microRNA Expression Profile of Purified Alveolar Epithelial Type II Cells.

Alveolar type II (ATII) cells are essential for the maintenance of the alveolar homeostasis. However, knowledge of the expression of the miRNAs and miRNA-regulated networks which control homeostasis and coordinate diverse functions of murine ATII cells is limited. Therefore, we asked how miRNAs expressed in ATII cells might contribute to the regulation of signaling pathways. We purified "untouched by antibodies" ATII cells using a flow cytometric sorting method with a highly autofluorescent population of lung cells. TaqMan® miRNA low-density arrays were performed on sorted cells and intersected with miRNA profiles of ATII cells isolated according to a previously published protocol. Of 293 miRNAs expressed in both ATII preparations, 111 showed equal abundances. The target mRNAs of bona fide ATII miRNAs were used for pathway enrichment analysis. This analysis identified nine signaling pathways with known functions in fibrosis and/or epithelial-to-mesenchymal transition (EMT). In particular, a subset of 19 miRNAs was found to target 21 components of the TGF-ß signaling pathway. Three of these miRNAs (miR-16-5p, -17-5p and -30c-5p) were down-modulated by TGF-ß1 stimulation in human A549 cells, and concomitant up-regulation of associated mRNA targets (BMPR2, JUN, RUNX2) was observed. These results suggest an important role for miRNAs in maintaining the homeostasis of the TGF-ß signaling pathway in ATII cells under physiological conditions.

Oronasal versus Nasal Masks for Non-Invasive Ventilation in COPD: A Randomized Crossover Trial.

PURPOSE: The impact of oronasal and nasal masks on the quality of nocturnal non-invasive ventilation (NIV) needs to be clarified. This trial was designed to compare the impact of oronasal and nasal masks on the objective quality and subjective acceptance of nocturnal NIV in COPD-patients. PATIENTS AND METHODS: In a randomized crossover trial, 30 COPD-patients with well-established high-intensity NIV (mean inspiratory/expiratory positive airway pressure 26±3/5±1 cmH2O, mean respiratory back-up rate 17±1/min) were ventilated for two consecutive nights on oronasal and nasal masks, respectively. RESULTS: Full polysomnography, nocturnal blood gas measurements, and subjective assessments were performed. There was a tendency towards improved sleep efficiency (primary outcome) when an oronasal mask was worn (+9.9%; 95% CI:-0.2%-20.0%; P=0.054). Sleep stages 3/4 were favored by the oronasal mask (+12.7%; 95% CI: 6.0%-19.3%; P=<0.001). Subjective assessments were comparable with the exception of items related to leakage (P<0.05 in favor of nasal masks). The mean transcutaneous PCO2 value for oronasal masks (47.7±7.4 mmHg) was comparable to that of nasal masks (48.9±6.6 mmHg) (P=0.11). There was considerable diversity amongst individual patients in terms of sleep quality and gas exchange following mask exchange. Subjective mask preference was not associated with sleep quality, but with nocturnal dyspnea. Over 40% of patients subsequently switched to the mask that they were not previously accustomed to. CONCLUSION: In general, oronasal and nasal masks are each similarly capable of successfully delivering NIV in COPD-patients. However, the individual response to different interfaces is extremely heterogeneous, while subjective mask preference is independent from objective measures, but associated with dyspnea. TRIAL REGISTRATION: German Clinical Trials Registry (DRKS00007741).

Long-Term Auscultation in Chronic Obstructive Pulmonary Disease: Renaissance of an Ideograph of Medical Care.

