Publications by authors named "Horst Olschewski"

213 Publications

Dysbalance of ACE2 levels - a possible cause for severe COVID-19 outcome in COPD.

J Pathol Clin Res 2021 May 12. Epub 2021 May 12.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin-converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS-CoV-2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open-access RNA sequencing datasets. Immunohistochemical and single-cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme-linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS-CoV-2 infection.
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http://dx.doi.org/10.1002/cjp2.224DOI Listing
May 2021

Pulmonary Arterial Hypertension: Diagnosis, Treatment, and Novel Advances.

Am J Respir Crit Care Med 2021 Apr 16. Epub 2021 Apr 16.

Columbia University Medical Center, 21611, New York, New York, United States.

The diagnosis and management of pulmonary arterial hypertension (PAH) includes several advances, such as broader recognition of extra-pulmonary vascular organ system involvement, validated point-of-care clinical assessment tools, and a focus on early-initiation of multiple pharmacotherapeutics in appropriate patients. Indeed, a principal goal in PAH today is early diagnosis for prompt initiation of treatment to achieve minimal symptom burden, optimize the patient's biochemical, hemodynamic, and functional profile, and limit adverse events. To accomplish this end, clinicians must be familiar with novel risk factors and the revised hemodynamic definition for PAH. Fresh insights into the role of developmental biology (i.e., perinatal health) may also be useful for predicting incident PAH in early adulthood. Emergent or underutilized approaches to PAH management include a novel TGF-β ligand trap pharmacotherapy, remote pulmonary artery pressure monitoring, next-generation imaging using inert gas-based magnetic resonance and other technologies, right atrial pacing, and pulmonary artery denervation. These and other PAH state-of-the-art advances are summarized here for the wider pulmonary medicine community.
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http://dx.doi.org/10.1164/rccm.202012-4317SODOI Listing
April 2021

[Chronic obstructive pulmonary disease: the right treatment for the right patient].

Internist (Berl) 2021 Apr 16. Epub 2021 Apr 16.

Klinik für Innere Medizin, Pneumologie, Intensiv- und Schlafmedizin, Universitätsklinikum Gießen und Marburg, Standort Marburg, Baldingerstr. 1, 35033, Marburg, Deutschland.

In recent years, large treatment studies have been published in the field of chronic obstructive pulmonary disease (COPD) and were supplemented by several post-hoc analyses in 2020. The new evidence was incorporated into the 2021 update of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report. This article describes the updated fundamentals of and recommendations for the treatment of COPD. Indications for inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA), and/or long-acting beta-mimetics (LABA) will be addressed. The treatment of COPD is contrasted with that of bronchial asthma. The impact of a concomitant asthma component on the treatment strategy for COPD is also discussed. In addition, the article focuses on triple therapy with LAMA, LABA, and ICS, for which the evidence and indications are described. Bronchodilation remains the foundation of COPD therapy. For patients with clustered exacerbations, triple therapy with LAMA + LABA + ICS confers a mortality benefit. Further analysis or studies are needed to clarify whether this effect is more pronounced for specific subgroups.
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http://dx.doi.org/10.1007/s00108-021-01021-0DOI Listing
April 2021

Impact of smoking behavior on survival following allogeneic hematopoietic stem cell transplantation - smoking cessation matters.

Nicotine Tob Res 2021 Apr 10. Epub 2021 Apr 10.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz.

Introduction: There are only few data on the impact of smoking and smoking cessation on outcome of patients treated with allogeneic hematopoietic stem cell transplantation, a well established therapy for hematologic malignancies.

Methods: In a retrospective cohort study design we examined impact of smoking and smoking cessation on survival among 309 eligible consecutive adults who underwent allogeneic hematopoietic stem cell transplantation using reduced-intensity (n=179) or myeloablative (n=130) conditioning between 1999 and 2018.

Results: Smoking and was independently associated with increased mortality with a five-year overall survival of 25% in current smokers vs. 53% in never smokers vs. 48% in past smokers. Never smokers lived significantly longer (HR: 2.00, 95%CI: 1.19-3.35, p=0.008) and had a better event-free survival (HR: 2.11, 95%CI: 1.27-3.49, p=0.004) than current smokers. In the long run never smokers also lived significantly longer than past smokers (HR: 1.45, 95%CI: 1.16-1.81, p = 0.001). Patients who quit smoking prior to allogeneic hematopoietic stem cell transplantation showed a tendency towards increased survival compared to those continued smoking (HR: 1.53, 95%CI: 0.95-2.45, p = 0.078). In relation to life-time cigarette dose smokers with low-dose (1-10 pack-years) cigarette consumption lived significantly longer (HR: 1.60, 95%CI: 1.03-2.50, p=0.037) and had a better event-free survival (HR: 1.66, 95%CI: 1.07-2.58, p=0.025) than patients with high-dose (≥ 10 pack-years) cigarette consumption.

