Alessandra Choqueta de Toledo-Arruda

Structure-Activity Association of Flavonoids in Lung Diseases

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.

The effects of elastic tubing-based resistance training compared with conventional resistance training in patients with moderate chronic obstructive pulmonary disease: a randomized clinical trial:

Objective: To investigate the effects of elastic tubing training compared with conventional resistance training on the improvement of functional exercise capacity, muscle strength, fat-free mass, and systemic inflammation in patients with chronic obstructive pulmonary disease. Design: A prospective, randomized, eight-week clinical trial. Setting: The study was conducted in a university-based, outpatient, physical therapy clinic. Subjects: A total of 49 patients with moderate chronic obstructive pulmonary disease. Interventions: Participants were randomly assigned to perform elastic tubing training or conventional resistance training three times per week for eight weeks. Main measures: The primary outcome measure was functional exercise capacity. The secondary outcome measures were peripheral muscle strength, health-related quality of life assessed by the Chronic Respiratory Disease Questionnaire (CRDQ), fat-free mass, and cytokine profile. Results: After eight weeks, the mean distance covered during six minutes increased by 73 meters (±69) in the elastic tubing group and by 42 meters (±59) in the conventional group (p < 0.05). The muscle strength and quality of life improved in both groups (P < 0.05), with no significant differences between the groups. There was a trend toward an improved fat-free mass in both groups (P = 0.05). After the first and last sessions, there was an increase in interleukin 1β (IL-1β) and interleukin 10 (IL-10) in both groups, while tumour necrosis factor alpha (TNF-α) was stimulated only in the conventional training group. Conclusion: Elastic tubing training had a greater effect on functional exercise capacity than conventional resistance training. Both interventions were equally effective in improving muscle strength and quality of life.

Acute cardiopulmonary effects induced by the inhalation of concentrated ambient particles during seasonal variation in the city of São Paulo.

Ambient particles may undergo modifications to their chemical composition as a consequence of climatic variability. The determination of whether these changes modify the toxicity of the particles is important for the understanding of the health effects associated with particle exposure. The objectives were to determine whether low levels of particles promote cardiopulmonary effects, and to assess if the observed alterations are influenced by season. Mice were exposed to 200 μg/m(3) concentrated ambient particles (CAPs) and filtered air (FA) in cold/dry and warm/humid periods. Lung hyperresponsiveness, heart rate, heart rate variability, and blood pressure were evaluated 30 min after each exposure. After 24 h, blood and tissue samples were collected. During both periods (warm/humid and cold/dry), CAPs induced alterations in red blood cells and lung inflammation. During the cold/dry period, CAPs reduced the mean corpuscular volume levels and increased erythrocytes, hemoglobin, mean corpuscular hemoglobin concentration, and red cell distribution width coefficient variation levels compared with the FA group. Similarly, CAPs during the warm/humid period decreased mean corpuscular volume levels and increased erythrocytes, hemoglobin, hematocrit, and red cell distribution width coefficient variation levels compared with the FA group. CAPs during the cold/dry period increased the influx of neutrophils in the alveolar parenchyma. Short-term exposure to low concentrations of CAPs elicited modest but significant pulmonary inflammation and, to a lesser extent, changes in blood parameters. In addition, our data support the concept that changes in climate conditions slightly modify particle toxicity because equivalent doses of CAPs in the cold/dry period produced a more exacerbated response.

Plant Proteinase Inhibitor BbCI Modulates Lung Inflammatory Responses and Mechanic and Remodeling Alterations Induced by Elastase in Mice

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, TNFα-, MMP-9-, MMP-12-, TIMP-1-, iNOS-, and eNOS-positive cells, 8-iso-PGF2α, 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 TNFα-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

A 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-α 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.

Exercise Inhibits the Effects of Smoke-Induced COPD Involving Modulation of STAT3

Purpose 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-1β (p < 0.001), CXCL1 (p < 0.001), IL-17 (p < 0.001), and TNF-α (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-1β (p < 0.01), CXCL1 (p < 0.01), IL-17 (p < 0.05), and TNF-α (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.

