Sequential changes of serum KL-6 predict the progression of interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is a slowly progressing fatal fibrotic lung disease with a widely variable clinical course and a poor prognosis. Clinicians and patients would benefit from a highly efficient and accurate predictor for ILD. The purpose of this study was to evaluate whether blood biomarkers can predict ILD progression. METHODS: In this study, 85 patients diagnosed as having ILD at the Guangzhou Institute of Respiratory Health participated, including 20 patients with idiopathic pulmonary fibrosis (IPF). During the mean follow-up time of 12 months, every patient was examined during four or five visits in our center. Serum samples were collected at baseline, and after 1, 2, 6, and 12 months and tested for the Klebs von den Lungen-6 (KL-6) concentration. Dynamic fluctuations in this biomarker concentration were examined using a logistic regression model to see if they reflected the progression of ILD. RESULTS: The baseline levels of serum KL-6 in the ILD patients were significantly increased compared to healthy controls. Serum KL-6 levels were significantly elevated in patients with progression of disease (1,985.2±1,497.8 vs. 1,387.6±1,313.1 µg/mL; P<0.001). Logistic regression revealed sequential changes of KL-6 was a significant predictor of ILD progression in the next follow-up (OR, 2.569; 95% CI, 2.260-2.880; P=0.001), and that sequential changes of KL-6 were significant predictors for the progression of IPF (OR, 3.611; 95% CI, 1.048-12.442; P<0.01). Baseline concentrations were not predictive for ILD or IPF. Univariate Cox analysis showed that KL-6 was significantly associated with survival [relative risk (RR), 1.901; 95% CI, 1.294-2.793; P<0.001], along with other variables. CONCLUSIONS: Serum levels of KL-6 were elevated in ILD patients with severe respiratory function compared to those without. The rate of poor prognosis and mortality was associated with increased biomarker concentrations. Sequential measurements of biomarkers could be valuable in disease monitoring and evaluations in clinical management.

Methacholine induces extracellular matrix production by human airway smooth muscle cells through ß-catenin signaling.

Altered extracellular matrix (ECM) production by airway smooth muscle cells (ASMCs) is an important feature of airway remodeling. Muscarinic receptor agonists contribute to ECM production in vivo, but the mechanisms involved remain unclear. This study attempted to investigate the role of methacholine in promoting ECM production by human ASMCs (HASMCs) and the underlying mechanism. We found that methacholine induced the expression of collagen I protein and multiple ECM genes. ß-catenin signaling was activated in this process upon GSK3ß phosphorylation, leading to upregulation of total and active ß-catenin. Silencing ß-catenin by specific small interfering RNA (siRNA) or with the ß-catenin inhibitor, PKF115-584, decreased collagen I expression. Conversely, overexpression of active ß-catenin by adenoviruses carrying the S33Y-ß-catenin mutant increased the methacholine-induced collagen I expression. Furthermore, methacholine induced TGF-ß expression in HASMCs, while pan-TGF-ß-neutralizing antibody only partially decreased collagen I expression. These findings suggest that methacholine induced ECM production through ß-catenin signaling and partially through TGF-ß.

Effects of two types of equal-intensity inspiratory muscle training in stable patients with chronic obstructive pulmonary disease: A randomised controlled trial.

PURPOSE: We conducted a randomised controlled trial to assess the effects of daily breathing pattern changes to stable patients with COPD excluding the confounding factors of inspiratory muscle mobilization, by ensuring the load intensities of two inspiratory training devices were equal. PATIENTS AND METHODS: Sixty patients with COPD were randomised to three groups: resistive-IMT group (T-IMT, 21 patients), threshold-IMT (R-IMT, 19 patients), and a control group (20 patients). Inspiratory load intensity for both methods was set at 60% of maximal inspiratory pressure (MIP), a measure of inspiratory muscle strength, which, along with health-related quality of life (HRQoL), degree of dyspnoea, and exercise capacity, were conducted before and after 8 weeks of daily IMT. RESULTS: At 8 weeks, there was no significantly difference of MIP between the R- and T-IMT groups (P > 0.05). Chronic Respiratory Disease Questionnaire and Transition Dyspnea Index scores improved significantly after each training program compared with controls (P < 0.05), and R-IMT was significant better (P < 0.05). R-IMT was better than T-IMT in performance of exercise (P < 0.05). CONCLUSIONS: In summary, in clinically stable patients with COPD, 8 weeks of R-IMT was superior to 8 weeks of equal-intensity T-IMT in improving HRQoL, degree of dyspnoea, and exercise capacity.

Transdiaphragmatic pressure and neural respiratory drive measured during inspiratory muscle training in stable patients with chronic obstructive pulmonary disease.