Conclusions: In allogeneic hematopoietic stem cell transplantation for hematologic malignancies, smoking history per se, life-time cigarette dose, and continued smoking, were significantly associated with increased all-cause mortality and reduced event-free survival.

Implications: Continued and past smoking represent established risk factors for malignant and non-malignant diseases, however, they are also a strong risk factor for a poor outcome after allogeneic hematopoietic stem cell transplantation for hematologic diseases. Our study shows that the hazard ratio for death after such a transplantation is doubled if patients continue smoking and even if they have quit smoking, their risk remains significantly elevated. This suggests that the smoking history provides important predictive factors for outcome of allogeneic hematopoietic stem cell transplantation and that smoking cessation should be implemented in the treatment of hematologic diseases as early as possible.
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http://dx.doi.org/10.1093/ntr/ntab070DOI Listing
April 2021

Combination Therapy in Pulmonary Arterial Hypertension-Targeting the Nitric Oxide and Prostacyclin Pathways.

J Cardiovasc Pharmacol Ther 2021 Apr 9:10742484211006531. Epub 2021 Apr 9.

Division of Cardiology, 12241Mercer University School of Medicine, Macon, GA, USA.

Pulmonary arterial hypertension (PAH) is a chronic and progressive disorder characterized by vascular remodeling of the small pulmonary arteries, resulting in elevated pulmonary vascular resistance and ultimately, right ventricular failure. Expanded understanding of PAH pathophysiology as it pertains to the nitric oxide (NO), prostacyclin (prostaglandin I) (PGI) and endothelin-1 pathways has led to recent advancements in targeted drug development and substantial improvements in morbidity and mortality. There are currently several classes of drugs available to target these pathways including phosphodiesterase-5 inhibitors (PDE5i), soluble guanylate cyclase (sGC) stimulators, prostacyclin class agents and endothelin receptor antagonists (ERAs). Combination therapy in PAH, either upfront or sequentially, has become a widely adopted treatment strategy, allowing for simultaneous targeting of more than one of these signaling pathways implicated in disease progression. Much of the current treatment landscape has focused on initial combination therapy with ambrisentan and tadalafil, an ERA and PDE5I respectively, following results of the AMBITION study demonstrating combination to be superior to either agent alone as upfront therapy. Consequently, clinicians often consider combination therapy with other drugs and drug classes, as deemed clinically appropriate, for patients with PAH. An alternative regimen that targets the NO and PGI pathways has been adopted by some clinicians as an effective and sometimes preferred therapeutic combination for PAH. Although there is a paucity of prospective data, preclinical data and results from secondary data analysis of clinical studies targeting these pathways may provide novel insights into this alternative combination as a reasonable, and sometimes preferred, alternative approach to combination therapy in PAH. This review of preclinical and clinical data will discuss the current understanding of combination therapy that simultaneously targets the NO and PGI signaling pathways, highlighting the clinical advantages and theoretical biochemical interplay of these agents.
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http://dx.doi.org/10.1177/10742484211006531DOI Listing
April 2021

The Challenge to Decide between Pulmonary Hypertension Due to Chronic Lung Disease and PAH with Chronic Lung Disease.

Authors:
Horst Olschewski

Diagnostics (Basel) 2021 Feb 15;11(2). Epub 2021 Feb 15.

Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.

Chronic lung diseases are strongly associated with pulmonary hypertension (PH), and even mildly elevated pulmonary arterial pressures are associated with increased mortality. Chronic obstructive pulmonary disease (COPD) is the most common chronic lung disease, but few of these patients develop severe PH. Not all these pulmonary pressure elevations are due to COPD, although patients with severe PH due to COPD may represent the largest subgroup within patients with COPD and severe PH. There are also patients with left heart disease (group 2), chronic thromboembolic disease (group 4, CTEPH) and pulmonary arterial hypertension (group 1, PAH) who suffer from COPD or another chronic lung disease as co-morbidity. Because therapeutic consequences very much depend on the cause of pulmonary hypertension, it is important to complete the diagnostic procedures and to decide on the main cause of PH before any decision on PAH drugs is made. The World Symposia on Pulmonary Hypertension (WSPH) have provided guidance for these important decisions. Group 2 PH or complex developmental diseases with elevated postcapillary pressures are relatively easy to identify by means of elevated pulmonary arterial wedge pressures. Group 4 PH can be identified or excluded by perfusion lung scans in combination with chest CT. Group 1 PAH and Group 3 PH, although having quite different disease profiles, may be difficult to discern sometimes. The sixth WSPH suggests that severe pulmonary hypertension in combination with mild impairment in the pulmonary function test (FEV1 > 60 and FVC > 60%), mild parenchymal abnormalities in the high-resolution CT of the chest, and circulatory limitation in the cardiopulmonary exercise test speak in favor of Group 1 PAH. These patients are candidates for PAH therapy. If the patient suffers from group 3 PH, the only possible indication for PAH therapy is severe pulmonary hypertension (mPAP ≥ 35 mmHg or mPAP between 25 and 35 mmHg together with very low cardiac index (CI) < 2.0 L/min/m), which can only be derived invasively. Right heart catheter investigation has been established nearly 100 years ago, but there are many important details to consider when reading pulmonary pressures in spontaneously breathing patients with severe lung disease. It is important that such diagnostic procedures and the therapeutic decisions are made in expert centers for both pulmonary hypertension and chronic lung disease.
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http://dx.doi.org/10.3390/diagnostics11020311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918977PMC
February 2021

Phospholipid dynamics in ex vivo lung cancer and normal lung explants.