Acute Mucociliary Clearance Response to Aerobic Exercise in Smokers

BACKGROUND: Mucociliary clearance is the main defense mechanism of the respiratory system, and it is influenced by several stimuli, including aerobic exercise and cigarette smoking. We evaluated the acute response of mucociliary clearance to aerobic exercise in smokers and nonsmokers compared with that found after acute smoking and smoking combined with exercise. Also, we investigated whether there was a correlation between mucociliary clearance and the autonomic nervous system under these conditions. METHODS: Twenty-one smokers were evaluated for mucociliary clearance by saccharin transit time (STT), and the response of the autonomic nervous system was evaluated by heart rate variability after aerobic exercise, after exercise followed by smoking, after acute smoking, and after rest. For comparison, 17 nonsmokers were also assessed during exercise. Repeated-measures analysis of variance with the Tukey test or the Friedman test followed by the Dunn test was used to evaluate the STT, autonomic response, and other variables to exercise and/or smoking in smokers. A paired t test or Wilcoxon test was used to analyze responses to exercise in nonsmokers. Correlations were evaluated using Pearson or Spearman coefficients. RESULTS: The STT was reduced after exercise in both groups, with similar responses between them. Other stimuli also reduced the STT. The STT showed a negative correlation with sympathetic activity in smokers and a positive correlation with the parasympathetic system in nonsmokers. CONCLUSIONS: Although impaired in smokers, mucociliary clearance responded to the stimulus of exercise, as demonstrated by similar STTs compared with nonsmokers. This response was correlated with the autonomic nervous system in both groups. In smokers, mucociliary clearance also responded to the stimuli of smoking and exercise followed by smoking.

Effects of 12 weeks of aerobic training on autonomic modulation, mucociliary clearance, and aerobic parameters in patients with COPD.

Introduction Patients with chronic obstructive pulmonary disease (COPD) exhibit aerobic function, autonomic nervous system, and mucociliary clearance alterations. These parameters can be attenuated by aerobic training, which can be applied with continuous or interval efforts. However, the possible effects of aerobic training, using progressively both continuous and interval sessions (ie, linear periodization), require further investigation. Aim To analyze the effects of 12-week aerobic training using continuous and interval sessions on autonomic modulation, mucociliary clearance, and aerobic function in patients with COPD. Methods Sixteen patients with COPD were divided into an aerobic (continuous and interval) training group (AT) (n=10) and a control group (CG) (n=6). An incremental test (initial speed of 2.0 km·h−1, constant slope of 3%, and increments of 0.5 km·h−1 every 2 minutes) was performed. The training group underwent training for 4 weeks at 60% of the peak velocity reached in the incremental test (vVO2peak) (50 minutes of continuous effort), followed by 4 weeks of sessions at 75% of vVO2peak (30 minutes of continuous effort), and 4 weeks of interval training (5×3-minute effort at vVO2peak, separated by 1 minute of passive recovery). Intensities were adjusted through an incremental test performed at the end of each period. Results The AT presented an increase in the high frequency index (ms2) (P=0.04), peak oxygen uptake (VO2peak) (P=0.01), vVO2peak (P=0.04), and anaerobic threshold (P=0.02). No significant changes were observed in the CG (P>0.21) group. Neither of the groups presented changes in mucociliary clearance after 12 weeks (AT: P=0.94 and CG: P=0.69). Conclusion Twelve weeks of aerobic training (continuous and interval sessions) positively influenced the autonomic modulation and aerobic parameters in patients with COPD. However, mucociliary clearance was not affected by aerobic training.

Exercise Prevents Diaphragm Wasting Induced by Cigarette Smoke through Modulation of Antioxidant Genes and Metalloproteinases

Background The present study aimed to analyze the effects of physical training on an antioxidant canonical pathway and metalloproteinases activity in diaphragm muscle in a model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD). Methods Male mice were randomized into control, smoke, exercise, and exercise + smoke groups, which were maintained in trial period of 24 weeks. Gene expression of kelch-like ECH-associated protein 1; nuclear factor erythroid-2 like 2; and heme-oxygenase1 by polymerase chain reaction was performed. Metalloproteinases 2 and 9 activities were analyzed by zymography. Exercise capacity was evaluated by treadmill exercise test before and after the protocol. Results Aerobic training inhibited diaphragm muscle wasting induced by cigarette smoke exposure. This inhibition was associated with improved aerobic capacity in those animals that were submitted to 24 weeks of aerobic training, when compared to the control and smoke groups, which were not submitted to training. The aerobic training also downregulated the increase of matrix metalloproteinases (MMP-2 and MMP-9) and upregulated antioxidant genes, such as nuclear factor erythroid-2 like 2 (NRF2) and heme-oxygenase1 (HMOX1), in exercise + smoke group compared to smoke group. Conclusions Treadmill aerobic training protects diaphragm muscle wasting induced by cigarette smoke exposure involving upregulation of antioxidant genes and downregulation of matrix metalloproteinases.