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Background and Purpose: The PDE4 family is considered a prime target for therapeutic intervention in several fibro-inflammatory diseases. We have investigated the molecular mechanisms of nerandomilast (BI 1015550), a preferential PDE4B inhibitor., Experimental Approach: In addition to clinically relevant parameters of idiopathic pulmonary fibrosis (IPF; lung function measurement/high-resolution computed tomography scan/AI-Ashcroft score), whole-lung homogenates from a therapeutic male Wistar rat model of pulmonary fibrosis were analysed by next-generation sequencing (NGS). Data were matched with public domain data derived from human IPF samples to investigate how well the rat model reflected human IPF. We scored the top counter-regulated genes following treatment with nerandomilast in human single cells and validated disease markers discovered in the rat model using a human disease-relevant in vitro assay of IPF., Key Results: Nerandomilast improved the decline of lung function parameters in bleomycin-treated animals. In the NGS study, most transcripts deregulated by bleomycin treatment were normalised by nerandomilast treatment. Most notably, a significant number of deregulated transcripts that were identified in human IPF disease were also found in the animal model and reversed by nerandomilast. Mapping to single-cell data revealed the strongest effects on mesenchymal, epithelial and endothelial cell populations. In a primary human epithelial cell culture system, several disease-related (bio)markers were inhibited by nerandomilast in a concentration-dependent manner., Conclusions and Implications: This study further supports the available knowledge about the anti-inflammatory/antifibrotic mechanisms of nerandomilast and provides novel insights into the mode of action and signalling pathways influenced by nerandomilast treatment of lung fibrosis., (© 2024 Boehringer Ingelheim Pharma GmbH & Co. KG. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFβ (Transforming Growth Factor β) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.

The anti-inflammatory and immunomodulatory abilities of oral selective phosphodiesterase 4 (PDE4) inhibitors enabled the approval of roflumilast and apremilast for use in chronic obstructive pulmonary disease and psoriasis/psoriatic arthritis, respectively. However, the antifibrotic potential of PDE4 inhibitors has not yet been explored clinically. BI 1015550 is a novel PDE4 inhibitor showing a preferential enzymatic inhibition of PDE4B. In vitro , BI 1015550 inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) and phytohemagglutinin-induced interleukin-2 synthesis in human peripheral blood mononuclear cells, as well as LPS-induced TNF-α synthesis in human and rat whole blood. In vivo , oral BI 1015550 shows potent anti-inflammatory activity in mice by inhibiting LPS-induced TNF-α synthesis ex vivo and in Suncus murinus by inhibiting neutrophil influx into bronchoalveolar lavage fluid stimulated by nebulized LPS. In Suncus murinus, PDE4 inhibitors induce emesis, a well-known gastrointestinal side effect limiting the use of PDE4 inhibitors in humans, and the therapeutic ratio of BI 1015550 appeared to be substantially improved compared with roflumilast. Oral BI 1015550 was also tested in two well-known mouse models of lung fibrosis (induced by either bleomycin or silica) under therapeutic conditions, and appeared to be effective by modulating various model-specific parameters. To better understand the antifibrotic potential of BI 1015550 in vivo , its direct effect on human fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) was investigated in vitro . BI 1015550 inhibited transforming growth factor-β-stimulated myofibroblast transformation and the mRNA expression of various extracellular matrix proteins, as well as basic fibroblast growth factor plus interleukin-1β-induced cell proliferation. Nintedanib overall was unremarkable in these assays, but interestingly, the inhibition of proliferation was synergistic when it was combined with BI 1015550, leading to a roughly 10-fold shift of the concentration-response curve to the left. In summary, the unique preferential inhibition of PDE4B by BI 1015550 and its anticipated improved tolerability in humans, plus its anti-inflammatory and antifibrotic potential, suggest BI 1015550 to be a promising oral clinical candidate for the treatment of IPF and other fibro-proliferative diseases., Competing Interests: FEH, CH, LW, and PN are employees of Boehringer Ingelheim Pharma GmbH & Co. KG., (Copyright © 2022 Herrmann, Hesslinger, Wollin and Nickolaus.)

