Publications by authors named "Werner Seeger"

619 Publications

Myeloid cell-specific deletion of inducible nitric oxide synthase protects against smoke-induced pulmonary hypertension in mice.

Eur Respir J 2021 Sep 2. Epub 2021 Sep 2.

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

Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), associated with increased mortality and morbidity. Intriguingly, pulmonary vascular alterations have been suggested to drive emphysema development. We previously identified inducible nitric oxide synthase (iNOS) as an essential enzyme for development and reversal of smoke-induced PH and emphysema, and showed that iNOS expression in bone-marrow-derived cells drives pulmonary vascular remodelling, but not parenchymal destruction. In this study, we aimed to identify the iNOS-expressing cell type driving smoke-induced PH and to decipher pro-proliferative pathways involved.To address this question we used 1) myeloid cell-specific iNOS knockout mice in chronic smoke exposure, 2) co-cultures of macrophages and pulmonary artery smooth muscle cells (PASMC) to decipher underlying signalling pathways.Myeloid cell-specific iNOS knockout prevented smoke-induced PH but not emphysema in mice. Moreover, iNOS deletion in myeloid cells ameliorated the increase in expression of CD206, a marker of M2 polarisation, on interstitial macrophages. Importantly, the observed effects on lung macrophages were hypoxia-independent, as these mice developed hypoxia-induced PH. , smoke-induced PASMC proliferation in co-cultures with M2-polarised macrophages could be abolished by iNOS deletion in phagocytic cells, as well as by ERK inhibition in PASMC. Crucially, CD206-positive and iNOS-positive macrophages accumulated in proximity of remodelled vessels in the lungs of COPD patients, as shown by immunohistochemistry.In summary, our results demonstrate that iNOS deletion in myeloid cells confers protection against PH in smoke-exposed mice and provide evidence for an iNOS-dependent communication between M2-like macrophages and PASMC in underlying pulmonary vascular remodelling.
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http://dx.doi.org/10.1183/13993003.01153-2021DOI Listing
September 2021

Reply to: Pulmonary Hypertension: A Predictor of Lung Cancer Prognosis?

Am J Respir Crit Care Med 2021 Sep 2. Epub 2021 Sep 2.

Max Planck Institute for Heart and Lung Research, Molecular Mechanisms in Lung Cancer, Bad Nauheim, Germany.

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http://dx.doi.org/10.1164/rccm.202106-1411LEDOI Listing
September 2021

Macrophage-derived IL-6 trans-signaling as a novel target in the pathogenesis of bronchopulmonary dysplasia.

Eur Respir J 2021 Aug 26. Epub 2021 Aug 26.

Department of Pediatric and Adolescent Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Translational Experimental Pediatrics - Experimental Pulmonology, Koln, Germany

Rationale: Premature infants exposed to oxygen are at risk for bronchopulmonary dysplasia (BPD), which is characterised by lung growth arrest. Inflammation is important, but the mechanisms remain elusive. Here, we investigated inflammatory pathways and therapeutic targets in severe clinical and experimental BPD.

Methods And Results: First, transcriptomic analysis with cellular deconvolution identified a lung-intrinsic M1-like-driven cytokine pattern in newborn mice after hyperoxia. These findings were confirmed by gene expression of macrophage-regulating chemokines (, , ) and markers (, , ). Second, hyperoxia-activated IL-6/STAT3 signaling was measured and related to loss of alveolar epithelial type II cells (ATII) as well as increased mesenchymal marker. null mice exhibited preserved ATII survival, reduced myofibroblasts and improved elastic fiber assembly, thus enabling lung growth and protecting lung function. Pharmacological inhibition of global IL-6 signaling and IL-6 trans-signaling promoted alveolarisation and ATII survival after hyperoxia. Third, hyperoxia triggered M1-like polarisation, possibly Klf4; hyperoxia-conditioned medium of macrophages and IL-6 impaired ATII proliferation. Finally, clinical data demonstrate elevated macrophage-related plasma cytokines as potential biomarkers that identify infants receiving oxygen at increased risk of developing BPD. Moreover, macrophage-derived and active STAT3 were related to loss of epithelial cells in BPD lungs.

Conclusion: We present a novel IL-6-mediated mechanism by which hyperoxia activates macrophages in immature lungs, impairs ATII homeostasis, and disrupts elastic fiber formation, thereby inhibiting lung growth. The data provide evidence that IL-6 trans-signaling could offer an innovative pharmacological target to enable lung growth in severe neonatal chronic lung disease.
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http://dx.doi.org/10.1183/13993003.02248-2020DOI Listing
August 2021

Evidence for Multiple Origins of De Novo Formed Vascular Smooth Muscle Cells in Pulmonary Hypertension: Challenging the Dominant Model of Pre-Existing Smooth Muscle Expansion.

