Jochen J. Rüdiger

Ligand-independent Activation of the Glucocorticoid Receptor by β2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor present in most cell types. Upon ligand binding, the GR is activated and translocates into the nucleus where it transmits the anti-inflammatory actions of glucocorticoids. Here, we describe the ligand-independent activation of GR by the β2-adrenergic receptor (β2-AR) agonists, salbutamol and salmeterol, in primary human lung fibroblasts and vascular smooth muscle cells. Immunohistochemistry demonstrated expression of GR and the β2-AR by fibroblasts and vascular smooth muscle cells. Treatment of the cells with the β2-AR agonists, salbutamol or salmeterol, resulted in translocation of GR into the nucleus beginning at 30 min, as shown by immunohistochemistry and Western blotting of cytosolic and nuclear cell extracts. In comparison, activation of GR induced by the corticosteroids dexamethasone and fluticasone occurred at the same time after treatment (30 min) but resulted in a more complete depletion of GR from the cytosolic compartment. Electrophoretic mobility shift assays confirmed that nuclear GR, activated by both β2-AR agonists and glucocorticoids, actively bound to the GR consensus sequence (GR element). Functional activation of the GR was confirmed by a Luciferase reporter gene assay, using a GR driven promoter fragment from the p21(WAF1/CIP1) gene. The effects of the β2-AR agonists, salbutamol and salmeterol, were dependent upon binding to the β2-AR, because blocking of β2-AR with propranolol abrogated GR activation. GR activation appeared to involve cAMP. In summary, these data show that β2-AR agonists are potent activators of GR. Ligand-independent activation of GR by β2-AR agonists may substantially mediate the anti-inflammatory actions of these drugs observed in vitroand in vivo.

Collagenase expression and activity is modulated by the interaction of collagen types, hypoxia, and nutrition in human lung cells.

Hypoxia not only controls organogenesis, embryogenesis, and wound repair, but also triggers tumor progression and metastasis. Matrix metalloproteinases (MMP), especially gelatinases (MMP‐2, MMP‐9) regulate the composition and stability of the extracellular matrix (ECM), which affects cell proliferation, migration, and differentiation. This study investigated the effect of hypoxia alone and in combination with ECM compounds and nutrition on MMP‐2 and MMP‐9 expression, activity, and synthesis in human lung fibroblasts and pulmonary vascular smooth muscle cells (VSMC). We also determined the expression of the tissue inhibitors of MMP (TIMP‐1, ‐2). Cells were grown on plastic, collagen‐I, collagen‐IV, or gelatin and in either starving medium (0.1% serum) or growth medium (5% serum), and were subjected to normoxia or hypoxia (1% O2). Collagenases expression was determined by zymography. TIMP‐1, ‐2 expression was assessed by Western blotting and RT‐PCR. Depending on serum concentration human lung cells expressed pro‐MMP‐2 on all substrates. Hypoxia increased pro‐MMP‐2 expression, on collagen type I or type IV further via Erk1/2 and p38 MAP kinase signaling. MMP‐9 was only expressed when cells were grown on collagen type IV and increased with serum concentration, and by hypoxia. TIMP‐1 expression was only expressed when cells were grown on collagen type I and was significantly increased by hypoxia, while TIMP‐2 expression was unchanged. We demonstrated that the hypoxia, ECM composition, and nutrition, rather than one of these conditions alone, modulate the expression and activity of collagenases and their inhibitors in primary human lung fibroblasts.

Baseline Predictors of Adherence to Positive Airway Pressure Therapy for Sleep Apnea: A 10-Year Single-Center Observational Cohort Study

