases in total leukocytes (p < 0 001), neutrophils (p < 0 05), lymphocytes (p < 0 001), and monocytes (p < 0 01) in blood, as well as serum levels of IL-1 beta (p < 0 01), CXCL1 (p < 0 01), IL-17 (p < 0 05), and TNF-a (p < 0 01), while increased the levels of IL-10 (p < 0 001). AE reduced smoke-induced emphysema (p < 0 001) and collagen fiber accumulation in the airways (p < 0 001). AE reduced smoke-induced STAT3 and phospho-STAT3 expression in airway epithelial cells (p < 0 001), peribronchial leukocytes (p < 0 001), and parenchymal leukocytes (p < 0 001). Conclusions. AE reduces smoke-induced COPD phenotype involving STAT3.