Exp Mol Med 2021 Jan 6;53(1):81-90. Epub 2021 Jan 6.

Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, 8036, Graz, Austria.

In cancer cells, metabolic pathways are reprogrammed to promote cell proliferation and growth. While the rewiring of central biosynthetic pathways is being extensively studied, the dynamics of phospholipids in cancer cells are still poorly understood. In our study, we sought to evaluate de novo biosynthesis of glycerophospholipids (GPLs) in ex vivo lung cancer explants and corresponding normal lung tissue from six patients by utilizing a stable isotopic labeling approach. Incorporation of fully C-labeled glucose into the backbone of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidylinositol (PI) was analyzed by liquid chromatography/mass spectrometry. Lung cancer tissue showed significantly elevated isotopic enrichment within the glycerol backbone of PE, normalized to its incorporation into PI, compared to that in normal lung tissue; however, the size of the PE pool normalized to the size of the PI pool was smaller in tumor tissue. These findings indicate enhanced PE turnover in lung cancer tissue. Elevated biosynthesis of PE in lung cancer tissue was supported by enhanced expression of the PE biosynthesis genes ETNK2 and EPT1 and decreased expression of the PC and PI biosynthesis genes CHPT1 and CDS2, respectively, in different subtypes of lung cancer in publicly available datasets. Our study demonstrates that incorporation of glucose-derived carbons into the glycerol backbone of GPLs can be monitored to study phospholipid dynamics in tumor explants and shows that PE turnover is elevated in lung cancer tissue compared to normal lung tissue.
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http://dx.doi.org/10.1038/s12276-020-00547-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080582PMC
January 2021

Successful treatment of severe interstitial pneumonia by removal of circulating autoantibodies: a case series.

BMC Pulm Med 2021 Jan 6;21(1):13. Epub 2021 Jan 6.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: There is only limited clinical data on the benefit of intense immunosuppression in patients with severe interstitial pneumonia associated with autoimmune features or new-onset connective tissue disease.

Case Presentation: We here report a series of three consecutive patients suffering from severe interstitial lung disease necessitating endotracheal intubation and mechanical ventilation. The first two patients fulfilled many diagnostic criteria for new-onset antisynthetase syndrome, the third patient for systemic lupus erythematosus. We decided to implement aggressive immunosuppressive strategies in these critically-ill patients including therapeutic plasma exchange, immunoadsorption, cyclophosphamide and rituximab. All three patients improved from respiratory failure, were successfully weaned from the respirator, and eventually dismissed from hospital with ongoing immunosuppressive therapy.

Conclusion: Patients suffering from severe connective tissue disease-associated interstitial lung disease and respiratory failure may benefit from an aggressive immunosuppressive regimen and extracorporeal blood purification with rapid reduction of circulating autoantibodies. The impressive clinical responses in this small case series warrant a controlled clinical trial.
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http://dx.doi.org/10.1186/s12890-020-01386-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788864PMC
January 2021

Bayesian Inference Associates Rare Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.

Circ Genom Precis Med 2020 Dec 15. Epub 2020 Dec 15.

Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay & AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire & INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.

- Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor () gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in . Four additional PAH cases with rare likely loss-of-function variants in were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. - The Bayesian inference approach allowed us to independently validate , which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
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http://dx.doi.org/10.1161/CIRCGEN.120.003155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892262PMC
December 2020

Standardized exercise training is feasible, safe, and effective in pulmonary arterial and chronic thromboembolic pulmonary hypertension: results from a large European multicentre randomized controlled trial.

Eur Heart J 2020 Nov 24. Epub 2020 Nov 24.

Department of Cardiology, Antonio Carderelli Hospital, Naples, Italy.

Aims: This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Methods And Results: For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2  P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group.

Conclusion: This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries.
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http://dx.doi.org/10.1093/eurheartj/ehaa696DOI Listing
November 2020

[Introduction to the topic].

Authors:
Horst Olschewski

Pneumologe (Berl) 2020 19;17(6):377. Epub 2020 Nov 19.

Klinische Abteilung für Pulmonologie, Universitätsklinik für Innere Medizin, Auenbruggerplatz 15, 8036 Graz, Österreich.

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http://dx.doi.org/10.1007/s10405-020-00360-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676407PMC
November 2020

[Masterplan 2025 of the Austrian Society of Pneumology (ASP)-the expected burden and management of respiratory diseases in Austria].

