Publications by authors named "Katharina Sinn"

18 Publications

  • Page 1 of 1

Oblique Carinal End-to-End-Anastomosis for Pig Bronchus in Organ Donor and Lung Transplant Recipient.

Ann Thorac Surg 2021 Jun 5. Epub 2021 Jun 5.

Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Pig bronchi are rare anomalies, in which the right upper lobe bronchus originates above the carina. During surgery, this can lead to technical challenges associated with the bronchial anastomosis, especially during lung transplantation. We herein report the case of a combined liver-lung transplantation with a pig bronchus in both, the organ donor and the transplant recipient. In both cases the bronchi originated slightly above the level of the carina facilitating an oblique resection and a single tracheobronchial anastomosis with a running suture. Follow-up bronchoscopy showed a completely healed anastomosis with no evidence of malacia or stenosis.
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http://dx.doi.org/10.1016/j.athoracsur.2021.05.029DOI Listing
June 2021

Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study.

Transl Lung Cancer Res 2021 Apr;10(4):1594-1607

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM).

Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome.

Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS.

Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.
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http://dx.doi.org/10.21037/tlcr-20-1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107750PMC
April 2021

Donor ventilation parameters as predictors for length of mechanical ventilation after lung transplantation: Results of a prospective multicenter study.

J Heart Lung Transplant 2021 01 28;40(1):33-41. Epub 2020 Oct 28.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: The evaluation of donor lungs heavily depends on the subjective judgment of the retrieval surgeon. As a consequence, acceptance rates vary significantly among transplant centers. We aimed to determine donor ventilation parameters in a prospective study and test if they could be used as objective quality criteria during organ retrieval.

Methods: A prospective evaluation of lung donors was performed in 3 transplant centers. Ventilation parameters were collected at the time of retrieval using a standardized ventilation protocol. Recipient length of mechanical ventilation (LMV) was defined as the primary end point, and collected data was used to build linear models predicting LMV.

Results: In total, 166 donors were included in this study. Median LMV after transplantation was 32 hours (interquartile range: 20-63 hours). Peak inspiratory pressure and dynamic compliance (C) at the time of retrieval, but not the partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio, correlated with recipient LMV in Spearman correlations (r = 0.280, p = 0.002; r = -0.245, p = 0.003; and r = 0.064, p = 0.432, respectively). Linear models were built to further evaluate the impact of donor ventilation parameters on LMV. The first model was based on donor P/F ratio, donor age, donor intubation time, donor smoking history, donor partial pressure of carbon dioxide, aspiration, chest trauma, and pathologic chest X-ray. This model performed poorly (multiple R-squared = 0.063). In a second model, donor ventilation parameters were included, and C was identified as the strongest predictor for LMV. The third model was extended by recipient factors, which significantly improved the robustness of the model (multiple R-squared = 0.293).

Conclusion: In this prospective evaluation of donor lung parameters, currently used donor quality criteria poorly predicted recipient LMV. Our data suggest that C is a strong donor-bound parameter to predict short-term graft performance; however, recipient factors are similarly relevant.
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http://dx.doi.org/10.1016/j.healun.2020.10.008DOI Listing
January 2021

Malignant pleural mesothelioma: recent developments.

Curr Opin Oncol 2021 01;33(1):80-86

Malignant Pleural Mesothelioma Program, Translational Thoracic Oncology, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Purpose Of Review: Malignant pleural mesothelioma (MPM) is a rare, but aggressive tumor with still poor prognosis. In this article, we focus on recent developments in the management of MPM including diagnosis, staging, biomarkers, and treatment strategies.

Recent Findings: Molecular markers such as programmed death-ligand 1 (PDL-1), Breast Cancer gene 1-associated protein gene, and cyclin-dependent kinase inhibitor 2A (CDKN2A) have prognostic impact and should be considered for assessment in patient samples. In addition to histological subtype and tumor pattern, tumor volumetry plays an increasing important role in staging, assessment of treatment response, and prediction of survival. Several new blood-based biomarkers have been recently reported including peripheral blood DNA methylation, microRNAs, fibulin, and high-mobility group box 1, but have not been established in clinical routine use yet. Regarding treatment, targeted therapies, immunotherapy, and vaccination are considered as new promising strategies. Moreover, extended pleurectomy/decortication is favored over extrapleural pneumonectomy (EPP) and intensity-modulated radiotherapy represents a possible approach in combination with EPP and pleurectomy/decortication. Intracavitary treatment options are promising and deserve further investigations.