BACKGROUND: Electronic auscultation technology has advanced dramatically in the last few years. Therefore, long-term pulmonary auscultation could provide additional information about respiratory system by monitoring acute chronic obstructive pulmonary disease (AECOPD) exacerbations or by identifying wheezing phenotypes amongst stable COPD patients. OBJECTIVES: Comparison of respiratory sounds in stable versus AECOPD patients recorded with a portable respiratory sound monitor over a period of 24 h. METHODS: This prospective trial evaluated cough and wheezing events using an auscultation monitor specially developed for this purpose with 4 integrated highly sensitive microphones, in stable and severely AECOPD patients for a period of 24 h in an inpatient setting. RESULTS: Twenty stable COPD patients (12 male, 60%) and 20 severely exacerbated COPD patients (14 male, 70%) were analyzed. In AECOPD patients, long-term auscultation revealed a significantly higher number of wheezing epochs than stable COPD patients (591 [IQR: 145-1,645] vs. 152 [IQR: 90-400]; p = 0.021). Conversely, cough epochs did not differ between AECOPD and stable COPD patients (213 [IQR: 140-327] vs. 162 [IQR: 123-243]; p = 0.256). The Borg-dyspnea scale, CAT score, and total CCQ score each showed no correlation with wheezing frequency, while CAT and CCQ scores did correlate with coughing frequency. CONCLUSION: Wheezing, but not coughing, occurs more frequently in AECOPD patients than in stable COPD patients, indicating that severe wheezing is an important clinical sign of exacerbation, while coughing is not. Therefore, the patterns of wheezing and coughing, as assessed by long-term auscultation, differ in stable versus exacerbated COPD patients.

Obesity hypoventilation syndrome treated with non-invasive ventilation: Is a switch to CPAP therapy feasible?

BACKGROUND AND OBJECTIVE: Obesity hypoventilation syndrome (OHS) can be treated with either continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) therapy; the device choice has important economic and operational implications. METHODS: This multicentre interventional trial investigated the safety and short-term efficacy of switching stable OHS patients who were on successful NIV therapy for ≥3 months to CPAP therapy. Patients underwent an autotitrating CPAP night under polysomnography (PSG); if the ensuing parameters were acceptable, they were sent home on a fixed CPAP for a 4-6-week period. It was hypothesized that blood gas analysis, PSG parameters and lung function tests would remain unchanged. RESULTS: A total of 42 OHS patients were recruited, of whom 37 patients were switched to CPAP therapy. All patients had a history of severe obstructive sleep apnoea syndrome; chronic obstructive pulmonary disease (COPD) (Global Initiative for Obstructive Lung Disease (GOLD) I/II) was present in 52%. Regarding the primary outcome, 30 of 42 patients (71%, 95% CI: 55-84%) maintained daytime partial pressure of carbon dioxide (PaCO2 ) levels ≤45 mm Hg after the home CPAP period. There was no further impairment in quality of life, sleep parameters or lung function. Interestingly, 24 patients (65%) preferred CPAP as their long-term therapy, despite the high pressure levels used (mean: 13.8 ± 1.8 mbar). After the CPAP period, 7 of 37 patients were categorized as CPAP failure, albeit only due to mild hypercapnia (mean: 47.9 ± 2.7 mm Hg). CONCLUSION: It is feasible to switch most stable OHS patients from NIV to CPAP therapy, a step that could significantly reduce health-related costs. The auto-adjusted CPAP device, used in combination with the analysis of the PSG and capnometry, is a valid titration method in OHS patients.

[Home Mechanical Ventilation in Germany]. / Außerklinische Beatmung in Deutschland.

DEVELOPMENT OF HOME MECHANICAL VENTILATION (HMV) IN GERMANY: HMV has become a well-established treatment option in Germany. However, during the last decade the number of patients established on HMV is exploding, and this has reached economical and ethical limits. Consequently, a discussion within the health policy concerning this issue is urgently needed. REVISION OF GUIDELINES: The German Respiratory Society has completely revised and thematically complemented its guidelines on HMV. Concerning the professional policy perspective, these guidelines cover essential aspects of the organisation and implementation of HMV, while simultaneously summarizing the current scientific evidence. Based on this, treatment algorithms for different entities are provided. NEW EVIDENCE FOR NON-INVASIVE VENTILATION (NIV) IN COPD: Current data provide evidence that the prognosis of COPD patients can be improved by NIV. This is true for patients with both chronic hypercapnia and persistent hypercapnia following exacerbation treated in the hospital.

[Evolving Epidemiology of Home Mechanical Ventilation: A Rapidly Growing Challenge for Patient Care]. / Epidemiologische Entwicklung der außerklinischen Beatmung: Eine rasant zunehmende Herausforderung für die ambulante und stationäre Patientenversorgung.

