Increased Ratio of Matrix Metalloproteinase-9 (MMP-9)/Tissue Inhibitor Metalloproteinase-1 from Alveolar Macrophages in Chronic Asthma with a Fast Decline in FEV1 at 5-Year Follow-up.

Chronic asthma is associated with progressive airway remodeling, which may contribute to declining lung function. An increase in matrix metalloproteinases-9 (MMP-9)/tissue inhibitor metalloproteinase-1 (TIMP-1) may indicate airway inflammation and bronchial injury. Bronchial biopsy specimens and alveolar macrophages (AMs) were obtained from patients with asthma under regular treatment with inhaled corticosteroids or combination therapy and normal subjects (n = 10). Asthmatics included those with a slow forced expiratory volume in one second (FEV1) decline (<30 mL/year, n = 13) and those with a fast FEV1 decline (≥30 mL/year, n = 8) in 5-year follow-up. Immunostaining expression of MMP-9 and TIMP-1 was detected in airway tissues. MMP-9 and TIMP-1 was measured from AMs cultured for 24 h. After the 5-year treatment, the methacholine airway hyperresponsiveness of the slow FEV1 decline group was decreased, but that of the fast FEV1 decline group was increased (PC20, provocative concentration causing a 20% decrease in FEV1, 3.12 ± 1.10 to 1.14 ± 0.34 mg/dL, p < 0.05). AMs of asthma with a fast FEV1 decline released a higher level of MMP-9 (8.52 ± 3.53 pg/mL, p < 0.05) than those of a slow FEV1 decline (0.99 ± 0.20 pg/mL). The MMP-9/TIMP ratio in the fast FEV1 decline group (0.089 ± 0.032) was higher than that of the slow FEV1 decline group (0.007 ± 0.001, p < 0.01). The annual FEV1 decline in 5 years was proportional to the level of MMP-9 (r = 57, p < 0.01) and MMP-9/TIMP-1 ratio (r = 0.58, p < 0.01). The airways of asthma with greater yearly decline in FEV1 showed an increased thickness of submucosa and strong expression of MMP-9. An increase in MMP-9 and MMP-9/TIMP-1 in airways or AMs could be indicators of chronic airway inflammation and contribute to a greater decline in lung function of patients with chronic asthma.

Maintenance Negative Pressure Ventilation Improves Survival in COPD Patients with Exercise Desaturation.

Negative pressure ventilation (NPV), when used as an adjuvant to pulmonary rehabilitation, improves lung function, increases exercise capacity, and reduces exacerbations. The aim of this study was to determine whether maintenance NPV improves long-term clinical outcomes and reduces mortality in patients with chronic obstructive pulmonary disease (COPD). Between 2003 and 2009, 341 patients were treated for COPD either with or without hospital-based NPV. We measured forced expiratory volume in one second (FEV1), 6-min walking distance (6MWD), and oxygen saturation by pulse oximetry (SpO2) during a 6-min walk test (6MWT) every 3-6 months. Desaturation (D) during the 6MWT was defined as a reduction in SpO2 of ≥10% from baseline. The NPV group had a better survival outcome than the Non-NPV group. The 8-year survival probabilities for the NPV and Non-NPV groups were 60% and 20%, respectively (p < 0.01). Baseline desaturation was a significant risk factor for death, and the risk of death increased with desaturation severity (SpO2 80~89: hazard ratios (HR) 2.7, 95% confidence interval (CI) 1.4-5.3; SpO2 < 80: HR 3.1, 95% CI 1.3-7.4). The NPV group had a slower decline in lung function and 6MWD. The NPV + D and Non-NPV+D had a threefold and fourfold increase in the risks of all-cause mortality compared with the NPV-ND, respectively. Maintenance non-invasive NPV reduced long-term mortality in COPD patients. The desaturating COPD patients had an increased mortality risk compared with non-desaturating COPD patients.

Oxygen desaturation during the 6-min walk test as a risk for osteoporosis in non-cystic fibrosis bronchiectasis.