Unveiling the molecular mechanisms of tissue remodelling following injury is imperative to elucidate its regenerative capacity and aberrant repair in disease. Using different omics approaches, we identified enhancer of zester homolog 2 (EZH2) as a key regulator of fibrosis in injured lung epithelium. Epithelial injury drives an enrichment of nuclear transforming growth factor-β-activated kinase 1 (TAK1) that mediates EZH2 phosphorylation to facilitate its liberation from polycomb repressive complex 2 (PRC2). This process results in the establishment of a transcriptional complex of EZH2, RNA-polymerase II (POL2) and nuclear actin, which orchestrates aberrant epithelial repair programmes. The liberation of EZH2 from PRC2 is accompanied by an EZH2-EZH1 switch to preserve H3K27me3 deposition at non-target genes. Loss of epithelial TAK1, EZH2 or blocking nuclear actin influx attenuates the fibrotic cascade and restores respiratory homeostasis. Accordingly, EZH2 inhibition significantly improves outcomes in a pulmonary fibrosis mouse model. Our results reveal an important non-canonical function of EZH2, paving the way for new therapeutic interventions in fibrotic lung diseases., (© 2021 Boehringer Ingelheim Pharma GmbH & Co. KG. Published under the terms of the CC BY NC ND 4.0 license.)

Background: The pfm Nit-Occlud ® patent ductus arteriosus (PDA) device is well established for interventional closure of PDA. However, there are still limited data concerning its efficacy and follow-up in larger patient groups., Aims: This study aimed to evaluate the safety and efficacy of the Nit-Occlud ® PDA device, implanted both through transpulmonary and transaortic approach, in a large cohort., Methods: From July 2008 to December 2015, 268 consecutive patients were admitted for transcatheter closure of a PDA and were treated with the Nit-Occlud ® coil. Clinical, echocardiographic, and angiographic data were evaluated., Results: The median age was 5.2 years (range, 5 months to 62 years), and the median weight was 19.3 kg (range: 5.5-97 kg). Ten (3.7%) patients had weight <10 kg. The most common ductus types treated were Krichenko Type E and A (44.0% and 33.2%, respectively). Twelve (4.5%) patients were treated for residual shunting after surgical PDA closure. The median diameter at the narrowest point was 1.5 mm (range: 0.4-4 mm), the median size of the ampulla was 5 mm (range: 1-15 mm), and the median length was 9 mm (range: 2-25 mm). Device implantation could be successfully achieved in all cases. Closure rates documented immediately after the procedure, at 3-10 days, 1 month, and 6 months after intervention were 62%, 95.1%, 97.8%, and 98.5%, respectively. With the exception of one minor thromboembolic event, there were no procedure-related complications., Conclusion: Closure of PDA with various anatomic variations and sizes can be performed effectively and safely using the Nit-Occlud ® coil., Competing Interests: There are no conflicts of interest.

Background: Percutaneous pulmonary valve implantation (PPVI) numbers are rising but are still minor compared to surgery due to several contraindications. We sought to analyze the impact of PPVI compared to standard surgery in an unselected cohort with dysfunctional right ventricular outflow tract (RVOT). Reasons for PPVI failure and possible contraindications were explored., Methods: Between 2010 and 2015 all consecutive patients who underwent surgery or intervention for a dysfunctional RVOT were investigated., Results: A total of 382 cases was identified - 246 patients underwent successful valve insertion: 166 surgeries (166/246=67.4%) with 55/166 homografts (33.1%), 106 Contegra ® grafts (63.8%), 5 Hancock valves (3.0%). Overall, 70/246 patients presented a priori with an enlarged RVOT>28mm (28.5%) not appropriate for PPVI and 14/246 (5.7%) had additional defects necessitating surgery. Some 31/246 patients had surgery for initial repair of congenital defects or were too small (<20kg) for PPVI (12.6%). 80 underwent successful PPVI (32.5% of 246 valves implanted) [51 Edwards Sapien ® valves (63.7%), 29 Melody valves (36.3%)]. The RVOT was too large for PPVI in 22/246 patients (8.9%). A total 20/246 patients (8.1%) showed coronary compression after balloon interrogation. In 4/246 patients PPVI was not possible due to technical issues (1.4%)., Conclusion: PPVI could be performed successfully in 80/382 patients (20.9%). An enlarged RVOT, small patient size, and coronary compression were the major obstacles for interventional management. Future developments for larger RVOTs and smaller body weight may expand the indication for PPVI., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

