Henrique T. Moriya

Aerobic exercise attenuates pulmonary injury induced by exposure to cigarette smoke

It has recently been suggested that regular exercise reduces lung function decline and risk of chronic obstructive pulmonary disease (COPD) among active smokers; however, the mechanisms involved in this effect remain poorly understood. The present study evaluated the effects of regular exercise training in an experimental mouse model of chronic cigarette smoke exposure. Male C57BL/6 mice were divided into four groups (control, exercise, smoke and smoke+exercise). For 24 weeks, we measured respiratory mechanics, mean linear intercept, inflammatory cells and reactive oxygen species (ROS) in bronchoalveolar lavage (BAL) fluid, collagen deposition in alveolar walls, and the expression of antioxidant enzymes, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase (TIMP)1, interleukin (IL)-10 and 8-isoprostane in alveolar walls. Exercise attenuated the decrease in pulmonary elastance (p<0.01) and the increase in mean linear intercept (p=0.003) induced by cigarette smoke exposure. Exercise substantially inhibited the increase in ROS in BAL fluid and 8-isoprostane expression in lung tissue induced by cigarette smoke. In addition, exercise significantly inhibited the decreases in IL-10, TIMP1 and CuZn superoxide dismutase induced by exposure to cigarette smoke. Exercise also increased the number of cells expressing glutathione peroxidase. Our results suggest that regular aerobic physical training of moderate intensity attenuates the development of pulmonary disease induced by cigarette smoke exposure.

Diaphragmatic Breathing Training Program Improves Abdominal Motion During Natural Breathing in Patients With Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial

OBJECTIVE To investigate the effects of a diaphragmatic breathing training program (DBTP) on thoracoabdominal motion and functional capacity in patients with chronic obstructive pulmonary disease. DESIGN A prospective, randomized controlled trial. SETTING Academic medical center. PARTICIPANTS Subjects (N=30; forced expiratory volume in 1s, 42%±13% predicted) were randomly allocated to either a training group (TG) or a control group (CG). INTERVENTIONS Subjects in the TG completed a 4-week supervised DBTP (3 individualized weekly sessions), while those in the CG received their usual care. MAIN OUTCOME MEASURES Effectiveness was assessed by amplitude of the rib cage to abdominal motion ratio (RC/ABD ratio) (primary outcome) and diaphragmatic mobility (secondary outcome). The RC/ABD ratio was measured using respiratory inductive plethysmography during voluntary diaphragmatic breathing and natural breathing. Diaphragmatic mobility was measured by ultrasonography. A 6-minute walk test and health-related quality of life were also evaluated. RESULTS Immediately after the 4-week DBTP, the TG showed a greater abdominal motion during natural breathing quantified by a reduction in the RC/ABD ratio when compared with the CG (F=8.66; P<.001). Abdominal motion during voluntary diaphragmatic breathing after the intervention was also greater in the TG than in the CG (F=4.11; P<.05). The TG showed greater diaphragmatic mobility after the 4-week DBTP than did the CG (F=15.08; P<.001). An improvement in the 6-minute walk test and in health-related quality of life was also observed in the TG. CONCLUSIONS DBTP for patients with chronic obstructive pulmonary disease induced increased diaphragm participation during natural breathing, resulting in an improvement in functional capacity.

Effects of Residual Oil Fly Ash (ROFA) in Mice with Chronic Allergic Pulmonary Inflammation

Exposure to particulate matter (PM) air pollution is associated with increased asthma morbidity. Residual oil flash ash (ROFA) is rich in water-soluble transition metals, which are involved in the pathological effects of PM. The objective of this study was to investigate the effects of intranasal administration of ROFA on pulmonary inflammation, pulmonary responsiveness, and excess mucus production in a mouse model of chronic pulmonary allergic inflammation. BALB/c mice received intraperitoneal injections of ovalbumin (OVA) solution (days 1 and 14). OVA challenges were performed on days 22, 24, 26, and 28. After the challenge, mice were intranasally instilled with ROFA. After forty-eight hours, pulmonary responsiveness was performed. Mice were sacrificed, and lungs were removed for morphometric analysis. OVA-exposed mice presented eosinophilia in the bronchovascular space (p < .001), increased pulmonary responsiveness (p < .001), and epithelial remodeling (p = .003). ROFA instillation increased pulmonary responsiveness (p = .004) and decreased the area of ciliated cells in the airway epithelium (p = .006). The combined ROFA instillation and OVA exposure induced a further increase in values of pulmonary responsiveness (p = .043) and a decrease in the number of ciliated cells in the airway epithelium (p = .017). PM exposure results in pulmonary effects that are more intense in mice with chronic allergic pulmonary inflammation.