Int J Environ Res Public Health 2021 08 14;18(16). Epub 2021 Aug 14.

Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), 35392 Giessen, Germany.

Vascular remodeling is a prominent feature of pulmonary hypertension. This process involves increased muscularization of already muscularized vessels as well as neo-muscularization of non-muscularized vessels. The cell-of-origin of the newly formed vascular smooth muscle cells has been a subject of intense debate in recent years. Identifying these cells may have important clinical implications since it opens the door for attempts to therapeutically target the progenitor cells and/or reverse the differentiation of their progeny. In this context, the dominant model is that these cells derive from pre-existing smooth muscle cells that are activated in response to injury. In this mini review, we present the evidence that is in favor of this model and, at the same time, highlight other studies indicating that there are alternative cellular sources of vascular smooth muscle cells in pulmonary vascular remodeling.
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http://dx.doi.org/10.3390/ijerph18168584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391896PMC
August 2021

Exposomes to Exosomes: Exosomes as Tools to Study Epigenetic Adaptive Mechanisms in High-Altitude Humans.

Int J Environ Res Public Health 2021 08 5;18(16). Epub 2021 Aug 5.

Max-Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.

Humans on earth inhabit a wide range of environmental conditions and some environments are more challenging for human survival than others. However, many living beings, including humans, have developed adaptive mechanisms to live in such inhospitable, harsh environments. Among different difficult environments, high-altitude living is especially demanding because of diminished partial pressure of oxygen and resulting chronic hypobaric hypoxia. This results in poor blood oxygenation and reduces aerobic oxidative respiration in the mitochondria, leading to increased reactive oxygen species generation and activation of hypoxia-inducible gene expression. Genetic mechanisms in the adaptation to high altitude is well-studied, but there are only limited studies regarding the role of epigenetic mechanisms. The purpose of this review is to understand the epigenetic mechanisms behind high-altitude adaptive and maladaptive phenotypes. Hypobaric hypoxia is a form of cellular hypoxia, which is similar to the one suffered by critically-ill hypoxemia patients. Thus, understanding the adaptive epigenetic signals operating in in high-altitude adjusted indigenous populations may help in therapeutically modulating signaling pathways in hypoxemia patients by copying the most successful epigenotype. In addition, we have summarized the current information about exosomes in hypoxia research and prospects to use them as diagnostic tools to study the epigenome of high-altitude adapted healthy or maladapted individuals.
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http://dx.doi.org/10.3390/ijerph18168280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392481PMC
August 2021

Hidden Treasures: Macrophage Long Non-Coding RNAs in Lung Cancer Progression.

Cancers (Basel) 2021 Aug 17;13(16). Epub 2021 Aug 17.

Max-Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Parkstr. 1, 61231 Bad Nauheim, Germany.

Ever since RNA sequencing of whole genomes and transcriptomes became available, numerous RNA transcripts without having the classic function of encoding proteins have been discovered. Long non-coding RNAs (lncRNAs) with a length greater than 200 nucleotides were considered as "junk" in the beginning, but it has increasingly become clear that lncRNAs have crucial roles in regulating a variety of cellular mechanisms and are often deregulated in several diseases, such as cancer. Lung cancer is the leading cause of cancer-related deaths and has a survival rate of less than 10%. Immune cells infiltrating the tumor microenvironment (TME) have been shown to have a great effect on tumor development with macrophages being the major cell type within the TME. Macrophages can inherit an inflammatory M1 or an anti-inflammatory M2 phenotype. Tumor-associated macrophages, which are predominantly polarized to M2, favor tumor growth, angiogenesis, and metastasis. In this review, we aimed to describe the complex roles and functions of lncRNAs in macrophages and their influence on lung cancer development and progression through the TME.
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http://dx.doi.org/10.3390/cancers13164127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392679PMC
August 2021

Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2.

Commun Biol 2021 08 24;4(1):1002. Epub 2021 Aug 24.