BACKGROUND: Osteoporosis is a common comorbidity in non-cystic fibrosis (non-CF) bronchiectasis patients. We determined whether desaturation during 6-min walk test (6MWT) can be a predictor for osteoporosis risk. METHODS: This was a retrospective cross-sectional study. Sixty-six non-CF bronchiectasis patients were enrolled. Lung function, walking distance, the lowest oxygen saturation (SpO2), the fall in SpO2 (ΔSpO2), and the distance-saturation product (DSP) were determined during the 6MWT. Desaturators (n = 45) were defined as those with ΔSpO2 > 10% or the lowest SpO2 < 88%. Bone mineral density (BMD) was determined through dual-energy X-ray absorptiometry. The severity of non-CF bronchiectasis was evaluated using high-resolution computed tomography. RESULTS: Osteoporosis was evident in more desaturators (82%) than non-desaturators (43%, p < 0.01). BMD at the level of the femoral neck was significantly lower in desaturators than in non-desaturators (- 3.6 ± 1.1 vs. - 2.4 ± 0.9, p < 0.01). BMD was correlated positively with the lowest SpO2 and negatively with ΔSpO2 and severe exacerbations. In multivariate linear regression analysis, desaturation during 6MWT was the most significant predictive factor for osteoporosis (95% confidence interval - 1.60 to - 0.26, p = 0.01). Other risk factors included old age, low body mass index and severe exacerbation. CONCLUSIONS: Exertional desaturation during the 6MWT was a significant predictive factor for osteoporosis in Asian non-CF bronchiectasis patients. The 6MWT may be useful in identifying the osteoporotic phenotype of non-CF bronchiectasis and increasing clinician awareness to promote early intervention.

Increased matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1 ratio in smokers with airway hyperresponsiveness and accelerated lung function decline.

BACKGROUND: Airway hyperresponsiveness (AHR) is associated with airway inflammation and a rapid decline in lung function and is a predictor of future risk of COPD among smokers. Alveolar macrophages (AMs) from patients with COPD release a greater amount of matrix metalloproteinase (MMP)-9. We hypothesized that the imbalance between MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) is related to AHR in smokers. PATIENTS AND METHODS: Healthy smokers with AHR (AHR + S) or smokers without AHR (AHR - S; divided according to a methacholine challenge test) and nonsmokers without AHR (AHR - NS) were enrolled. Spirometry was performed during enrollment and repeated after 5 years. Initially, AMs recovered from bronchoalveolar lavage (BAL) fluid were cultured in the presence of p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), MAPK kinase (MEK) 1/2 (the MEK of extracellular signal-regulated kinase [ERK] inhibitor, PD98059), or medium alone for 24 h. The release of MMP-9 and TIMP-1 in culture supernatants was measured by enzyme-linked immunosorbent assay. RESULTS: A greater reduction in forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC), FEV1 (as a percentage of the predicted value [%pred]), and maximal mid-expiratory flow (MMEF) was observed among AHR + S in the 5-year period. There was a higher proportion of neutrophils and a lower proportion of AMs in BAL fluid recovered from AHR + S. Compared to AMs from AHR - NS and AHR - S, AMs from nonsmokers with AHR (AHR + NS) released more MMP-9 and less TIMP-1, with an increase in MMP-9/TIMP-1 ratios. The MMP-9/TIMP-1 ratio in smokers was positively correlated with the annual decline in FEV1%pred, FVC%pred, and MMEF%pred. Both SB203580 and PD98059 significantly reduced MMP-9, but not TIMP-1, from AMs of smokers. CONCLUSION: AMs of AHR + NS produce excessive MMP-9 over TIMP-1, which may be a predictor of the development of airway obstruction. Inhibition of p38 MAPK and ERK suppresses the generation of MMP-9 by AMs from smokers.

Pulmonary rehabilitation coupled with negative pressure ventilation decreases decline in lung function, hospitalizations, and medical cost in COPD: A 5-year study.

Pulmonary rehabilitation (PR) brings benefits to patients with chronic obstructive pulmonary disease (COPD). Negative pressure ventilation (NPV) increases ventilation and decreases hyperinflation as well as breathing work in COPD. We evaluated the long-term effects of a hospital-based PR program coupled with NPV support in patients with COPD on clinical outcomes.One hundred twenty-nine patients with COPD were followed up for more than 5 years, with the NPV group (n = 63) receiving the support of NPV (20-30 cm H2O delivery pressure for 60 min) and unsupervised home exercise program of 20 to 30 min daily walk, while the control group (n = 6) only received unsupervised home exercise program. Pulmonary function tests and 6 min walk tests (6MWT) were performed every 3 to 6 months. Emergency room (ER) visits and hospitalization with medical costs were recorded.A significant time-by-group interaction in the yearly decline of forced expiratory volume in 1 s in the control group analyzed by mixed-model repeated-measure analysis was found (P = 0.048). The 6MWT distance of the NPV group was significantly increased during the first 4 years, with the interaction of time and group (P = 0.003), the time alone (P = 0.014), and the quadratic time (P < 0.001) being significant between the 2 groups. ER exacerbations and hospitalizations decreased by 66% (P < 0.0001) and 54% (P < 0.0001) in the NPV group, respectively. Patients on PR program coupled with NPV had a significant reduction of annual medical costs (P = 0.022).Our hospital-based multidisciplinary PR coupled with NPV reduced yearly decline of lung function, exacerbations, and hospitalization rates, and improved walking distance and medical costs in patients with COPD during a 5-year observation.