Critical closing pressure during midazolam-induced sleep

The critical closing pressure (Pcrit) is the airway pressure at which the airway collapses and reflects the anatomical contribution to the genesis of obstructive sleep apnea. Pcrit is usually determined during non-rapid eye movement sleep at night, but has been determined under midazolam sedation during the day in the absence of sleep stage monitoring. Indeed, little is known about the effects of midazolam on sleep architecture. Moreover, deeper sedation with midazolam can decrease upper airway muscle activity and increase collapsibility compared with natural sleep. Pcrit under sedation has not been systematically compared with the usual method performed during natural sleep. Therefore, this study aimed to test the hypothesis that Pcrit following low doses of midazolam during the day would be comparable to Pcrit measured during natural sleep in the same patient. Fifteen men (age 54 ± 10 yr, body mass index 30 ± 4 kg/m(2)) with obstructive sleep apnea underwent a baseline standard overnight polysomnogram (apnea-hypopnea index 38 ± 22 events/h, range: 8-66 events/h), and Pcrit was determined during natural sleep and following midazolam. Sleep induction was obtained with low doses of midazolam (2.4 mg, range 2.0-4.4 mg), and sleep architecture was comparable to natural sleep. Natural sleep and induced sleep Pcrit were similar (-0.82 ± -3.44 and -0.97 ± 3.21 cmH(2)O, P = 0.663) and closely associated (intraclass correlation coefficient = 0.92; 95% confidence interval, 0.78-0.97, P < 0.001). Natural and midazolam-induced Pcrit correlated with obstructive sleep apnea severity, indicating that both Pcrit measures provided meaningful physiological information. Pcrit determined during the day with sleep induction is similar to natural overnight sleep and is a valid alternative approach in which to determine Pcrit.

Exposure to ambient levels of particles emitted by traffic worsens emphysema in mice

OBJECTIVES We investigated effects of chronic exposure (2 months) to ambient levels of particulate matter (PM) on development of protease-induced emphysema and pulmonary remodeling in mice. METHODS Balb/c mice received nasal drop of either papain or normal saline and were kept in two exposure chambers situated in an area with high traffic density. One of them received ambient air and the other had filters for PM. RESULTS mean concentration of PM10 was 2.68 +/- 0.38 and 33.86 +/- 2.09 microg/m3, respectively, in the filtered and ambient air chambers (p < 0.001). After 2 months of exposure, lungs from papain-treated mice kept in the chamber with ambient air presented greater values of mean linear intercept, an increase in density of collagen fibers in alveolar septa and in expression of 8-isoprostane (p = 0.002, p < 0.05 and p = 0.002, respectively, compared to papain-treated mice kept in the chamber with filtered air). We did not observe significant differences between these two groups in density of macrophages and in amount of cells expressing matrix metalloproteinase-12. There were no significant differences in saline-treated mice kept in the two chambers. CONCLUSIONS We conclude that exposure to urban levels of PM worsens protease-induced emphysema and increases pulmonary remodeling. We suggest that an increase in oxidative stress induced by PM exposure influences this response. These pulmonary effects of PM were observed only in mice with emphysema.

Upper airway collapsibility is associated with obesity and hyoid position.