Summary: Overall, there has not been a real breakthrough in the treatment of MPM. Further research and clinical trials are needed to evaluate outcome and to identify new potential treatment candidates.
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http://dx.doi.org/10.1097/CCO.0000000000000697DOI Listing
January 2021

Ventilation parameters and early graft function in double lung transplantation.

J Heart Lung Transplant 2021 01 13;40(1):4-11. Epub 2020 Oct 13.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Currently, the primary graft dysfunction (PGD) score is used to measure allograft function in the early post-lung transplant period. Although PGD grades at later time points (T48 hours and T72 hours) are useful to predict mid- and long-term outcomes, their predictive value is less relevant within the first 24 hours after transplantation. This study aimed to evaluate the capability of PGD grades to predict prolonged mechanical ventilation (MV) and compare it with a model derived from ventilation parameters measured on arrival at the intensive care unit (ICU).

Methods: A retrospective single-center analysis of 422 double lung transplantations (LTxs) was performed. PGD was assessed 2 hours after arrival at ICU, and grades were associated with length of MV (LMV). In addition, peak inspiratory pressure (P), ratio of the arterial partial pressure of oxygen to fraction of inspired oxygen (P/F ratio), and dynamic compliance (cDyn) were collected, and a logistic regression model was created. The predictive capability for prolonged MV was calculated for both (the PGD score and the model). In a second step, the created model was externally validated using a prospective, international multicenter cohort including 102 patients from the lung transplant centers of Vienna, Toronto, and Budapest.

Results: In the retrospective cohort, a high percentage of extubated patients was reported at 24 hours (35.1%), 48 hours (68.0%), and 72 hours (80.3%) after transplantation. At T0 (time point defined as 2 hours after arrival at the ICU), patients with PGD grade 0 had a shorter LMV with a median of 26 hours (interquartile range [IQR]: 16-47 hours) than those with PGD grade 1 (median: 42 hours, IQR: 27-50 hours), PGD grade 2 (median: 37.5 hours, IQR: 15.5-78.5 hours), and PGD grade 3 (median: 46 hours, IQR: 27-86 hours). However, IQRs largely overlapped for all grades, and the value of PGD to predict prolonged MV was poor. A total of 3 ventilation parameters (P, cDyn, and P/F ratio), determined at T0, were chosen on the basis of clinical reasoning. A logistic regression model including these parameters predicted prolonged MV (>72 hours) with an optimism-corrected area under the curve (AUC) of 0.727. In the prospective validation cohort, the model proved to be stable and achieved an AUC of 0.679.

Conclusions: The prediction model reported in this study combines 3 easily obtainable variables. It can be employed immediately after LTx to quantify the risk of prolonged MV, an important early outcome parameter.
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http://dx.doi.org/10.1016/j.healun.2020.10.003DOI Listing
January 2021

Prostaglandin D strengthens human endothelial barrier by activation of E-type receptor 4.

Biochem Pharmacol 2020 12 8;182:114277. Epub 2020 Oct 8.

Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Division of Pharmacology, Medical University of Graz, Graz, Austria; BioTechMed, Graz, Austria. Electronic address:

Life-threatening inflammatory conditions such as acute respiratory distress syndrome or sepsis often go hand in hand with severe vascular leakage. During inflammation, endothelial cell integrity and intact barrier function are crucial to limit leukocyte and plasma extravasation. Prostaglandin D (PGD) is a potent inflammatory lipid mediator with vasoactive properties. Previous studies suggest that PGD is involved in the regulation of endothelial barrier function; however, it is unclear whether this is also true for primary human pulmonary microvascular endothelial cells. Furthermore, as PGD is a highly promiscuous ligand, we set out to determine which receptors are important in human pulmonary endothelial cells. In the current study, we found that PGD and the DP1 agonist BW245c potently strengthened pulmonary and dermal microvascular endothelial cell barrier function and protected against thrombin-induced barrier disruption. Yet surprisingly, these effects were mediated only to a negligible extent via DP1 receptor activation. In contrast, we observed that the EP4 receptor was most important and mediated the barrier enhancement by PGD and BW245c. Stimulation with PGE or PGD reduced AKT phosphorylation which could be reversed by prior blockade of EP4 receptors. These data demonstrate a novel mechanism by which PGD may modulate inflammation and emphasizes the role of EP4 receptors in human endothelial cell function.
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http://dx.doi.org/10.1016/j.bcp.2020.114277DOI Listing
December 2020

TWIST1 Drives Smooth Muscle Cell Proliferation in Pulmonary Hypertension via Loss of GATA-6 and BMPR2.