Exercise-Induced Changes in Exhaled NO Differentiates Asthma With or Without Fixed Airway Obstruction From COPD With Dynamic Hyperinflation.

Asthmatic patients with fixed airway obstruction (FAO) and patients with chronic obstructive pulmonary disease (COPD) share similarities in terms of irreversible pulmonary function impairment. Exhaled nitric oxide (eNO) has been documented as a marker of airway inflammation in asthma, but not in COPD. To examine whether the basal eNO level and the change after exercise may differentiate asthmatics with FAO from COPD, 27 normal subjects, 60 stable asthmatics, and 62 stable COPD patients were studied. Asthmatics with FAO (n = 29) were defined as showing a postbronchodilator FEV1/forced vital capacity (FVC) ≤70% and FEV1 less than 80% predicted after inhaled salbutamol (400 µg). COPD with dynamic hyperinflation (n = 31) was defined as a decrease in inspiratory capacity (ΔIC%) after a 6 minute walk test (6MWT). Basal levels of eNO were significantly higher in asthmatics and COPD patients compared to normal subjects. The changes in eNO after 6MWT were negatively correlated with the percent change in IC (r = -0.380, n = 29, P = 0.042) in asthmatics with FAO. Their levels of basal eNO correlated with the maximum mid-expiratory flow (MMEF % predicted) before and after 6MWT. In COPD patients with air-trapping, the percent change of eNO was positively correlated to ΔIC% (rs = 0.404, n = 31, P = 0.024). We conclude that asthma with FAO may represent residual inflammation in the airways, while dynamic hyperinflation in COPD may retain NO in the distal airspace. eNO changes after 6MWT may differentiate the subgroups of asthma or COPD patients and will help toward delivery of individualized therapy for airflow obstruction.

Mobile-phone-based home exercise training program decreases systemic inflammation in COPD: a pilot study.

BACKGROUND: Moderate-intensity exercise training improves skeletal muscle aerobic capacity and increased oxidative enzyme activity, as well as exercise tolerance in COPD patients. METHODS: To investigate whether the home-based exercise training program can reduce inflammatory biomarkers in patients with COPD, twelve patients using mobile phone assistance and 14 with free walk were assessed by incremental shuttle walk test (ISWT), spirometry, strength of limb muscles, and serum C-reactive protein (CRP) and inflammatory cytokines. RESULTS: Patients in the mobile phone group improved their ISWT walking distance, with decrease in serum CRP after 2 months, and sustained at 6 months. Patients in the control group had no improvement. Serum IL-8 in the mobile phone group was significantly reduced at 2, 3 and 6 months after doing home exercise training compared to baseline. IL-6 and TNF-α were significantly elevated at 3 and 6 months in control group, while there were no changes in mobile phone group. The strength of limb muscles was significantly greater compared to baseline at 3 and 6 months in the mobile phone group. CONCLUSIONS: A mobile-phone-based system can provide an efficient home endurance exercise training program with improved exercise capacity, strength of limb muscles and a decrease in serum CRP and IL-8 in COPD patients. Decreased systemic inflammation may contribute to these clinical benefits. (Clinical trial registration No.: NCT01631019).

Matrix metalloproteinase-1 polymorphism (-1607G) and disease severity in non-cystic fibrosis bronchiectasis in Taiwan.