PURPOSE: Inspiratory muscle training (IMT) is a rehabilitation therapy for stable patients with COPD. However, its therapeutic effect remains undefined due to the unclear nature of diaphragmatic mobilization during IMT. Diaphragmatic mobilization, represented by transdiaphragmatic pressure (Pdi), and neural respiratory drive, expressed as the corrected root mean square (RMS) of the diaphragmatic electromyogram (EMGdi), both provide vital information to select the proper IMT device and loads in COPD, therefore contributing to the curative effect of IMT. Pdi and RMS of EMGdi (RMSdi%) were measured and compared during inspiratory resistive training and threshold load training in stable patients with COPD. PATIENTS AND METHODS: Pdi and neural respiratory drive were measured continuously during inspiratory resistive training and threshold load training in 12 stable patients with COPD (forced expiratory volume in 1 s ± SD was 26.1%±10.2% predicted). RESULTS: Pdi was significantly higher during high-intensity threshold load training (91.46±17.24 cmH2O) than during inspiratory resistive training (27.24±6.13 cmH2O) in stable patients with COPD, with P<0.01 for each. Significant difference was also found in RMSdi% between high-intensity threshold load training and inspiratory resistive training (69.98%±16.78% vs 17.26%±14.65%, P<0.01). CONCLUSION: We concluded that threshold load training shows greater mobilization of Pdi and neural respiratory drive than inspiratory resistive training in stable patients with COPD.

Evaluation of carbon dioxide rebreathing during exercise assisted by noninvasive ventilation with plateau exhalation valve.

Noninvasive ventilation with a plateau exhalation valve (PEV) is often used as an adjunct to exercise to achieve a physiologic training effect in severe chronic obstructive pulmonary disease (COPD) patients. However, during exercise, with the increase of exhalation flow and respiratory rate and limited capability of PEV to exhale gases out of the circuit, it is still unknown whether CO2 rebreathing occurs in COPD patients ventilated during exercise assisted by single-limb circuit with a PEV. A maximal symptom-limited cycle exercise test was performed while ventilated on pressure support (inspiratory:expiratory pressure 14:4 cmH2O) in 18 male patients with stable severe COPD (mean ± standard deviation, forced expiratory volume in 1 s: 29.5%±6.9% predicted). At rest and during exercise, breathing pattern, mean expiratory flow, mean expiratory flow of PEV, and the mean inspiratory fraction of CO2 (tidal fractional concentration of inspired CO2 [FiCO2]) reinsufflated from the circuit was measured for each breath. In comparison with rest, with the significant increase of mean expiratory flow (0.39±0.15 vs 0.82±0.27 L/s), fractional concentration of end-tidal CO2 (2.6%±0.7% vs 5.5%±0.6%), and the significant decrease of mean expiratory flow of PEV (0.41±0.02 vs 0.39±0.03 L/s), tidal FiCO2 significantly increased at peak exercise (0.48%±0.19% vs 1.8%±0.6%) in patients with stable severe COPD. The inflection point of obvious CO2 rebreathing was 0.67±0.09 L/s (95% confidence interval 0.60-0.73 L/s). Ventilated by a single-limb tubing with PEV caused CO2 rebreathing to COPD patients during exercise. Patients with mean expiratory flow >0.60-0.73 L/s may be predisposed to a higher risk of CO2 rebreathing.

Efficacy of non-invasive ventilation as a rescue therapy for relieving dyspnea in patients with stable severe COPD.

Exertional Dyspnea is a troublesome symptom in chronic obstructive pulmonary disease (COPD) even after optimal therapy, which is a physiological and perceptional burden to limit their activities. Non-invasive ventilation (NIV) might provide rescue therapy for this population to relieve exertional dyspnea. This was a randomized crossover study in 18 patients with stable severe COPD. Exertional dyspnea was induced with maximal symptom-limited incremental cycle exercise. Then the patients would randomly receive oxygen or NIV plus oxygen therapy. Patients were crossed to another therapy in the second day. During the whole process, breathing pattern were monitored continuously until complete recovery. At every 30s interval, inspiratory capacity (IC) and Borg scale were assessed. Changes were compared between two interventions. Compared with oxygen therapy, NIV plus oxygen therapy resulted in increase of tidal volume and minute ventilation, decrease in dyspnea intensity at isotime (reduction of 1.0 ± 2.0 Borg units, p < 0.05) and a tendency but not statistically significant shortening in total dyspnea recovery time (326.2 ± 132.0s vs 356.5 ± 156.9s, p = 0.225). These improvements were negatively correlated with baseline FEV1 (r = -0.617, p < 0.01). Subjects were divided into responders (n = 9) with dyspnea recovery time shortening > 30s or non-responders. Responder subgroup had significantly poorer pulmonary function in FEV1, FEV1%, IC than non-responder subgroup, indicating that NIV is effective as rescue therapy for exertional dyspnea in stable COPD with poorer pulmonary function. NIV as rescue therapy could help relieve dyspnea after exercise in patients with stable severe COPD with a poor pulmonary function.