Am J Respir Crit Care Med 2020 11;202(9):1283-1296

Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany; and.

The bHLH (basic helix-loop-helix) transcription factor TWIST1 (Twist-related protein 1) controls cell proliferation and differentiation in tissue development and disease processes. Recently, endothelial TWIST1 has been linked to pulmonary hypertension (PH) and endothelial-to-mesenchymal transition, yet the role of TWIST1 in smooth muscle cells (SMCs) remains so far unclear. To define the role of TWIST1 in SMCs in the pathogenesis of PH. SMC-specific TWIST1-deficient mice, SMC-specific TWIST1 silencing in rats, mass spectrometry, immunoprecipitation, and chromatin immunoprecipitation were used to delineate the role of SMC TWIST1 in PH. In pulmonary vessels from patients with PH and rodent PH models, TWIST1 expression was markedly increased and predominantly localized to SMCs. SMC-specific TWIST1 deficiency or silencing attenuated the development of PH and distal vessel muscularization in chronically hypoxic mice and in monocrotaline-treated rats. , TWIST1 inhibition or silencing prevented pulmonary artery SMC proliferation and migration. Mechanistically, the observed effects were mediated, at least in part, by TWIST1-dependent degradation of GATA-6 (GATA-binding protein 6). BMPR2 (bone morphogenetic protein receptor-2) was identified as a novel downstream target of GATA-6, which directly binds to its promoter. Inhibition of TWIST1 promoted the recruitment of GATA-6 to the promoter and restored BMPR2 functional expression. Our findings identify a key role for SMC TWIST1 in the pathogenesis of lung vascular remodeling and in PH that is partially mediated via reduced GATA-6-dependent expression. Inhibition of SMC TWIST1 may constitute a new therapeutic strategy for the treatment of PH.
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http://dx.doi.org/10.1164/rccm.201909-1884OCDOI Listing
November 2020

Long-term Survival After Salvage Surgery for a Giant Primary Rib Osteosarcoma.

Ann Thorac Surg 2021 01 15;111(1):e45-e47. Epub 2020 Jun 15.

Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria. Electronic address:

A 29-year-old woman with a primary rib osteosarcoma declined treatment and was readmitted 20 months later in life-threatening condition caused by major local tumor progression with severe mediastinal shifting, and without distant metastases. She underwent extended tumor resection with palliative intent and recovered well after a prolonged course with post-pneumonectomy empyema. Further treatment was declined, and she presented again 4.5 years later with local chest wall recurrence that was completely resected. Currently, 7 years after diagnosis, the patient is free from disease. In this rare case, salvage surgery was associated with an unexpected favorable long-term outcome.
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http://dx.doi.org/10.1016/j.athoracsur.2020.04.116DOI Listing
January 2021

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

The Determination of Immunomodulation and Its Impact on Survival of Rectal Cancer Patients Depends on the Area Comprising a Tissue Microarray.

Cancers (Basel) 2020 Feb 29;12(3). Epub 2020 Feb 29.

Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.

Background: T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA).

Methods: A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0-3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area.

Results: Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS.

Conclusion: Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential.
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http://dx.doi.org/10.3390/cancers12030563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139832PMC
February 2020

PDGFRα and αSMA mark two distinct mesenchymal cell populations involved in parenchymal and vascular remodeling in pulmonary fibrosis.

Am J Physiol Lung Cell Mol Physiol 2020 04 5;318(4):L684-L697. Epub 2020 Feb 5.