Wien Klin Wochenschr 2020 Sep;132(Suppl 3):89-113

Klinik für Lungenheilkunde, Kepler Universitätsklinikum, Linz, Österreich.

Scientific Members of the Austrian Society of Pneumology describe the expected development in respiratory health and provide guidance towards patient-oriented and cost-efficient respiratory care in Austria.Methods: In November 2017, respiratory care providers (physicians, nurses, physiotherapists) together with patient's advocacy groups and experts in health development, collaborated in workshops on: respiratory health and the environment, bronchial asthma and allergy, COPD, pediatric respiratory disease, respiratory infections, sleep disorders, interventional pneumology, thoracic oncology and orphan diseases.Results: Respiratory disease is extremely prevalent and driven by ill-health behavior, i.e. cigarette smoking, over-eating and physical inactivity. For the majority of respiratory diseases increased prevalence, but decreased hospitalizations are expected.The following measures should be implemented to deal with future challenges:1. Screening and case-finding should be implemented for lung cancer and COPD.2. E-health solutions (telemedicine, personal apps) should be used to facilitate patient management.3. Regional differences in respiratory care should be reduced through E‑health and harmonization of health insurance benefits across Austria.4. Patient education and awareness, to reduce respiratory health illiteracy should be increased, which is essential for sleep disorders but relevant also for other respiratory diseases.5. Respiratory care should be inter-professional, provided via disease-specific boards beyond lung cancer (for ILDs, sleep, allergy)6. Programs for outpatient's pulmonary rehabilitation can have a major impact on respiratory health.7. Increased understanding of molecular pathways will drive personalized medicine, targeted therapy (for asthma, lung cancer) and subsequently health care costs.
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http://dx.doi.org/10.1007/s00508-020-01722-wDOI Listing
September 2020

MR 4D flow-based mean pulmonary arterial pressure tracking in pulmonary hypertension.

Eur Radiol 2021 Apr 24;31(4):1883-1893. Epub 2020 Sep 24.

Division of General Radiology, Department of Radiology, Medical University of Graz, Graz, Austria.

Objectives: Longitudinal hemodynamic follow-up is important in the management of pulmonary hypertension (PH). This study aimed to evaluate the potential of MR 4-dimensional (4D) flow imaging to predict changes in the mean pulmonary arterial pressure (mPAP) during serial investigations.

Methods: Forty-four adult patients with PH or at risk of developing PH repeatedly underwent routine right heart catheterization (RHC) and near-term MR 4D flow imaging of the main pulmonary artery. The duration of vortical blood flow along the main pulmonary artery was evaluated from MR 4D velocity fields using prototype software and converted to an MR 4D flow imaging-based mPAP estimate (mPAP) by a previously established model. The relationship of differences between RHC-derived baseline and follow-up mPAP values (ΔmPAP) to corresponding differences in mPAP (ΔmPAP) was analyzed by means of regression and Bland-Altman analysis; the diagnostic performance of ΔmPAP in predicting mPAP increases or decreases was investigated by ROC analysis.

Results: Areas under the curve for the prediction of mPAP increases and decreases were 0.92 and 0.93, respectively. With the natural cutoff ΔmPAP = 0 mmHg, mPAP increases (decreases) were predicted with an accuracy, sensitivity, and specificity of 91% (91%), 85% (89%), and 94% (92%), respectively. For patients in whom 4D flow allowed a point estimate of mPAP (mPAP > 16 mmHg), ΔmPAP correlated strongly with ΔmPAP (r = 0.91) and estimated ΔmPAP bias-free with a standard deviation of 5.1 mmHg.

Conclusions: MR 4D flow imaging allows accurate non-invasive prediction and quantification of mPAP changes in adult patients with PH or at risk of developing PH.

Trial Registration: ClinicalTrials.gov identifier: NCT00575692 and NCT01725763 KEY POINTS: • MR 4D flow imaging allows accurate non-invasive prediction of mean pulmonary arterial pressure increases and decreases in adult patients with or at risk of developing pulmonary hypertension. • In adult patients with mean pulmonary arterial pressure > 16 mmHg, MR 4D flow imaging allows estimation of longitudinal mean pulmonary arterial pressure changes without bias with a standard deviation of 5.1 mmHg.
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http://dx.doi.org/10.1007/s00330-020-07287-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979582PMC
April 2021

Exercise Pulmonary Resistances Predict Long-Term Survival in Systemic Sclerosis.

Chest 2021 Feb 12;159(2):781-790. Epub 2020 Sep 12.

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Background: Pulmonary hemodynamics during exercise may reveal early pulmonary vascular disease and may be of clinical and prognostic relevance in systemic sclerosis (SSc). We aimed to assess the prognostic relevance of exercise pulmonary resistances in patients with SSc with no or mildly increased mean pulmonary arterial pressure (mPAP).

Research Question: Are pulmonary resistances at peak exercise independent predictors of mortality in systemic sclerosis?

