Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD

Our previous studies have shown that nutritional zinc restriction exacerbates airway inflammation accompanied by an increase in caspase-3 activation and an accumulation of apoptotic epithelial cells in the bronchioles of the mice. Normally, apoptotic cells are rapidly cleared by macrophage efferocytosis, limiting any secondary necrosis and inflammation. We therefore hypothesized that zinc deficiency is not only pro-apoptotic but also impairs macrophage efferocytosis. Impaired efferocytic clearance of apoptotic epithelial cells by alveolar macrophages occurs in chronic obstructive pulmonary disease (COPD), cigarette-smoking and other lung inflammatory diseases. We now show that zinc is a factor in impaired macrophage efferocytosis in COPD. Concentrations of zinc were significantly reduced in the supernatant of bronchoalveolar lavage fluid of patients with COPD who were current smokers, compared to healthy controls, smokers or COPD patients not actively smoking. Lavage zinc was positively correlated with AM efferocytosis and there was decreased efferocytosis in macrophages depleted of Zn in vitro by treatment with the membrane-permeable zinc chelator TPEN. Organ and cell Zn homeostasis are mediated by two families of membrane ZIP and ZnT proteins. Macrophages of mice null for ZIP1 had significantly lower intracellular zinc and efferocytosis capability, suggesting ZIP1 may play an important role. We investigated further using the human THP-1 derived macrophage cell line, with and without zinc chelation by TPEN to mimic zinc deficiency. There was no change in ZIP1 mRNA levels by TPEN but a significant 3-fold increase in expression of another influx transporter ZIP2, consistent with a role for ZIP2 in maintaining macrophage Zn levels. Both ZIP1 and ZIP2 proteins were localized to the plasma membrane and cytoplasm in normal human lung alveolar macrophages. We propose that zinc homeostasis in macrophages involves the coordinated action of ZIP1 and ZIP2 transporters responding differently to zinc deficiency signals and that these play important roles in macrophage efferocytosis.

Influence of pursed-lip breathing on heart rate variability and cardiorespiratory parameters in subjects with chronic obstructive pulmonary disease (COPD)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Analysis of cardiovascular system responses to forced vital capacity in COPD

CONTEXTUALIZAÇÃO: O teste de capacidade vital forçada (CVF) é rotineiramente realizado na avaliação da função pulmonar de pacientes com doença pulmonar obstrutiva crônica (DPOC). Entretanto, permanece pouco compreendida a influência do teste de CVF sobre o sistema cardiovascular de pacientes com DPOC. OBJETIVOS: Analisar o comportamento da frequência cardíaca (FC), pressão arterial (PA) e variabilidade da frequência cardíaca (VFC) no teste de CVF na DPOC. MÉTODOS: Dezenove homens com DPOC (72 ± 7 anos, no estágio de gravidade GOLD I=3, II=5, III=7 e IV=4 pacientes) realizaram a manobra de CVF e tiveram sua FC monitorada durante todo o exame, e a VFC analisada nos domínios do tempo (rMSSD) e da frequência (BF, AF e BF/AF) durante o repouso, antes e após a melhor manobra de CVF. A PA foi analisada no repouso, imediatamente ao final da manobra de CVF e 10 minutos após o término de todos os testes. RESULTADOS: Ao início da manobra de CVF, a FC reduziu (p<0,001) e, em seguida, aumentou progressivamente até o final do teste (p<0,001). Após término da manobra, a FC continuou a aumentar até atingir um pico (p<0,001) e depois caiu rapidamente a valores inferiores aos de repouso (p<0,001) e retornou ao seu valor basal. A PA e os índices da VFC não sofreram alterações nos períodos analisados. CONCLUSÃO: O teste de CVF influencia o comportamento da FC, sem alterar o seu controle autonômico, bem como a PA em pacientes com DPOC nos períodos analisados.