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

Pulmonary fibrosis is characterized by pronounced collagen deposition and myofibroblast expansion, whose origin and plasticity remain elusive. We utilized a fate-mapping approach to investigate α-smooth muscle actin (αSMA)+ and platelet-derived growth factor receptor α (PDGFRα)+ cells in two lung fibrosis models, complemented by cell type-specific next-generation sequencing and investigations on human lungs. Our data revealed that αSMA+ and PDGFRα+ cells mark two distinct mesenchymal lineages with minimal transdifferentiation potential during lung fibrotic remodeling. Parenchymal and perivascular fibrotic regions were populated predominantly with PDGFRα+ cells expressing collagen, while αSMA+ cells in the parenchyma and vessel wall showed variable expression of collagen and the contractile protein desmin. The distinct gene expression profile found in normal conditions was retained during pathologic remodeling. Cumulatively, our findings identify αSMA+ and PDGFRα+ cells as two separate lineages with distinct gene expression profiles in adult lungs. This cellular heterogeneity suggests that anti-fibrotic therapy should target diverse cell populations.
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http://dx.doi.org/10.1152/ajplung.00128.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189793PMC
April 2020

Bilateral lung transplantation on intraoperative extracorporeal membrane oxygenator: An observational study.

J Thorac Cardiovasc Surg 2020 Jul 27;160(1):320-327.e1. Epub 2019 Nov 27.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.

Objective: Intraoperative extracorporeal membrane oxygenation (ECMO) is usually reserved to support patients during complex lung transplantation. We hypothesized that a routine application of intraoperative ECMO in all patients improves primary graft function.

Methods: Patients receiving a bilateral lung transplantation between November 2016 and July 2018 at the Medical University of Vienna were included in this prospective, single-center observational study. All transplantations were uniformly performed on central venoarterial ECMO support, with the possibility to extend ECMO into the early postoperative period whenever graft function did not meet established quality criteria at the end of implantation. Primary graft dysfunction (PGD) grades were evaluated at 24, 48, and 72 hours after transplantation. Perioperative complications and survival outcome were assessed.

Results: A total of 159 patients were included in the study. At 24 hours post-transplantation, 38.4% (n = 61) of patients were already extubated, 48.4% (n = 77) were classified as PGD0, 4.4% (n = 7) as PGD1, 3.1% (n = 5) as PGD2, 2.5% (n = 4) as PGD3, and 3.1% (n = 5) were "ungradable" due to prophylactic postoperative prolongation of ECMO. At 72 hours after transplantation, 76.7% (n = 122) of the patients were extubated, as opposed to only 1.3% (n = 2) of patients classified as PGD3. The median time of mechanical ventilation was 29 hours (interquartile range, 17-58). The 90-day-mortality was 3.1%, and 2-year survival was 86%.

Conclusions: Routine use of intraoperative ECMO resulted in excellent primary graft function and mid-term outcome in patients undergoing lung transplantation. To the best of our knowledge, the herein measured PGD rates are the lowest reported in the literature to date. Our results advocate a routine intraoperative use of ECMO in bilateral lung transplantation.
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http://dx.doi.org/10.1016/j.jtcvs.2019.10.155DOI Listing
July 2020

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

Expression of FGFR1-4 in Malignant Pleural Mesothelioma Tissue and Corresponding Cell Lines and its Relationship to Patient Survival and FGFR Inhibitor Sensitivity.

Cells 2019 09 16;8(9). Epub 2019 Sep 16.

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.

Malignant pleural mesothelioma (MPM) is a devastating malignancy with limited therapeutic options. Fibroblast growth factor receptors (FGFR) and their ligands were shown to contribute to MPM aggressiveness and it was suggested that subgroups of MPM patients could benefit from FGFR-targeted inhibitors. In the current investigation, we determined the expression of all four FGFRs (FGFR1-FGFR4) by immunohistochemistry in tissue samples from 94 MPM patients. From 13 of these patients, we were able to establish stable cell lines, which were subjected to FGFR1-4 staining, transcript analysis by quantitative RT-PCR, and treatment with the FGFR inhibitor infigratinib. While FGFR1 and FGFR2 were widely expressed in MPM tissue and cell lines, FGFR3 and FGFR4 showed more restricted expression. FGFR1 and FGFR2 showed no correlation with clinicopathologic data or patient survival, but presence of FGFR3 in 42% and of FGFR4 in 7% of patients correlated with shorter overall survival. Immunostaining in cell lines was more homogenous than in the corresponding tissue samples. Neither transcript nor protein expression of FGFR1-4 correlated with response to infigratinib treatment in MPM cell lines. We conclude that FGFR3 and FGFR4, but not FGFR1 or FGFR2, have prognostic significance in MPM and that FGFR expression is not sufficient to predict FGFR inhibitor response in MPM cell lines.
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http://dx.doi.org/10.3390/cells8091091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769772PMC
September 2019

Long non-coding RNAs influence the transcriptome in pulmonary arterial hypertension: the role of PAXIP1-AS1.