BACKGROUND: Home mechanical ventilation is dramatically evolving in Germany. Patients with non-invasive and invasive ventilation are increasingly treated at home. In-hospital treatment of these patients is also necessary either for control visits or the management of acute medical problems. However, the development of in-hospital patient care, morbidity and mortality of these patients is unknown. METHODS: All patients with long-term dependence on mechanical ventilation for more than three months requiring hospitalisation between 2006 and 2016 were analysed (data obtained from the Federal Statistical Office of Germany). RESULTS: There was an exponential increase in the number of in-patients with long-term dependence of mechanical ventilation. While 24 845 patients were treated in-hospital in 2006, 86 117 patients were treated in 2016. Correspondingly, mortality decreased from 13.2 % (2006) to 5.7 % (2016). In addition, in 2016 47 % of all patients were treated on the intensive care or high dependency care unit. Overall, patients had been severely ill, as there were plenty of medical and neurological co-morbidities. The most common diagnosis was COPD with 58 % of all cases, followed by several cardiology diagnosis. A high number of patients had an impairment of renal function (24 %), in part requiring dialysis. CONCLUSIONS: The rapid development of home mechanical ventilation substantially impacts on the development of the hospital landscape in Germany. The exponential increase of these care-intensive patients is challenging for the health care system and requires a discussion about its limits.

Clinical evidence for respiratory insufficiency type II predicts weaning failure in long-term ventilated, tracheotomised patients: a retrospective analysis.

BACKGROUND: Patients who require a prolonged weaning process comprise a highly heterogeneous group of patients amongst whom the outcome differs significantly. The present study aimed to identify the factors that predict whether the outcome for prolonged weaning will be successful or unsuccessful. METHODS: Data from tracheotomised patients who underwent prolonged weaning on a specialised weaning unit were assessed retrospectively via an electronic and paper-bound patient chart. Factors for weaning success were analysed by univariate and multivariate analyses. RESULTS: Out of the 124 patients examined, 48.4% were successfully weaned (n = 60). Univariate analysis revealed that long-term home mechanical ventilation prior to current weaning episode; time between intubation and the first spontaneous breathing trial (SBT); time between intubation and the first SBT of less than 30 days; lower PaCO2 prior to, and at the end of, the first SBT; and lower pH values at the end of the first SBT were predictors for successful weaning. Following multivariate analysis, the absence of home mechanical ventilation prior to admission, a maximum time period of 30 days between intubation and the first SBT, and a non-hypercapnic PaCO2 value at the end of the first SBT were predictive of successful weaning. CONCLUSIONS: The current analysis demonstrates that the evidence for respiratory insufficiency type II provided by clinical findings serves as a predictor of weaning failure.

Home noninvasive ventilatory support for patients with chronic obstructive pulmonary disease: patient selection and perspectives.

Long-term or home mechanical noninvasive ventilation (Home-NIV) has become a well-established form of therapy over the last few decades for chronic hypercapnic COPD patients in European countries. However, meta-analyses and clinical guidelines do not recommend Home-NIV for COPD patients on a routine basis. In particular, there is ongoing debate about Home-NIV in chronic hypercapnic COPD regarding the overall effects, the most favorable treatment strategy, the selection of eligible patients, and the time point at which it is prescribed. The current review focuses on specific aspects of patient selection and discusses the various scientific as well as clinical-guided perspectives on Home-NIV in patients suffering from chronic hypercapnic COPD. In addition, special attention will be given to the topic of ventilator settings and interfaces.

Is Outpatient Control of Long-Term Non-Invasive Ventilation Feasible in Chronic Obstructive Pulmonary Disease Patients?

BACKGROUND: Long-term non-invasive ventilation (NIV) is an established and increasingly used treatment option for patients with chronic hypercapnic chronic obstructive pulmonary disease (COPD). Following inpatient NIV establishment, inpatient control visits regularly occur thereafter. However, it remains unclear whether such control visits can also be performed in an outpatient setting, which, in turn, would reduce costs, patient burden and the complications related to hospitalization. OBJECTIVES: To investigate an outpatient setting with predefined criteria for hospitalization for patients with chronic hypercapnic COPD. METHODS: An outpatient clinic located within the hospital in the vicinity of the respiratory care unit provided predefined criteria for hospitalization of COPD patients receiving long-term NIV therapy. The results of this setting were retrospectively analysed. RESULTS: A total of 130 outpatient visits (80 patients) were analysed. In 93 cases (71.5%), hospital admission was not necessary, while hospitalization was performed in 37 cases (28.5%). Out of these, 7 cases with acute conditions required prompt hospitalization. Patients without hospitalization had better PaCO2 values (45.40 ± 5.27 vs. 50.05 ± 8.04, p = 0.002) and Severe Respiratory Insufficiency Questionnaire Summary scores (55.54 ± 19.74 vs. 41.82 ± 19.59, p = 0.012). CONCLUSION: Outpatient control of long-term NIV in a hospital setting is feasible and has the capacity to identify stable COPD patients in whom NIV therapy is sufficient according to predefined criteria. These patients may not require hospitalization and may account for more than two thirds of cases.