OBJECTIVES: Bronchiectasis is characterized by an irreversible dilatation of bronchi and is associated with lung fibrosis. MMP-1 polymorphism may alter its transcriptional activity, and differentially modulate bronchial destruction and lung fibrosis. DESIGN: To investigate the association of MMP-1 polymorphisms with disease severity in non-cystic fibrosis (CF) bronchiectasis patients, 51 normal subjects and 113 patients with bronchiectasis were studied. The associations between MMP-1 polymorphisms, lung function, and disease severity evaluated by high resolution computed tomography (HRCT) were analyzed. RESULTS: The frequency of MMP-1(-1607G) allele was significantly higher in patients with bronchiectasis than normal subjects (70.8% vs 45.1%, p<0.01). Forced expiratory volume in 1 second (FEV1) was decreased in bronchiectasis patients with 1G/1G (1.2±0.1 L, n = 14) and 1G/2G (1.3±0.1 L, n = 66) genotypes compared to the 2G/2G genotype (1.7±0.1 L, n = 33, p<0.01). Six minute walking distance was decreased in bronchiectasis patients with 1G/1G and 1G/2G compared to that of 2G/2G genotype. Disease severity evaluated by HRCT score significantly increased in bronchiectasis patients with 1G/1G and 1G/2G genotypes compared to that of 2G/2G genotype. Bronchiectasis patients with at least one MMP-1 (-1607G) allele showed increased tendency for hospitalization. Serum levels of pro-MMP-1, active MMP-1 and TGF-ß1 were significantly increased in patients with bronchiectasis with 1G/1G and 1G/2G genotype compared with 2G/2G genotype or normal subjects. Under IL-1ß stimulation, peripheral blood monocytes from subjects with 1G/2G or 1G/1G genotype secreted higher levels of TGF-ß1compared to subjects with 2G/2G genotype. CONCLUSION: This is the first report to address the influence of MMP-1 polymorphisms on lung function and airway destruction in non-CF bronchiectasis patients. Bronchiectasis patients with MMP-1(-1607G) polymorphism may be more vulnerable to permanent lung fibrosis or airway destruction due to the enhanced MMP-1 and TGF-ß1 activity. Upregulated MMP-1 activity results in proteolytic destruction of matrix, and leads to subsequent fibrosis.

Exercise training with negative pressure ventilation improves exercise capacity in patients with severe restrictive lung disease: a prospective controlled study.

BACKGROUND: Exercise training is of benefit for patients with restrictive lung disease. However, it tends to be intolerable for those with severe disease. We examined whether providing ventilatory assistance by using negative pressure ventilators (NPV) during exercise training is feasible for such patients and the effects of training. METHODS: 36 patients with restrictive lung disease were prospectively enrolled for a 12-week multidisciplinary rehabilitation program. During this program, half of them (n:18; 60.3 ± 11.6 years; 6 men; FVC: 32.5 ± 11.7% predicted ) received regular sessions of exercise training under NPV, whilst the 18 others (59.6 ± 12.3 years; 8 men; FVC: 37.7 ± 10.2% predicted) did not. Exercise capacity, pulmonary function, dyspnea and quality of life were measured. The primary endpoint was the between-group difference in change of 6 minute-walk distance (6MWD) after 12 weeks of rehabilitation. RESULTS: All patients in the NPV-exercise group were able to tolerate and completed the program. The between-group differences were significantly better in the NPV-exercise group in changes of 6MWD (34.1 ± 12.7 m vs. -32.5 ± 17.5 m; P = 0.011) and St George Score (-14.5 ± 3.6 vs. 11.8 ± 6.0; P < 0.01). There was an improvement in dyspnea sensation (Borg's scale, from 1.4 ± 1.5 point to 0.8 ± 1.3 point, P = 0.049) and a small increase in FVC (from 0.85 ± 0.09 L to 0.91 ± 0.08 L, P = 0.029) in the NPV-exercise group compared to the control group. CONCLUSION: Exercise training with NPV support is feasible for patients with severe restrictive lung diseases, and improves exercise capacity and health-related quality of life.

Association Between Emphysema Score, Six-Minute Walk and Cardiopulmonary Exercise Tests in COPD.