With rapid progress in medicine, a thorough understanding of pharmacology remains crucial. Currently, lecturers are implementing competency-based learning objectives in medical curricula around the world. Advancing teaching modalities need to be integrated into pharmacology courses in a reasonable way. At Ludwig-Maximilians-Universität (LMU) Munich Medical Faculty, a systematic evidence-based approach was used to modernize pharmacology classes. The needs assessment was conducted by final-year students. It included focus groups and a large-scale online survey, which was distributed among all medical students at LMU, with 1018 students participating (response rate 20%). Survey results showed that most of the students (92%) aimed to become pharmacology-adept doctors. Also, a majority (88%) stated that their goal was to understand the material most critical to application of pharmacology concepts as well as prescribing practice. Only 38% of the students reported satisfaction with the current curriculum, and 93% supported modernization. Thus far, pharmacology teaching at LMU Munich had mainly consisted of lectures attended by 200 students. Now, students advocated for a stronger integration of clinical pharmacology teaching into clinical subjects in the last 2 years of medical school. Specifically, they called for classes with smaller groups of students including problem-based learning as well as video podcasts. These results provided the foundation for change in curriculum at the LMU medical school. In conclusion, a structured approach for curriculum development that considers students' views is feasible and can reveal their actual goals and demands. The approach has proven successful at LMU Munich and is transferrable to other universities., (© 2019, The American College of Clinical Pharmacology.)

Aims: Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors such as platelet derived growth factor, fibroblast growth factor and vascular endothelial growth factor. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH)., Methods and Results: Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for 3 weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization, and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular (RV) systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodelling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy, and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib., Conclusion: Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favourable effects on RV remodelling.

Background and Purpose: Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by excessive fibroblast activation ultimately leading to scarring of the lungs. Although, the activation of β 2 -adrenoceptors (β 2 -AR) has been shown to inhibit pro-fibrotic events primarily in cell lines, the role of β 2 -adrenoceptor agonists has not yet been fully characterized. The aim of our study was to explore the anti-fibrotic activity of the long-acting β 2 -adrenoceptor agonist olodaterol in primary human lung fibroblasts (HLF) and in murine models of pulmonary fibrosis., Experimental Approach: We assessed the activity of olodaterol to inhibit various pro-fibrotic mechanisms, induced by different pro-fibrotic mediators, in primary HLF from control donors and patients with IPF (IPF-LF). The in vivo anti-fibrotic activity of olodaterol, given once daily by inhalation in either a preventive or therapeutic treatment regimen, was explored in murine models of lung fibrosis induced by either bleomycin or the overexpression of TGF-β1., Key Results: In both HLF and IPF-LF, olodaterol attenuated TGF-β-induced expression of α-smooth muscle actin, fibronectin and endothelin-1 (ET-1), FGF- and PDGF-induced motility and proliferation and TGF-β/ET-1-induced contraction. In vivo olodaterol significantly attenuated the bleomycin-induced increase in lung weight, reduced bronchoalveolar lavage cell counts and inhibited release of pro-fibrotic mediators (TGF-ß, MMP-9 and tissue inhibitor of metalloproteinase-1). Forced vital capacity was increased only with the preventive treatment regimen. In the TGF-β-overexpressing model, olodaterol additionally reduced the Col3A1 mRNA expression., Conclusion and Implications: Olodaterol showed anti-fibrotic properties in primary HLF from control and IPF patients and in murine models of lung fibrosis., (© 2017 The British Pharmacological Society.)