Capillary PO2 does not adequately reflect arterial PO2 in hypoxemic COPD patients.

PURPOSE: To compare arterial (PaO2) with capillary (PcO2) partial pressure of oxygen in hypoxemic COPD patients because capillary blood gas analysis (CBG) is increasingly being used as an alternative to arterial blood gas analysis (ABG) in a non-intensive care unit setting, although the agreement between PcO2 and PaO2 has not been evaluated in hypoxemic COPD patients. PATIENTS AND METHODS: Bland-Altman comparison of PaO2 and PcO2 served as the primary outcome parameter if PcO2 values were ≤60 mmHg and the secondary outcome parameter if PcO2 values were ≤55 mmHg. Pain associated with the measurements was assessed using a 100-mm visual analog scale. RESULTS: One hundred and two PaO2/PcO2 measurement pairs were obtained. For PcO2 values ≤60 mmHg, the mean difference between PaO2 and PcO2 was 5.99±6.05 mmHg (limits of agreement: -5.88 to 17.85 mmHg). For PcO2 values ≤55 mmHg (n=73), the mean difference was 5.33±5.52 mmHg (limits of agreement: -5.48 to 16.15 mmHg). If PaO2 ≤55 (≤60) mmHg was set as the cut-off value, in 20.6% (30.4%) of all patients, long-term oxygen therapy have been unnecessarily prescribed if only PcO2 would have been assessed. ABG was rated as more painful compared with CBG. CONCLUSIONS: PcO2 does not adequately reflect PaO2 in hypoxemic COPD patients, which can lead to a relevant number of unnecessary long-term oxygen therapy prescriptions.

Interfaces and ventilator settings for long-term noninvasive ventilation in COPD patients.

INTRODUCTION: The establishment of high-intensity (HI) noninvasive ventilation (NIV) that targets elevated PaCO2 has led to an increase in the use of long-term NIV to treat patients with chronic hypercapnic COPD. However, the role of the ventilation interface, especially in more aggressive ventilation strategies, has not been systematically assessed. METHODS: Ventilator settings and NIV compliance were assessed in this prospective cross-sectional monocentric cohort study of COPD patients with pre-existing NIV. Daytime arterialized blood gas analyses and lung function testing were also performed. The primary end point was the distribution among study patients of interfaces (full-face masks [FFMs] vs nasal masks [NMs]) in a real-life setting. RESULTS: The majority of the 123 patients studied used an FFM (77%), while 23% used an NM. Ventilation settings were as follows: mean ± standard deviation (SD) inspiratory positive airway pressure (IPAP) was 23.2±4.6 mbar and mean ± SD breathing rate was 16.7±2.4/minute. Pressure support ventilation (PSV) mode was used in 52.8% of patients, while assisted pressure-controlled ventilation (aPCV) was used in 47.2% of patients. Higher IPAP levels were associated with an increased use of FFMs (IPAP <21 mbar: 73% vs IPAP >25 mbar: 84%). Mean compliance was 6.5 hours/day, with no differences between FFM (6.4 hours/day) and NM (6.7 hours/day) users. PaCO2 assessment of ventilation quality revealed comparable results among patients with FFMs or NMs. CONCLUSION: This real-life trial identified the FFM as the predominantly used interface in COPD patients undergoing long-term NIV. The increased application of FFMs is, therefore, likely to be influenced by higher IPAP levels, which form part of the basis for successful application of HI-NIV in clinical practice.

Continuous non-invasive PCO2 monitoring in weaning patients: Transcutaneous is advantageous over end-tidal PCO2.