BACKGROUND: High-resolution computed tomography (HRCT) has allowed in detection of airway wall abnormalities and emphysema, whose extent may correlate with the clinical severity of the disease in patients with chronic obstructive pulmonary disease (COPD). Six minute walk test (6MWT) and cardiopulmonary exercise test (CPET) can determine functional status. METHODS: A study was undertaken to investigate whether the extent of emphysema in COPD patients quantitatively confirmed by HRCT scoring was associated with distance walked, inspiratory capacity (IC) changes after exercise, anaerobic threshold of cardiopulmonary exercise and the BODE index (body mass index, airflow obstruction, dyspnea, exercise performance). RESULTS: Seventeen patients with COPD underwent HRCT scanning, 6MWT and CPET. The emphysema score was highly correlated to forced vital capacity (FVC) (r=-0.748, p<0.001), forced expiratory volume in 1 second (FEV1) (r=-0.615, p<0.01), IC post exercise (r=-0.663, p<0.01) and dyspnea score post exercise (r=0.609, p<0.01), but was not associated with the BODE index. The distance walked during 6MWT was inversely correlated to emphysema score (r=-0.557, p<0.05). IC before exercise was highly related to the 6MWT. The change in IC after exercise was associated with the percent decline of oxygen saturation after exercise (r=0.633, p<0.01). Severity of lung emphysema in COPD patients was inversely correlated to VO(2) max (r=-0.514, p<0.05) and anaerobic threshold (r=-0.595, p<0.01) of cardiopulmonary exercise. CONCLUSIONS: These results suggest that COPD associated with emphysema on HRCT is characterized by more severe lung function impairment, greater exercise impairment and cardiopulmonary dysfunction.

Evaluation of the feasibility of a school-based asthma management programme in Taiwan.

AIMS AND OBJECTIVES: To investigate the feasibility of a school-based asthma management programme for middle school children. BACKGROUND: Asthma rates are increasing among school-aged children. Successful asthma treatment in children depends in part on clear communication and effective education. DESIGN: This feasibility study employed a one-group only longitudinal design with four time points over 18 months. METHODS: Nineteen female and twelve male (n = 31) seventh-grade children with asthma (13 SD 0·71 years) were identified using a six-stage asthma case-finding approach. Teachers and school staff were trained in the principles and methods of the proposed school-based asthma management programme. An individualised guided asthma self-management programme was developed for each child by a clinical team at a major academic medical centre. We assisted teachers in implementing the school programme; building a support network and monitoring children's activities. Outcome measures included lung function tests (at 0, six, 12 and 18 months), disease-related symptoms, psychosocial status and impact of asthma on learning (at 0 and 18 months). School provided data on academic achievement and school absences at 0, six, 12 and 18 months. RESULTS: Significant improvements were noted at six, 12 and 18 months on forced vital capacity (FVC)% of predicted (p = 0·001, 0·015, 0·015, respectively), forced expiratory volume in one second (FEV(1) )% of predicted (p = 0·001, 0·006, 0·088, respectively) and FEV(1) /FVC% of predicted (p = 0·001, 0·015, 0·099, respectively). There was a trend towards improved asthma symptoms (p = 0·050) and a significant decrease in positive perception of curriculum (p = 0·017) at 18 months after adjustment for covariates. CONCLUSIONS: This programme was associated with respiratory benefits on physiological asthma markers commonly, with a trend for symptom control. Academic and psychosocial outcomes are subject of further inquiry. RELEVANCE TO CLINICAL PRACTICE: School-based asthma management holds promise as a feasible clinical option for middle school children with asthma in the Taiwanese school system.

Efficacy of nocturnal nasal positive pressure ventilation in hypercapnic patients with severe obstructive lung diseases.

BACKGROUND: The study objective was to investigate the efficacy of 6 months of nocturnal nasal positive pressure ventilation (NNPPV) on arterial blood gas, exercise capacity, respiratory muscle function, and the frequency of hospital admission in hypercapnic patients with severe obstructive lung diseases. METHODS: This was a prospective, randomized, controlled study. Twenty-seven patients with hypercapnic obstructive lung diseases were randomized to either the NNPPV group (N = 13) or the control group (N = 14). Arterial blood gas, exercise capacity and respiratory muscle function were measured before and after 6 months of NNPPV intervention. The number of hospital admissions and the length of stay during the 6-month period before and after NNPPV intervention were recorded. RESULTS: Subjects in the NNPPV group showed a significant reduction in arterial carbon dioxide partial pressure (PaCO2). bicarbonate (HCO3-), and base excess (BE), compared with those before intervention and of the control group. Six-minute walk distance (6MWD) also increased significantly from 232.2 +/- 79.3 m to 333.4 +/- 81.3 m in the NNPPV group after 6 months of intervention. The maximum voluntary ventilation (MVV) also increased significantly after NNPPV intervention. Moreover, the NNPPV group had significantly lower frequency of admission and fewer days of hospital stay during the intervention period compared with those before intervention and of the control group. CONCLUSION: Six months of NNPPV improved the arterial blood gas, increased exercise capacity and respiratory muscle endurance, and helped to reduce the frequency and the length of hospitalization in hypercapnic patients with severe obstructive lung disease.