A patient presented with a decompensated cardiomyopathy requiring invasive hemodynamic support with an Impella® heart pump. Extracorporeal life support (ECLS) became necessary during the further course and the patient was bridged to left ventricular assist device (LVAD) implantation. Postoperatively, the patient did not improve as expected due to new aortic regurgitation (AR) that was most likely caused by the previously placed Impella. A SAPIEN 3 transcatheter aortic valve was implanted as a bail-out strategy; an additional valve-in-valve rescue was required due to paravalvular regurgitation. This resulted in a restitution of valvular function and hemodynamic improvement. TAVI appears to be a valuable bail-out option for postoperative AR following LVAD implantation.

Background: After around 10% of heart transplant patients require pacemaker implantation. The bradyarrhythmias causing pacemaker requirement include sinus node dysfunction (SND) and atrioventricular block (AVB). This study sought to define clinical predictors for pacemaker requirement as well as identify differences in the patient groups developing SND and AVB., Methods: Our operative database was used to collect retrospective recipient, donor, and operative data of all patients receiving orthotopic heart transplants between 1981 and 2016., Results: In the 35-year period 1,179 transplants were performed (mean recipient age 45.5 ± 0.5 years, 20.4% female, 90.6% biatrial technique) with bradyarrhythmias requiring pacemaker implantation developing in 135 patients (11.5%). Independent risk factors were prolonged operative time 340 minutes versus 313 minutes (P = 0.027) and a biatrial anastomosis (P = 0.036). Ischemia time, cardiopulmonary bypass time, aortic cross clamp time, and reperfusion time all had no significant effect on pacemaker implantation rates. Similarly, whether the transplant was a reoperation, a retransplant, or performed after primary assist implantation had no effects on pacemaker implantation rates. There was no survival difference between the paced and nonpaced groups. The donor age was higher in the patients who developed AVB as the indication for pacemaker implantation (43 vs 34 years, P = 0.031). Patients with AVB had longer aortic cross clamp times and developed the arrhythmia later than those who developed SND., Conclusions: Use of the bicaval instead of the biatrial technique and shortened operative times should reduce pacemaker requirement after heart transplantation. Survival is not affected by this complication., (© 2017 Wiley Periodicals, Inc.)

BIBF1000 is a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) and is a powerful inhibitor of fibrogenesis. BIBF1000 is very similar to BIBF1120 (nintedanib), a drug recently approved for the treatment of idiopathic pulmonary fibrosis (IPF). A safety concern pertaining to VEGFR, FGFR, and PDGFR inhibition is the possible interference with right ventricular (RV) responses to an increased afterload, which could adversely affect clinical outcome in patients with IPF who developed pulmonary hypertension. We tested the effect of BIBF1000 on the adaptation of the RV in rats subjected to mechanical pressure overload. BIBF1000 was administered for 35 days in pulmonary artery-banded (PAB) rats. RV adaptation was assessed by echocardiography, pressure volume loop analysis, histology, and determination of atrial natriuretic peptide (ANP) expression. BIBF1000 treatment resulted in growth attenuation but had no effects on RV function after PAB, given absence of changes in cardiac index, end-systolic elastance, connective tissue disposition, and capillary density. We conclude that, in this experimental model of increased afterload, combined VEGFR, FGFR, and PDGFR inhibition does not hamper RV adaptation to pressure overload., (Copyright © 2016 the American Physiological Society.)

Background: Pathology is a discipline that provides the basis of the understanding of disease in medicine. The past decades have seen a decline in the emphasis laid on pathology teaching in medical schools and outdated pathology curricula have worsened the situation. Student opinions and thoughts are central to the questions of whether and how such curricula should be modernized., Methods: A survey was conducted among 1018 German medical students regarding their preferences in pathology teaching modalities and their satisfaction with lecture-based courses. A qualitative analysis was performed comparing a recently modernized pathology curriculum with a traditional lecture-based curriculum. The differences in modalities of teaching used were investigated., Results: Student satisfaction with the lecture-based curriculum positively correlated with student grades (spearman's correlation coefficient 0.24). Additionally, students with lower grades supported changing the curriculum (spearman's correlation coefficient 0.47). The majority supported virtual microscopy, autopsies, seminars and podcasts as preferred didactic methods., Conclusions: The data supports the implementation of a pathology curriculum where tutorials, autopsies and supplementary computer-based learning tools play important roles.