Study Design And Methods: All SSc patients with resting mPAP < 25 mm Hg and at least one year of follow-up data who underwent symptom-limited exercise right heart catheterization between April 2005 and December 2018 were analyzed retrospectively. Age-adjusted Cox regression analysis was used to evaluate the association between pulmonary resistances and all-cause mortality.

Results: The cohort consisted of 80 patients: 73 women and 7 men with a mean age of 57 years (interquartile range [IQR], 47-67 years) and a mean follow-up time of 10.4 years (IQR, 8.5-11.8 years). At baseline, resting mPAP of ≤ 20 mm Hg and 21 to 24 mm Hg was found in 68 and 12 patients, respectively. Pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR) at peak exercise were associated significantly with mortality (P = .006 [hazard ratio (HR), 2.20; 95% CI, 1.26-3.87] and P = .026 [HR, 1.56; 95% CI, 1.06-2.29]), whereas resting PVR and TPR were not (P = .087 [HR, 2.27; 95% CI, 0.89-5.83] and P = .079 [HR, 1.88; 95% CI, 0.93-3.80]). The mPAP per cardiac output (CO) and transpulmonary gradient (TPG) per CO slopes were associated significantly with mortality (P = .047 [HR, 1.14; 95% CI, 1.002-1.286] and P = .034 [HR, 1.34; 95% CI, 1.02-1.76]) as well. The area under the receiver operating characteristic curve for exercise PVR to predict 10-year mortality was 0.917 (95% CI, 0.797-1.000).

Interpretation: PVR and TPR at peak exercise, mPAP/CO slope, and TPG/CO slope are predictors of age-adjusted long-term mortality in SSc patients with no or mildly increased pulmonary arterial pressure.
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http://dx.doi.org/10.1016/j.chest.2020.08.2110DOI Listing
February 2021

Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries.

Cells 2020 08 28;9(9). Epub 2020 Aug 28.

Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstraße 6, 8010 Graz, Austria.

Endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (PAH). Ion channelome changes have long been connected to vascular remodeling in PAH, yet only recently has the focus shifted towards Ca-activated Cl channels (CaCC). The most prominent member of the CaCC TMEM16A has been shown to contribute to the pathogenesis of idiopathic PAH (IPAH) in pulmonary arterial smooth muscle cells, however its role in the homeostasis of healthy human pulmonary arterial endothelial cells (PAECs) and in the development of endothelial dysfunction remains underrepresented. Here we report enhanced TMEM16A activity in IPAH PAECs by whole-cell patch-clamp recordings. Using adenoviral-mediated TMEM16A increase in healthy primary human PAECs in vitro and in human pulmonary arteries ex vivo, we demonstrate the functional consequences of the augmented TMEM16A activity: alterations of Ca dynamics and eNOS activity as well as decreased NO production, PAECs proliferation, wound healing, tube formation and acetylcholine-mediated relaxation of human pulmonary arteries. We propose that the ERK1/2 pathway is specifically affected by elevated TMEM16A activity, leading to these pathological changes. With this work we introduce increased TMEM16A activity in the cell membrane of human PAECs for the development of endothelial dysfunction in PAH.
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http://dx.doi.org/10.3390/cells9091984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563136PMC
August 2020

C-Reactive Protein (CRP) Levels in Immune Checkpoint Inhibitor Response and Progression in Advanced Non-Small Cell Lung Cancer: A Bi-Center Study.

Cancers (Basel) 2020 Aug 17;12(8). Epub 2020 Aug 17.

Division of Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.

Background: Biomarkers for predicting response to immune checkpoint inhibitors (ICI) are scarce and often lack external validation. This study provides a comprehensive investigation of pretreatment C-reactive protein (CRP) levels as well as its longitudinal trajectories as a marker of treatment response and disease outcome in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy with anti PD-1 or anti PD-L1 agents.

Methods: We performed a retrospective bi-center study to assess the association between baseline CRP levels and anti PD-(L)1 treatment outcomes in the discovery cohort ( = 90), confirm these findings in an external validation cohort ( = 101) and explore the longitudinal evolution of CRP during anti PD-(L)1 treatment and the potential impact of dynamic CRP changes on treatment response and disease outcome in the discovery cohort. Joint models were implemented to evaluate the association of longitudinal CRP trajectories and progression risk. Primary treatment outcomes were progression-free survival (PFS) and overall survival (OS), while the objective response rate (ORR) was a secondary outcome, respectively.

Results: In the discovery cohort, elevated pretreatment CRP levels emerged as independent predictors of worse PFS (HR per doubling of baseline CRP = 1.37, 95% CI: 1.16-1.63, < 0.0001), worse OS (HR per doubling of baseline CRP = 1.42, 95% CI: 1.18-1.71, < 0.0001) and a lower ORR ((odds ratio (OR) of ORR per doubling of baseline CRP = 0.68, 95% CI: 0.51-0.92, = 0.013)). In the validation cohort, pretreatment CRP could be fully confirmed as a predictor of PFS and OS, but not ORR. Elevated trajectories of CRP during anti PD-(L)1 treatment (adjusted HR per 10 mg/L increase in CRP = 1.22, 95% CI: 1.15-1.30, < 0.0001), as well as a faster increases of CRP over time (HR per 10 mg/L/month faster increase in CRP levels = 13.26, 95% CI: 1.14-154.54, = 0.039) were strong predictors of an elevated progression risk, whereas an early decline of CRP was significantly associated with a reduction in PFS risk (HR = 0.91, 95% CI: 0.83-0.99, = 0.036), respectively.