BACKGROUND AND OBJECTIVE: Continuous partial pressure of carbon dioxide (PCO2 ) assessment is essential for the success of mechanical ventilation (MV). Non-invasive end-tidal PCO2 (PetCO2 ) and transcutaneous PCO2 (PtcCO2 ) measurements serve as alternatives to the gold standard arterial PCO2 (PaCO2 ) method, but their eligibility in critical care is unclear. METHODS: The present study therefore performed methodological comparisons of PaCO2 versus PetCO2 and PtcCO2 , respectively, in weaning patients receiving invasive MV via tracheal cannulas. PetCO2 and PtcCO2 were recorded continuously, while PaCO2 was analysed at baseline, and after 30 and 60 min. Using the Bland-Altman analysis, a clinically acceptable range was defined as a mean difference of ±4 mm Hg between PaCO2 and non-invasive strategies. RESULTS: A total of 60 patients (COPD (n = 30) and non-COPD (n = 30)) completed the protocol. Mean PCO2 values were 42.4 ± 8.6 mm Hg (PaCO2 ), 36.5 ± 7.5 mm Hg (PetCO2 ) and 41.7 ± 8.7 mm Hg (PtcCO2 ). Mean differences between PtcCO2 and PaCO2 were -0.7 ± 3.6 mm Hg (95% CI: -1.6/0.3 mm Hg; 95% limits of agreement: -7.8 to 6.4 mm Hg), and between PetCO2 and PaCO2 -5.9 ± 5.3 mm Hg (95% CI: -7.2/-4.5 mm Hg; 95% limits of agreement: -16.2 to 4.5 mm Hg). Underestimation of PaCO2 by PetCO2 was most pronounced in COPD patients. CONCLUSION: Our data therefore support PtcCO2 as a suitable means for monitoring PCO2 in patients undergoing invasive MV. This is in contrast to PetCO2 , which clearly underestimated PaCO2 , especially in patients with COPD.

Impact of High-Intensity-NIV on the heart in stable COPD: a randomised cross-over pilot study.

BACKGROUND: Although high-intensity non-invasive ventilation has been shown to improve outcomes in stable COPD, it may adversely affect cardiac performance. Therefore, the aims of the present pilot study were to compare cardiac and pulmonary effects of 6 weeks of low-intensity non-invasive ventilation and 6 weeks of high-intensity non-invasive ventilation in stable COPD patients. METHODS: In a randomised crossover pilot feasibility study, the change in cardiac output after 6 weeks of each NIV mode compared to baseline was assessed with echocardiography in 14 severe stable COPD patients. Furthermore, CO during NIV, gas exchange, lung function, and health-related quality of life were investigated. RESULTS: Three patients dropped out: two deteriorated on low-intensity non-invasive ventilation, and one presented with decompensated heart failure while on high-intensity non-invasive ventilation. Eleven patients were included in the analysis. In general, cardiac output and NTproBNP did not change, although individual effects were noticed, depending on the pressures applied and/or the co-existence of heart failure. High-intensity non-invasive ventilation tended to be more effective in improving gas exchange, but both modes improved lung function and the health-related quality of life. CONCLUSIONS: Long-term non-invasive ventilation with adequate pressure to improve gas exchange and health-related quality of life did not have an overall adverse effect on cardiac performance. Nevertheless, in patients with pre-existing heart failure, the application of very high inspiratory pressures might reduce cardiac output. TRIAL REGISTRATION: The trial was registered in the Deutsches Register Klinischer Studien (DRKS-ID: DRKS00007977 ).

Long-Term Oxygen Therapy: Comparison of the German and British Guidelines.