A cardiac patch is a construct devised in regenerative medicine to replace necrotic heart tissue after myocardial infarctions. The cardiac patch consists of a scaffold seeded with stem cells. To identify the best scaffold for cardiac patch construction we compared polyurethane, Collagen Cell Carriers, ePTFE, and ePTFE SSP1-RGD regarding their receptiveness to seeding with mesenchymal stem cells isolated from umbilical cord tissue. Seeding was tested at an array of cell seeding densities. The bioartificial patches were cultured for up to 35 days and evaluated by scanning electron microscopy, microscopy of histological stains, fluorescence microscopy, and mitochondrial assays. Polyurethane was the only biomaterial which resulted in an organized multilayer (seeding density: 0.750 × 10(6) cells/cm(2)). Cultured over 35 days at this seeding density the mitochondrial activity of the cells on polyurethane patches continually increased. There was no decrease in the E Modulus of polyurethane once seeded with cells. Seeding of CCC could only be realized at a low seeding density and both ePTFE and ePTFE SSP1-RGD were found to be unreceptive to seeding. Of the tested scaffolds polyurethane thus crystallized as the most appropriate for seeding with mesenchymal stem cells in the framework of myocardial tissue engineering., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Small pulmonary arteries (PAs) are often considered as a contraindication for the Fontan operation (FO). The aim of this study was to evaluate if the PA size is still one of the major impact factors on the postoperative early outcome., Methods: Data of 146 patients, with a median age of 2.0 years (range, 1.5 to 18 years) and a median weight of 12.45 kg (range, 7.7 to 64.7 kg) who underwent a modified FO in the same center between 2007 and 2012 were retrospectively analyzed with respect to the traditional McGoon ratio, Nakata index, and modified indices (measuring the narrowest diameters)., Results: Patients with a McGoon ratio of 1.6 or less (modified≤1.2) or a Nakata index of 150 mm2/m2 or less (modified≤100 mm2/m2) were not at a higher risk of longer mechanical ventilation (p=0.87 [0.1] and p=0.68 [0.52], respectively), longer stay (p=0.52 [0.18] and p=0.54 [0.38], respectively) in the intensive care unit, prolonged hospital stay (p=0.08 [0.26] and p=0.22 [0.29], respectively) or effusions (p=0.25 [0.37] and p=0.13 [0.06]), respectively). Younger and smaller children tended to have smaller PAs, but younger age (<24 months) and lower weight (<12 kg) were not predictive for poor early postoperative outcome., Conclusions: Small PAs do not significantly affect the early postoperative period after FO. In our opinion, there is no need to postpone the FO due to "smaller" PAs. The palliative procedures performed before FO to increase the size of the PA at the expense of volume overload of the single ventricle and the possible complications of prolonged cyanosis must be carefully weighed., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Dermatology fulfills the prerequisites for telemedicine. An important application of telemedicine might be the field of dermatologic consultations. In this comparative study images of skin disease were taken of 120 patients hospitalized in the University Hospitals of Tuebingen to answer the following questions: (1) are the preconditions in daily routine given for teledermatology, (2) is there adequate agreement between the diagnoses reached in dermatologic consultations and with teledermatology, and (3) can the images be utilized for teaching purposes. Patient acceptance was very good and the images captured with a digital camera were easily obtained. The results of intraobserver analysis for the two teledermatologists without any knowledge of the patients' history were 70.2% and 46.4%, respectively, and with knowledge of the history 76.6% and 64.3%. The results of interobserver analysis without any knowledge of the patients' history were 46.4% and 57.2% and with knowledge of the history 64.3% and 66%, respectively. With the reduction of the image quality, reduced reliability of the diagnoses was observed. Seven of ten images could be used for teaching purposes. It was demonstrated that in dermatology telemedicine is applicable in many, but not in all patients who are referred for dermatologic consultations.