Reproducibility of 6-minute walking test in patients with COPD

The reproducibility of the 6-min walking test (6MWT) needs to be more solidly studied. This study aimed to investigate the reproducibility of two 6MWTs performed on subsequent days in a large and representative sample of patients with chronic obstructive pulmonary disease (COPD), and to quantify the learning effect between the two tests, as well as its determinants.In a retrospective observational study, 1,514 patients with COPD performed two 6MWTs on subsequent days. Other measurements included body composition (dual X-ray absorptiometry), dyspnoea (Medical Research Council scale) and comorbidity (Charlson index).Although the 6MWT was reproducible (intraclass correlation coefficient=0.93), patients walked farther in the second test (391 m, 95% CI 155-585 m versus 418 m, 95% CI 185-605 m; p < 0.0001). on average, the second 6MWT increased by 27 m (or 7%), and 82% of patients improved in the second test. Determinants of improvement >= 42 m in the second test (upper limit of the clinically important change) were as follows: first 6MWT < 350 m, Charlson index < 2 and body mass index < 30 kg.m(-2) (OR 2.49, 0.76 and 0.60, respectively).The 6MWT was statistically reproducible in a representative sample of patients with COPD. However, the vast majority of patients improved significantly in the second test by an average learning effect of 27 m.

Energy expenditure during daily activities as measured by two motion sensors in patients with COPD

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Improvement of heart rate variability after exercise training and its predictors in COPD

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Relationship of upper-limb and thoracic muscle strength to 6-min walk distance in COPD patients

Study objectives: This study was developed to investigate the influence of thoracic and upperlimb muscle function on 6-min walk distance (6MWD) in patients with COPD.Design: A prospective, cross-sectional study.Setting: the pulmonary rehabilitation center of a university hospital.Patients: Thirty-eight patients with mild to very severe COPD were evaluated.Measurements and results: Pulmonary function and baseline dyspnea index (BDI) were assessed, handgrip strength, maximal inspiratory pressure (Pimax), and 6MWD were measured, and the one-repetition maximum (1RM) was determined for each of four exercises (bench press, lat pull down, leg extension, and leg press) performed on gymnasium equipment. Quality of life was assessed using the St. George Respiratory Questionnaire (SGRQ). We found statistically significant positive correlations between 6MWD and body weight (r = 0.32; p < 0.05), BDI (r = 0.50; p < 0.01), FEV, (r = 0.33; p < 0.05), PImax (r = 0.53; p < 0.01), and all values of 1RM. A statistically significant negative correlation was observed between 6MWD and dyspnea at the end of the 6-min walk test (r = -0.29; p < 0.05), as well as between 6MWD and the SGRQ activity domain (r = -0.45; p < 0.01) and impact domain (r = -0.34; p < 0.05) and total score (r = -0.40; p < 0.01). Multiple regression analysis selected body weight, BDI, Pimax, and lat pull down IRM as predictive factors for 6MWD (R-2 = 0.589).Conclusions: the results of this study showed the importance of the skeletal musculature of the thorax and upper limbs in submaximal exercise tolerance and could open new perspectives for training programs designed to improve functional activity in COPD patients.

Gender and Health Status Response to Long-Term Oxygen Therapy in COPD Patients

Introduction: The association of gender with health status (HS) response to long-term oxygen therapy (LTOT) in very severe COPD is unclear. The aims of this study were: (1) to compare dyspnea perception and HS between male and female with very severe COPD at baseline and (2) to provide a prospective assessment of HS response to LTOT, according to gender.Patients and methods: Hypoxemic COPD (n =97, age: 65.5 +/- 9.6 years, 53% males) were enrolled in a prospective longitudinal study over 12 months or until death. St. George's Respiratory Questionnaire (SGRQ) and baseline dyspnea index (BDI) were assessed.Results: At baseline, HS impairment and dyspnea sensation were similar between genders. After 12 months of LTOT, women presented improvement in symptom (64.1 +/- 120.6 versus 40.6 +/- 122.9; P < 0.0001) and total SGRQ scores. Men also showed improvement in symptoms after 12 months (62.7 +/- 23.3 versus 49.6 +/- 22.8; P < 0.0005); however, they presented deterioration of activity, impact and total scores during the study period, with markedly decline of activity domain (68.5 +/- 20.0 versus 75.9 +/- 16.9; P = 0.008). BDI did not show significant difference by gender over the study period.Conclusions: Our results show that the HS course in very severe COPD patients differs according to gender, as females show greater response longitudinally to LTOT. (C) 2010 SEPAR. Published by Elsevier Espana, S.L. All rights reserved.