BACKGROUND: The German guideline on long-term oxygen therapy (LTOT) was published in 2008 by the German Respiratory Society (DGP), while the British Thoracic Society (BTS) published their most recent guideline in 2015. OBJECTIVES: The aim of the present article was to highlight the major areas of consensus and disagreement in the recently published BTS and DGP guidelines on LTOT. METHODS: The BTS and DGP guidelines were directly compared in terms of congruencies and differences. A critical appraisal was then performed and authors' suggestions were provided. RESULTS: The 2 guidelines are almost congruent in 2 major areas, namely, (1) the indication criteria for LTOT in chronic obstructive pulmonary disease (COPD) patients at rest and (2) the recommended duration of LTOT over a 24-h period. However, 8 major areas in which the guidelines differ considerably were identified: (1) techniques for blood gas analysis; (2) timing of LTOT in stable patients; (3) LTOT in post-exacerbation COPD patients; (4) ambulatory oxygen therapy; (5) nocturnal oxygen therapy; (6) titration of oxygen flow rates; (7) follow-up visits; and (8) LTOT for patients who still smoke. Furthermore, the BTS guideline is much more detailed, includes more references (161 vs. 71) and is more up to date than the DGP guideline. CONCLUSION: There are major differences between the 2 guidelines. Many of the aspects raised by the BTS guideline appear to be reasonable with regard to the current literature, clinical experience and prescription practices. However, an international consensus on LTOT is lacking.

Impact of Pseudomonas aeruginosa Infection on Respiratory Muscle Function in Adult Cystic Fibrosis Patients.

BACKGROUND: Pseudomonas aeruginosa infection impairs respiratory muscle function in adolescents with cystic fibrosis, but its impact on adult patients has not been characterised. OBJECTIVES: To investigate respiratory muscle function in adult cystic fibrosis patients according to P. aeruginosa status (repetitive samples over 12 months). METHODS: The pressure-time index of the respiratory muscles (PTImus), a measure of their efficiency, served as the primary outcome. In addition, respiratory load and maximal respiratory muscle strength were assessed. RESULTS: In 51 patients examined (65% female; median age 32 years, IQR 24-40), a median of 3.0 (IQR 2-4) different pathogens was found in each patient. The PTImus was 0.113 and 0.126 in Pseudomonas-positive (n = 33) and -negative (n = 18) patients, respectively (p = 0.53). Univariate analysis showed a lower PTImus in male than in female patients (p = 0.006). Respiratory muscle load and strength were otherwise comparable, with the exception of higher nasal sniff pressures in Pseudomonas-positive patients who were chronically infected (>50% of positive samples). Quality of Life (according to the Cystic Fibrosis Questionnaire-Revised) was higher if both respiratory load and the PTImus were low (high respiratory muscle efficiency). CONCLUSIONS: Chronic P. aeruginosa infection does not influence respiratory muscle efficiency in adult cystic fibrosis patients with otherwise multiple co-infections. In addition, patients with reduced respiratory muscle efficiency had worse Quality of Life.

Augmentation of the effects of vasoactive intestinal peptide aerosol on pulmonary hypertension via coapplication of a neutral endopeptidase 24.11 inhibitor.

A deficiency of the pulmonary vasodilative vasoactive intestinal peptide (VIP) has been suggested to be involved in the pathophysiology of pulmonary hypertension (PH). Supplementation of VIP as an aerosol is hampered by the fact that it is rapidly inactivated by neutral endopeptidases (NEP) located on the lung surface. Coapplication of thiorphan, an NEP 24.11 inhibitor, could augment the biological effects of inhaled VIP alone. A stable pulmonary vasoconstriction with a threefold increase of pulmonary artery pressure was established by application the thromboxane mimetic U46619 in the isolated rabbit lung model. VIP and thiorphan were either applied intravascularly or as an aerosol. VIP caused a significant pulmonary vasodilation either during intravascular application or inhalation. These effects were of short duration. Thiorphan application had no effects on pulmonary vasoconstriction per se but significantly augmented the effects of VIP aerosol. Thiorphan, not only augmented the maximum hemodynamic effects of VIP aerosol, but also led to a significant prolongation of these effects. VIP causes pulmonary vasodilation in a model of acute experimental PH. The hemodynamic effects of VIP aerosol can be significantly augmented via coapplication of an NEP inhibitor.

Activation of the WNT/ß-catenin pathway attenuates experimental emphysema.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. OBJECTIVES: To characterize WNT/ß-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. METHODS: The expression, localization, and activity of WNT/ß-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. The role of WNT/ß-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild-type mice in vivo. MEASUREMENTS AND MAIN RESULTS: No differences in the mRNA expression profile of the main WNT/ß-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear ß-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/ß-catenin signaling was down-regulated in both experimental emphysema models. Preventive and therapeutic, WNT/ß-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. CONCLUSIONS: Decreased WNT/ß-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/ß-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/ß-catenin activation as a future therapeutic approach for emphysema.