Background: Positive airway pressure (PAP) therapy is the standard treatment for obstructive sleep apnea syndrome (OSAS). Objectives: The aim of the current study was to determine operational long-term adherence to PAP and its predictors. Methods: In a retrospective single-center observational cohort study, we analyzed all patients referred to our center with suspected OSAS between November 2001 and November 2011. Baseline results and last follow-up data of each patient were analyzed. Kaplan-Meier estimates of adherence and Cox proportional hazard regression for age, gender, Epworth sleepiness scale (ESS) scores, body mass index, apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) were performed. Evolution of adherence was analyzed in yearly cohorts comparing the proportion of patients discontinuing PAP within 6 and 12 months. Results: Of 4,638 referrals, 2,187 confirmed OSAS patients started PAP, 297 (14%) were referred out to other centers to follow-up, 42 (2%) died, and 92 (5%) no longer needed PAP. Of 1,756 patients, the median follow-up was 36 months [95% confidence interval (CI) 33.6-37.8], and adherence at 1, 5 and 10 years was 74 (CI 71-75; n = 1,028), 55 (CI 53-58; n = 281) and 51% (CI 48-55; n = 10), respectively. Adherence is associated with ESS score [hazard ratio (HR) 0.60; CI 0.47-0.78], ODI (HR 0.50; CI 0.32-0.77) and AHI (HR 0.56; CI 0.37-0.85). In yearly cohorts according to inclusion date, the absconder rate at 6 and 12 months was 20 (CI 18-22) and 27% (CI 25-30) for the first 8 years and improved to 10 (CI 7-15) and 14% (CI 10-19) for the last 2 years, respectively. Conclusions: Long-term adherence to PAP in OSAS is associated with baseline measures of disease severity. After 2009, an improvement in the adherence rate was observed.

Fast beneficial systemic anti-inflammatory effects of inhaled budesonide and formoterol on circulating lymphocytes in asthma.

Inhaled glucocorticoids and long acting β2‐agonists reduce airway inflammation. It is unclear if this effect is based on the local action of the drugs or is due to a systemic effect on circulating peripheral blood lymphocytes. We assessed whether inhaled budesonide and/or formoterol modify the activity of circulating peripheral blood lymphocytes.

Accuracy of the Hospital Anxiety and Depression Scale for Identifying Depression in Chronic Obstructive Pulmonary Disease Patients

Psychological morbidity is common in chronic respiratory diseases. The diagnostic accuracy of the Hospital Anxiety and Depression Scale (HADS) and risk factors for comorbid depression in chronic obstructive pulmonary disease (COPD) are addressed. Consecutive COPD patients (GOLD stage I–IV, 40–75 years old) were enrolled in a multicentre, cross-sectional cohort study. Diagnosis of depression was ascertained through clinical records. Lung function, HADS score, 6-minute walking test (6-MWT), MRC dyspnoea score, and COPD Assessment Test (CAT) were evaluated. Two hundred fifty-nine COPD patients (mean age 62.5 years; 32% female; mean FEV1 48% predicted) were included. Patients diagnosed with depression (29/259; 11.2%) had significantly higher HADS-D and HADS-Total scores than nondepressed patients (median (quartiles) HADS-D 6 [4; 9] versus 4 [2; 7], median HADS-Total 14 [10; 20] versus 8 [5; 14]). Receiver-operating characteristic plots showed moderate accuracy for HADS-D, AUC 0.662 (95%CI 0.601–0.719), and HADS-Total, AUC 0.681 (95%CI 0.620–0.737), with optimal cut-off scores of >5 and >9, respectively. Sensitivity and specificity were 62.1% and 62.6% for HADS-D compared to 75.9% and 55.2% for HADS-Total. Age, comorbidities, sex, and lower airflow limitation predicted depression. The HADS exhibits low diagnostic accuracy for depression in COPD patients. Younger men with comorbidities are at increased risk for depression.

Treatment of COPD Exacerbation in Switzerland: Results and Recommendations of the European COPD Audit

Background: The European COPD Audit initiated by the European Respiratory Society (ERS) evaluated the management of hospital admissions due to exacerbation of chronic obstructive pulmonary disease (COPD) in several European countries. Data on the treatment of severe acute exacerbations of COPD (AECOPDs) in Switzerland are scarce. Objectives: In light of the GOLD 2010 guidelines, this work aims to examine the quality of care for AECOPD and to provide specific recommendations for the management of severe AECOPD in Switzerland. Methods: A total of 295 patients requiring hospital admission to 19 Swiss hospitals due to exacerbation of COPD during a predefined 60 days in 2011 were included in the study. We compared the Swiss data to the official GOLD 2010 recommendations and to the results of the other European countries. Results: Approximately 43% of the Swiss patients with severe AECOPD were current smokers at hospital admission, compared to 33% of the patients in other European countries (p < 0.001). In Switzerland and in Europe, spirometry data were not available for most patients at hospital admission (65 and 60%, respectively; p = 0.08). In comparison to other European countries, antibiotics were prescribed 14% less often in Switzerland (p < 0.001). Only 79% of the patients in the Swiss cohort received treatment with a short-acting bronchodilator at admission. Conclusions: Considering the overall high standard of health care in Switzerland, in light of the GOLD 2010 guidelines we are able to make 7 recommendations to improve and standardize the management of severe AECOPD for patients treated in Switzerland.