J Pathol 2019 03 16;247(3):357-370. Epub 2019 Jan 16.

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

In idiopathic pulmonary arterial hypertension (IPAH), global transcriptional changes induce a smooth muscle cell phenotype characterised by excessive proliferation, migration, and apoptosis resistance. Long non-coding RNAs (lncRNAs) are key regulators of cellular function. Using a compartment-specific transcriptional profiling approach, we sought to investigate the link between transcriptional reprogramming by lncRNAs and the maladaptive smooth muscle cell phenotype in IPAH. Transcriptional profiling of small remodelled arteries from 18 IPAH patients and 17 controls revealed global perturbations in metabolic, neuronal, proliferative, and immunological processes. We demonstrated an IPAH-specific lncRNA expression profile and identified the lncRNA PAXIP1-AS1 as highly abundant. Comparative transcriptomic analysis and functional assays revealed an intrinsic role for PAXIP1-AS1 in orchestrating the hyperproliferative and migratory actions of IPAH smooth muscle cells. Further, we showed that PAXIP1-AS1 mechanistically interferes with the focal adhesion axis via regulation of expression and phosphorylation of its downstream target paxillin. Overall, we show that changes in the lncRNA transcriptome contribute to the disease-specific transcriptional landscape in IPAH. Our results suggest that lncRNAs, such as PAXIP1-AS1, can modulate smooth muscle cell function by affecting multiple IPAH-specific transcriptional programmes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900182PMC
March 2019

Docking of Meprin α to Heparan Sulphate Protects the Endothelium from Inflammatory Cell Extravasation.

Thromb Haemost 2018 Oct 20;118(10):1790-1802. Epub 2018 Sep 20.

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

Pulmonary arterial hypertension (PAH) is a rare disease characterized by increased pulmonary pressure and vascular remodelling as a consequence of smooth muscle cell proliferation, endothelial cell dysfunction and inflammatory infiltrates. Meprin α is a metalloproteinase whose substrates include adhesion and cell-cell contact molecules involved in the process of immune cell extravasation. In this study, we aimed to unravel the role of meprin α in PAH-induced vascular remodelling. Our results showed that meprin α was present in the apical membrane of endothelial cells in the lungs and pulmonary arteries of donors and idiopathic PAH (IPAH) patients. Elevated circulating meprin α levels were detected in the plasma of IPAH patients. In vitro binding assays and electron microscopy confirmed binding of meprin α to the glycocalyx of human pulmonary artery endothelial cells (hPAECs). Enzymatic and genetic approaches identified heparan sulphate (HS) as an important determinant of the meprin α binding capacity to hPAEC. Meprin α treatment protected from excessive neutrophil infiltration and the protective effect observed in the presence of neutrophils was partially reversed by removal of HS from hPAEC. Importantly, HS levels in pulmonary arteries were decreased in IPAH patients and binding of meprin α to HS was impaired in IPAH hPAEC. In summary, our results suggest a role of HS in docking meprin α to the endothelium and thus in the modulation of inflammatory cell extravasation. In IPAH, the decreased endothelial HS results in the reduction of meprin α binding which might contribute to enhanced inflammatory cell extravasation and potentially to pathological vascular remodelling.
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http://dx.doi.org/10.1055/s-0038-1670657DOI Listing
October 2018

Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis.

Eur Respir J 2018 11 22;52(5). Epub 2018 Nov 22.

Dept of Biochemistry, Universities of Giessen and Marburg Lung Center, Giessen, Germany.

Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node "extracellular matrix". We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions.
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http://dx.doi.org/10.1183/13993003.00564-2018DOI Listing
November 2018

Cartilage damage and bone erosion are more prominent determinants of functional impairment in longstanding experimental arthritis than synovial inflammation.

Dis Model Mech 2016 11 16;9(11):1329-1338. Epub 2016 Sep 16.

Medical University of Vienna, Department of Internal Medicine III, Division of Rheumatology, Vienna 1090, Austria.

Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 - the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory destructive arthritis. Our findings indicate that cartilage damage and bone erosion, but not synovial inflammation, are the most important determinants for progressive functional impairment in this chronic erosive arthritis model.
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http://dx.doi.org/10.1242/dmm.025460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117225PMC
November 2016
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