Conclusion: These findings support the concept that CRP should be further explored by future prospective studies as a simple non-invasive biomarker for assessing treatment benefit during anti PD-(L)1 treatment in advanced NSCLC.
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http://dx.doi.org/10.3390/cancers12082319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464328PMC
August 2020

Distribution and prognostic significance of gluconeogenesis and glycolysis in lung cancer.

Mol Oncol 2020 11 1;14(11):2853-2867. Epub 2020 Sep 1.

Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Austria.

Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer. Abbreviated gluconeogenesis, mediated by phosphoenolpyruvate carboxykinase (PEPCK), was recently discovered to partially circumvent the need for glycolysis in lung cancer cells. However, the interplay of glycolysis and gluconeogenesis in lung cancer is still poorly understood. Here, we analyzed the expression of GLUT1, the prime glucose transporter, and of PCK1 and PCK2, the cytoplasmic and mitochondrial isoforms of PEPCK, in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays and whole tumor sections. Spatial distribution was assessed by automated image analysis. Additionally, glycolytic and gluconeogenic gene expression was inferred from The Cancer Genome Atlas (TCGA) datasets. We found that PCK2 was preferentially expressed in the lung adenocarcinoma subtype, while GLUT1 expression was higher in squamous cell carcinoma. GLUT1 and PCK2 were inversely correlated, GLUT1 showing elevated expression in larger tumors while PCK2 was highest in smaller tumors. However, a mixed phenotype showing the presence of both, glycolytic and gluconeogenic cancer cells was frequent. In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1. The metabolic tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, since PCK2 expression preferentially occurred at the tumor margin and hypoxia regulated both, glycolysis and gluconeogenesis, in NSCLC cells in vitro, albeit in opposite directions. PCK1/2 expression was enhanced in metastases compared to primary tumors, possibly related to the different environment. The results of this study show that glycolysis and gluconeogenesis are activated in NSCLC in a tumor size and oxygenation modulated manner and differentially correlate with outcome. The frequent co-activation of gluconeogenesis and glycolysis in NSCLC should be considered in potential future therapeutic strategies targeting cancer cell metabolism.
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http://dx.doi.org/10.1002/1878-0261.12780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607181PMC
November 2020

Quality of Life and Limitations in Daily Life of Stable COPD Outpatients in a Real-World Setting in Austria - Results from the CLARA Project.

Int J Chron Obstruct Pulmon Dis 2020 12;15:1655-1663. Epub 2020 Jul 12.

Department of Pulmonology, Kepler University Hospital, Linz, Austria.

Background: COPD patients suffer from respiratory symptoms and limitations in daily life. We aimed to characterize the impact of disease on overall health, daily life, and perceived well-being in COPD outpatients.

Methods: We conducted a national, cross-sectional study among pulmonologists and general practitioners (GPs). The St. George's Respiratory Questionnaire for COPD patients (SGRQ-C) was used. Inclusion criteria were a physician's diagnosis of COPD and age ≥40 years. Subjects with a history of lung surgery, lung cancer or COPD exacerbation within the last four weeks were excluded.

Results: Sixty-seven pulmonologists and 6 GPs enrolled 1175 COPD patients. Two hundred forty-eight of those did not fulfill GOLD criteria for COPD (FEV/FVC <0.7) and 77 were excluded due to missing data. Finally, 850 patients (62.8% men; mean age 66.2 ± 0.3 (SE) years; mean FEV%pred. 51.5 ± 0.6 (SE)) were analyzed. Last year, 55.4% reported at least one exacerbation, and 12.7% were hospitalized for COPD exacerbation. Mean SGRQ-C total score was 43.1 ± 0.83 (SE) and mean component scores for symptoms, activity and impacts were 55.6, 55.4 and 30.5, respectively. Half of the patients (50.3%) reported not being able to do any sports and 78.7% stated that their respiratory symptoms did not allow them doing anything they would like to do. In patients with less severe COPD (FEVpred ≥50% and non-frequent exacerbations), global health status was overrated, ie, estimated as better by the physician than by the patient, while it was underrated in more severe COPD.

Conclusion: In Austria, the burden of disease in COPD outpatients tends to be underestimated in patients with milder airway obstruction and less exacerbations and overestimated in patients with more severe airway obstruction and frequent exacerbations. Our finding suggests that validated assessment of global health status might decrease these differences of perception.
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http://dx.doi.org/10.2147/COPD.S252033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367938PMC
July 2020

Pulmonary vascular resistance and clinical outcomes in patients with pulmonary hypertension: a retrospective cohort study.