Transcutaneous versus blood carbon dioxide monitoring during acute noninvasive ventilation in the emergency department – a retrospective analysis

QUESTIONS UNDER STUDY Transcutaneous measurement of carbon dioxide (PtCO2) has been suggested as an alternative to invasively obtained PaCO2 for the monitoring of patients with hypercapnic respiratory failure during noninvasive ventilation (NIV). Current data on monitoring in hypoxaemic respiratory failure are scarce and show conflicting results in hypercapnic patients in the emergency department. METHODS AND SETTING We performed a retrospective comparison of real-time PtCO2 (SenTec Digital Monitor) and arterial/venous carbon dioxide tension (PaCO2/PvCO2) measurements in patients with severe hypoxaemic and/or hypercapnic respiratory failure during NIV. Agreement between PtCO2 and PaCO2/PvCO2 was the primary endpoint. Bland-Altman analysis and linear regression were used. RESULTS 102 patients had at least one matched measurement of PtCO2 and PaCO2/PvCO2. For patients with arterial blood gas analysis, the mean difference was 0.46 kPa at baseline (95% confidence interval [CI] 0.23 to 0.60, limits of agreement 95% CI -0.54 to 1.45) and 0.12 kPa after NIV (95% CI -0.04 to 0.29, limits of agreement 95% CI: -0.61 to 0.86). The linear regression analysis found a correlation R2 of 0.88 (p <0.001) at baseline and an R2 of 0.99 (p <0.001) after initiating NIV. For patients with venous blood gas analysis, the mean difference was 0.64 kPa at baseline (95% CI 0.04 to 1.24, limits of agreement 95% CI -0.72 to 2) and 0.80 kPa after NIV (95% CI 0.51 to 1.10, limits of agreement 95% CI 0.29 to 1.32), R2 0.78 (p <0.001) at baseline and R2 0.91 (p <0.001) after initiating NIV. A PaCO2/PvCO2 >8 kPa was associated with a lesser degree of agreement between the levels of PtCO2 and PaCO2/PvCO2 (p <0.001). CONCLUSION Transcutaneous PCO2 monitoring shows a good concordance with PaCO2 and is a reliable, feasible, patient-friendly and safe alternative to repeated blood gas analysis for patients with severe hypoxaemic and/or hypercapnic respiratory failure receiving emergency NIV in the emergency department. An initial blood gas analysis to evaluate the respiratory and metabolic state and to rule out a significant discrepancy compared with the transcutaneous measurement is recommended.

Erratum to: NIV by an interdisciplinary respiratory care team in severe respiratory failure in the emergency department limited to day time hours

Non-invasive ventilatory support is frequently used in patients with severe respiratory failure (SRF), but is often limited to intensive care units (ICU). We hypothesized that an instantaneous short course of NIV (up to 2 h), limited to regular working hours as an additional therapy on the emergency department (ED) would be feasible and could improve patient´s dyspnoea measured by respiratory rate and Borg visual dyspnea scale. NIV was set up by an interdisciplinary respiratory care team. Outside these predefined hours NIV was performed in the ICU. This is an observational cohort study over 1 year in the ED in a non-university hospital. Fifty-one % of medical emergencies arrived during regular working hours (5475 of 10,718 patients). In total, 63 patients were treated with instantaneous NIV. Door to NIV in the ED was 56 (31–97) min, door to ICU outside regular working hours was 84 (57–166) min. Within 1 h of NIV, the respiratory rate decreased from 30/min (25–35) to 19/min (14–24, p < 0.001), the Borg dyspnoea scale improved from 7 (5–8) to 2 (0–3, p < 0.001). In hypercapnic patients, the blood-pH increased from 7.29 (7.24–7.33) to 7.35 (7.29–7.40) and the pCO2 dropped from 8.82 (8.13–10.15) to 7.45 (6.60–8.75) kPa. In patients with SRF of varying origin, instantaneous NIV in the ED during regular working hours was feasible in a non-university hospital setting, and rapidly and significantly alleviated dyspnoea and reduced respiratory rate. This approach proved to be useful as a bridge to the ICU as well as an efficient palliative dyspnoea treatment.