STUDY OBJECTIVES Upper airway anatomy plays a major role in obstructive sleep apnea (OSA) pathogenesis. An inferiorly displaced hyoid as measured by the mandibular plane to hyoid distance (MPH) has been consistently associated with OSA. The hyoid is also a common landmark for pharyngeal length, upper airway volume, and tongue base. Tongue dimensions, pharyngeal length, and obesity are associated with OSA severity, although the link between these anatomical variables and pharyngeal collapsibility is less well known. We hypothesized that obesity as measured by body mass index (BMI), neck and waist circumferences, and variables associated with hyoid position (pharyngeal length, upper airway volume, and tongue dimensions) would be associated with passive pharyngeal critical closing pressure (Pcrit). DESIGN Cross-sectional. SETTING Academic hospital. PATIENTS 34 Japanese-Brazilian males age 21 to 70 y. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS We performed computed tomography scans of the upper airway, overnight polysomnography, and Pcrit measurements in all subjects. On average, subjects were overweight (BMI = 28 ± 4 kg/m(2)) and OSA was moderately severe (apnea-hypopnea index = 29 [13-51], range 1-90 events/h). Factor analysis identified two factors among the studied variables: obesity (extracted from BMI, neck and waist circumferences) and hyoid position (MPH, pharyngeal length, tongue length, tongue volume, and upper airway volume). Both obesity and hyoid position correlated with Pcrit (r = 0.470 and 0.630, respectively) (P < 0.01). In addition, tongue volume, tongue length, pharyngeal length, and MPH correlated with waist and neck circumferences (P < 0.05). CONCLUSIONS Pharyngeal critical closing pressure is associated with obesity and hyoid position. Tongue dimensions, pharyngeal length, and the mandibular plane to hyoid distance are associated with obesity variables. These findings provide novel insight into the potential factors mediating upper airway collapse in obstructive sleep apnea.

Short-term exposure of mice to cigarette smoke and/or residual oil fly ash produces proximal airspace enlargements and airway epithelium remodeling

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-β1 (TGF-β1), 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-β1 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-β1.

Respiratory mechanics do not always mirror pulmonary histological changes in emphysema

OBJECTIVE : To verify the accordance of functional and morphometric parameters during the development of emphysema. METHODS : BALB/c mice received a nasal drop of either papain or saline solution and were studied after 1, 3, 15, 28, and 40 days. Functional parameters, such as airway resistance, tissue damping, and tissue elastance, were analyzed. To evaluate the structural changes and possible mechanisms involved in this disease, we measured the mean linear intercept, the volume proportions of elastic and collagen fibers, the number of macrophages, the numbers of cells expressing metalloprotease 12 and 8-isoprostane in lung parenchyma. RESULTS : We only observed decreases in tissue elastance and tissue damping on the 28th day, with a concomitant increase in the mean linear intercept, indicating the presence of emphysema. However, only the mean linear intercept values remained increased until the 40th day. The volume proportion of collagen fibers was increased from the 15th day to the 40th day, whereas the volume proportion of elastic fibers was only increased on the 40th day. The number of macrophages increased beginning on the 1st day. The expression of metalloproteinase 12 was increased from the 3rd day until the 40th day. However, 8-isoprostane expression was only increased on the 1st and 3rd days. CONCLUSIONS : In this study, morphometric parameters were found to be more reliable for detecting the presence of emphysema than the functional parameters measured by respiratory mechanics. Further investigations are necessary to understand how the extracellular matrix remodeling observed in the lung parenchyma could be involved in this process.

Cigarette smoke dissociates inflammation and lung remodeling in OVA-sensitized and challenged mice.

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 μg+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-γ, 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.

Pletismografia respiratória por indutância: estudo comparativo entre calibração por manobra de isovolume e calibração qualitativa diagnóstica em voluntários saudáveis avaliados em diferentes posturas

OBJECTIVE: To compare two methods of respiratory inductive plethysmography (RIP) calibration in three different positions. METHODS: We evaluated 28 healthy subjects (18 women and 10 men), with a mean age of 25.4 ± 3.9 years. For all of the subjects, isovolume maneuver calibration (ISOCAL) and qualitative diagnostic calibration (QDC) were used in the orthostatic, sitting, and supine positions. In order to evaluate the concordance between the two calibration methods, we used ANOVA and Bland-Altman plots. RESULTS: The values of the constant of proportionality (K) were significantly different between ISOCAL and QDC in the three positions evaluated: 1.6 ± 0.5 vs. 2.0 ± 1.2, in the supine position, 2.5 ± 0.8 vs. 0.6 ± 0.3 in the sitting position, and 2.0 ± 0.8 vs. 0.6 ± 0.3 in the orthostatic position (p < 0.05 for all). CONCLUSIONS: Our results suggest that QDC is an inaccurate method for the calibration of RIP. The K values obtained with ISOCAL reveal that RIP should be calibrated for each position evaluated.