Predictors of first-year survival in patients with advanced COPD treated using long-term oxygen therapy

Little evidence-based guidance is available to aid clinicians in determining short-term prognoses in very severe COPD patients. Therefore, the present study was designed to provide a prospective assessment (1) of the mortality rates and (2) whether the baseline measurements may be determinants of 1-year mortality in hypoxemic COPD patients receiving long-term oxygen therapy (LTOT).Seventy-eight clinically stable patients with advanced COPD treated using LTOT were enrolled in a prospective cohort study. Outcome variable: first-year mortality. Baseline measurements: categorical variables: age (<60 or >= 60 years); gender; body mass index (<20 or >= 20 kg/m(2)); fat-free mass (FFM) index (<16 [men] and <15kg/m(2) [women]; baseline dyspnea index (BDI) (<= 3 or >3); and corticosteroid use. Continuous variables: smoking history; lung function; FFM; fat mass; hemoglobin; hematocrit; arterial blood gases; forearm muscle strength; St. George's Respiratory Questionnaire (SGRQ); and comorbidity score. By the end of 1-year of follow-up, 12 patients (15.4%) had died. Kaplan-Meier curves showed that BDI <= 3 was the only variable associated with higher mortality. Cox proportional hazards analysis revealed that tower PaO2 and SPO2, higher PaCO2 and SGRQ scores were associated with reduced survival. In the multivariate analysis, BDI remained predictive of mortality (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.31-0.81), as did PaO2 (HR, 0.49; 95% CI, 0.26-0.95). These data suggest that readily available parameters as dyspnea intensity and hypoxemia severity may be useful in predicting first-year survival rates in advanced COPD patients receiving LTOT (C) 2007 Elsevier Ltd. All rights reserved.

Resting energy expenditure and carbohydrate oxidation are higher in elderly patients with COPD: a case control study

Background: Elderly patients with chronic obstructive pulmonary disease (COPD) usually have a compromised nutritional status which is an independent predictor of morbidity and mortality. To know the Resting Energy Expenditure (REE) and the substrate oxidation measurement is essential to prevent these complications. This study aimed to compare the REE, respiratory quotient (RQ) and body composition between patients with and without COPD.Methods: This case-control study assessed 20 patients with chronic obstructive pulmonary disease attending a pulmonary rehabilitation program. The group of subjects without COPD (control group) consisted of 20 elderly patients attending a university gym, patients of a private service and a public healthy care. Consumption of oxygen (O-2) and carbon dioxide (CO2) was determined by indirect calorimetry and used for calculating the resting energy expenditure and respiratory quotient. Body mass index (BMI) and waist circumference (WC) were also measured. Percentage of body fat (%BF), lean mass (kg) and muscle mass (kg) were determined by bioimpedance. The fat free mass index (FFMI) and muscle mass index (MMI) were then calculated.Results: The COPD group had lower BMI than control (p = 0.02). However, WC, % BF, FFMI and MM-I did not differ between the groups. The COPD group had greater RQ (p = 0.01), REE (p = 0.009) and carbohydrate oxidation (p = 0.002).Conclusions: Elderly patients with COPD had higher REE, RQ and carbohydrate oxidation than controls.

Obesity and Physical Activity in the Daily Life of Patients with COPD

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Gender differences in predictors of health status in patients with COPD

Objective: To evaluate the health status (HS) of COPD patients and to identify the main predictors of HS in these patients according to gender. Methods: The study included 90 COPD patients (60 males and 30 females; mean age = 64 +/- 9 years) with a wide range of airway obstruction disorders (mean FEV(1) = 56 +/- 19% of predicted). The men were individually matched to the women by % of predicted FEV(1) (ratio: 2:1). The patients were assessed regarding body composition; six-minute walk distance; perception of dyspnea using the Modified Medical Research Council Dyspnea Scale; Saint George's Respiratory Questionnaire (SGRQ); Charlson comorbidity index; and the multidimensional Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index. Multiple linear regression analysis was performed to identify the predictors of HS by gender. Results: Impairment of HS was greater among the women than among the men for SGRQ total score and for all SGRQ domains (total: 51 +/- 18% vs. 38 19%; p = 0.002; symptoms: 61 +/- 22% vs. 42 +/- 21%; p < 0.001; activity: 62 +/- 18% vs. 49 +/- 21%; p = 0.004; and impact: 41 +/- 19% vs. 27 +/- 18%; p = 0.001). The multiple linear regression showed that age and perception of dyspnea correlated with SGRQ total score for both genders (males, r(2) = 0.42; females, r(2) = 0.70; p < 0.05). Conclusions: Our results showed an association between gender and HS in COPD patients. Age and dyspnea are determinants of HS in both genders.

Smoking status and tumor necrosis factor-alpha mediated systemic inflammation in COPD patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)