Lancet Respir Med 2020 09 27;8(9):873-884. Epub 2020 Jul 27.

Providence Veterans Affairs Medical Center, Providence, RI, USA; Division of Cardiovascular Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA.

Background: In pulmonary hypertension subgroups, elevated pulmonary vascular resistance (PVR) of 3·0 Wood units or more is associated with poor prognosis. However, the spectrum of PVR risk in pulmonary hypertension is not known. To address this area of uncertainty, we aimed to analyse the relationship between PVR and adverse clinical outcomes in pulmonary hypertension.

Methods: We did a retrospective cohort study of all patients undergoing right heart catheterisation (RHC) in the US Veterans Affairs health-care system (Oct 1, 2007-Sep 30, 2016). Patients were included in the analyses if data from a complete RHC and at least 1 year of follow-up were available. Both inpatients and outpatients were included, but individuals with missing mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure, or cardiac output were excluded. The primary outcome measure was time to all-cause mortality assessed by the Veteran Affairs vital status file. Cox proportional hazards models were used to assess the association between PVR and outcomes, and the mortality hazard ratio was validated in a RHC cohort from Vanderbilt University Medical Center (Sept 24, 1998-June 1, 2016).

Findings: The primary cohort (N=40 082; 38 751 [96·7%] male; median age 66·5 years [IQR 61·1-73·5]; median follow-up 1153 days [IQR 570-1971]), included patients with a history of heart failure (23 201 [57·9%]) and chronic obstructive pulmonary disease (13 348 [33·3%]). We focused on patients at risk for pulmonary hypertension based on a mPAP of at least 19 mm Hg (32 725 [81·6%] of 40 082). When modelled as a continuous variable, the all-cause mortality hazard for PVR was increased at around 2·2 Wood units compared with PVR of 1·0 Wood unit. Among patients with a mPAP of at least 19 mm Hg and pulmonary artery wedge pressure of 15 mm Hg or less, the adjusted hazard ratio (HR) for mortality was 1·71 (95% CI 1·59-1·84; p<0·0001) and for heart failure hospitalisation was 1·27 (1·13-1·43; p=0·0001), when comparing PVR of 2·2 Wood units or more to less than 2·2 Wood units. The validation cohort (N=3699, 1860 [50·3%] male, median age 60·4 years [49·5-69·2]; median follow-up 1752 days [IQR 1281-2999]) included 2870 patients [77·6%] with mPAP of at least 19 mm Hg (1418 [49·4%] male). The adjusted mortality HR for patients in the mPAP of 19 mm Hg or more group and with PVR of 2·2 Wood units or more and pulmonary artery wedge pressure of 15 mm or less Hg (1221 [42·5%] of 2870) was 1·81 (95% CI 1·33-2·47; p=0·0002).

Interpretation: These data widen the continuum of clinical risk for mortality and heart failure in patients referred for RHC with elevated pulmonary artery pressure to include PVR of around 2.2 Wood units and higher. Testing the generalisability of these findings in at-risk populations with fewer cardiopulmonary comorbidities is warranted.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(20)30317-9DOI Listing
September 2020

Multi-channel lung sound classification with convolutional recurrent neural networks.

Comput Biol Med 2020 07 23;122:103831. Epub 2020 May 23.

Signal Processing and Speech Communication Laboratory, Graz University of Technology, Graz, Austria.

In this paper, we present an approach for multi-channel lung sound classification, exploiting spectral, temporal and spatial information. In particular, we propose a frame-wise classification framework to process full breathing cycles of multi-channel lung sound recordings with a convolutional recurrent neural network. With our recently developed 16-channel lung sound recording device, we collect lung sound recordings from lung-healthy subjects and patients with idiopathic pulmonary fibrosis (IPF), within a clinical trial. From the lung sound recordings, we extract spectrogram features and compare different deep neural network architectures for binary classification, i.e. healthy vs. pathological. Our proposed classification framework with the convolutional recurrent neural network outperforms the other networks by achieving an F-score of F≈92%. Together with our multi-channel lung sound recording device, we present a holistic approach to multi-channel lung sound analysis.
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http://dx.doi.org/10.1016/j.compbiomed.2020.103831DOI Listing
July 2020

CDK4/6 inhibition enhances pulmonary inflammatory infiltration in bleomycin-induced lung fibrosis.

Respir Res 2020 Jul 2;21(1):167. Epub 2020 Jul 2.

Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstrasse 6/VI, 8010, Graz, Austria.

Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6) block cell cycle progression and are commonly used for treatment of several forms of cancer. Due to their anti-proliferative mode of action, we hypothesized that palbociclib could attenuate the development of bleomycin-induced lung fibrosis. In a preclinical setting, mice were treated with bleomycin and then co-treated with or without palbociclib. Lung function, collagen deposition and pulmonary inflammation were analysed after 14 days.Bleomycin treatment led to an increase of pulmonary fibrosis and inflammation, and concomitant decline of lung function. Palbociclib treatment significantly decreased collagen deposition in the lung after bleomycin treatment, but did not ameliorate lung function. Importantly, palbociclib augmented inflammatory cell recruitment (including macrophages and T cells) in the bronchoalveolar lavage fluid.This study supports the recent alert from the Food and Drug Administration (FDA) that use of CDK4/6 inhibitors, such as palbociclib, may have severe pulmonary adverse effects. Our study showing heightened pulmonary inflammation following palbociclib treatment highlights the risk of severe inflammatory adverse effects in the lung. This is of special interest in patients with known pulmonary risk factors and emphasizes the need of careful monitoring all patients treated with CDK4/6 inhibitors for signs of lung inflammation.
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http://dx.doi.org/10.1186/s12931-020-01433-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331186PMC
July 2020

Management of patients with SARS-CoV-2 infections and of patients with chronic lung diseases during the COVID-19 pandemic (as of 9 May 2020) : Statement of the Austrian Society of Pneumology (ASP).

Wien Klin Wochenschr 2020 Jul;132(13-14):365-386

Division of Paediatric Pulmonology and Allergology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34/2, 8036, Graz, Austria.

The coronavirus disease 2019 (COVID-19) pandemic is currently a challenge worldwide. In Austria, a crisis within the healthcare system has so far been prevented. The treatment of patients with community-acquired pneumonia (CAP), including SARS-CoV‑2 infections, should continue to be based on evidence-based CAP guidelines during the pandemic; however, COVID-19 specific adjustments are useful. The treatment of patients with chronic lung diseases has to be adapted during the pandemic but must still be guaranteed.
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http://dx.doi.org/10.1007/s00508-020-01691-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291190PMC
July 2020

Basement Membrane Remodeling Controls Endothelial Function in Idiopathic Pulmonary Arterial Hypertension.

Am J Respir Cell Mol Biol 2020 07;63(1):104-117

Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.

The extracellular matrix (ECM) increasingly emerges as an active driver in several diseases, including idiopathic pulmonary arterial hypertension (IPAH). The basement membrane (BM) is a specialized class of ECM proteins. In pulmonary arteries, the BM is in close contact and direct proximity to vascular cells, including endothelial cells. So far, the role of the BM has remained underinvestigated in IPAH. Here, we aimed to shed light on the involvement of the BM in IPAH, by addressing its structure, composition, and function. On an ultrastructural level, we observed a marked increase in BM thickness in IPAH pulmonary vessels. BM composition was distinct in small and large vessels and altered in IPAH. Proteoglycans were mostly responsible for distinction between smaller and larger vessels, whereas BM collagens and laminins were more abundantly expressed in IPAH. Type IV collagen and laminin both strengthened endothelial barrier integrity. However, only type IV collagen concentration dependently increased cell adhesion of both donor and IPAH-derived pulmonary arterial endothelial cells (PAECs) and induced nuclear translocation of mechanosensitive transcriptional coactivator of the hippo pathway YAP (Yes-activated protein). On the other hand, laminin caused cytoplasmic retention of YAP in IPAH PAECs. Accordingly, silencing of COL4A5 and LAMC1, respectively, differentially affected tight junction formation and barrier integrity in both donor and IPAH PAECs. Collectively, our results highlight the importance of a well-maintained BM homeostasis. By linking changes in BM structure and composition to altered endothelial cell function, we here suggest an active involvement of the BM in IPAH pathogenesis.
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http://dx.doi.org/10.1165/rcmb.2019-0303OCDOI Listing
July 2020

Pulmonary hypertension in chronic obstructive pulmonary disease.

Br J Pharmacol 2021 Jan 3;178(1):132-151. Epub 2020 Mar 3.

Cardio-Pulmonary Institute, University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.

Even mild pulmonary hypertension (PH) is associated with increased mortality and morbidity in patients with chronic obstructive pulmonary disease (COPD). However, the underlying mechanisms remain elusive; therefore, specific and efficient treatment options are not available. Therapeutic approaches tested in the clinical setting, including long-term oxygen administration and systemic vasodilators, gave disappointing results and might be only beneficial for specific subgroups of patients. Preclinical studies identified several therapeutic approaches for the treatment of PH in COPD. Further research should provide deeper insight into the complex pathophysiological mechanisms driving vascular alterations in COPD, especially as such vascular (molecular) alterations have been previously suggested to affect COPD development. This review summarizes the current understanding of the pathophysiology of PH in COPD and gives an overview of the available treatment options and recent advances in preclinical studies. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.
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http://dx.doi.org/10.1111/bph.14979DOI Listing
January 2021

Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue.

J Allergy Clin Immunol 2020 03 5;145(3):818-833.e11. Epub 2019 Dec 5.

Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE metabolism under the control of TGF-β and microRNA 218.

Objective: We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue.

Methods: In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis.

Results: We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro.

Conclusions: These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.
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http://dx.doi.org/10.1016/j.jaci.2019.11.032DOI Listing
March 2020