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

Pulmonary arterial hypertension (PAH), is a fatal disease characterized by a pseudo-malignant phenotype. We investigated the expression and the role of the receptor tyrosine kinase Axl in experimental (i.e., monocrotaline and Su5416/hypoxia treated rats) and clinical PAH. In vitro Axl inhibition by R428 and Axl knock-down inhibited growth factor-driven proliferation and migration of non-PAH and PAH PASMCs. Conversely, Axl overexpression conferred a growth advantage. Axl declined in PAECs of PAH patients. Axl blockage inhibited BMP9 signaling and increased PAEC apoptosis, while BMP9 induced Axl phosphorylation. Gas6 induced SMAD1/5/8 phosphorylation and ID1/ID2 increase were blunted by BMP signaling obstruction. Axl association with BMPR2 was facilitated by Gas6/BMP9 stimulation and diminished by R428. In vivo R428 aggravated right ventricular hypertrophy and dysfunction, abrogated BMPR2 signaling, elevated pulmonary endothelial cell apoptosis and loss. Together, Axl is a key regulator of endothelial BMPR2 signaling and potential determinant of PAH.
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http://dx.doi.org/10.1038/s42003-021-02531-1DOI Listing
August 2021

Renal markers for monitoring acute kidney injury transition to chronic kidney disease after COVID-19.

Nephrol Dial Transplant 2021 Aug 9. Epub 2021 Aug 9.

International Renal Research Institute of Vicenza, Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Vicenza, Italy.

URL http://www.clinicaltrials.gov. Unique identifier: NCT04353583.
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http://dx.doi.org/10.1093/ndt/gfab235DOI Listing
August 2021

Sex-specific differences in plasma levels of FXII, HK, and FXIIa-C1-esterase inhibitor complexes in community acquired pneumonia.

Am J Physiol Lung Cell Mol Physiol 2021 07 28. Epub 2021 Jul 28.

Hannover Medical School, Hannover, Germany.

Sex-dependent differences in immunity and coagulation play an active role in the outcome of community-acquired pneumonia (CAP). Contact phase proteins act at the crossroads between inflammation and coagulation thus representing a point of convergence in host defense against infection. Here, we measured the levels of factor XII (FXII), FXIIa-C1 esterase inhibitor (C1INH) complexes, and high molecular weight kininogen (HK) in plasma of CAP patients and correlated them to clinical disease severity. Levels of FXIIa-C1INH/albumin ratio were elevated, irrespective of sex, in plasma of CAP patients (n=139) as compared to age-matched donors (n=58). No simultaneous decrease in FXII levels, indicating its consumption, was observed. Stratification by sex revealed augmented FXII levels in plasma of CAP women as compared to sex-matched donors yet no apparent differences in men. This sex-specific effect was, however, attributable to lower FXII levels in female donors relative to men donors. Plasma estradiol levels mirrored those for FXII. Levels of HK/albumin ratio were decreased in CAP plasma as compared to donors, however, after stratification by sex, this difference was only observed in women and was related to higher HK/albumin values in female donors as opposed to male donors. Finally, strong negative correlation between plasma levels of HK/albumin ratio and CAP severity, as assessed by CRB65 score, in males and females was observed. Our study identifies sex-dependent differences in plasma levels of the contact phase proteins in elderly subjects that may contribute to specific clinical outcomes in CAP between men and women.
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http://dx.doi.org/10.1152/ajplung.00162.2021DOI Listing
July 2021

Osteopontin and galectin-3 as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension.

Biomark Med 2021 Aug 22;15(12):1021-1034. Epub 2021 Jul 22.

Department of Cardiology & Angiology, University of Giessen, Giessen, 35392, Germany.

This study assessed the utility of osteopontin (OPN) and galectin-3 (Gal-3) as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension (PH). We examined plasma levels of OPN and Gal-3 in patients with PH (n = 62), dilated cardiomyopathy (n = 34), left ventricular hypertrophy (LVH; n = 47), and controls without right ventricle (RV) or LV abnormalities (n = 38). OPN and Gal-3 levels were higher in PH, dilated cardiomyopathy and LVH than in the controls. OPN concentrations in PH patients with maladaptive RV were significantly higher than in those with adaptive RV. Gal-3 did not differentiate between adaptive and maladaptive RV remodeling in PH. OPN and Gal-3 levels did not correlate with parameters of LV remodeling. OPN is a potential biomarker of RV maladaptation.
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http://dx.doi.org/10.2217/bmm-2021-0009DOI Listing
August 2021

TRAF2 Is a Novel Ubiquitin E3 Ligase for the Na,K-ATPase β-Subunit That Drives Alveolar Epithelial Dysfunction in Hypercapnia.

Front Cell Dev Biol 2021 2;9:689983. Epub 2021 Jul 2.

Member of the German Center for Lung Research (DZL), Department of Internal Medicine, Justus Liebig University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.

Several acute and chronic lung diseases are associated with alveolar hypoventilation leading to accumulation of CO (hypercapnia). The β-subunit of the Na,K-ATPase plays a pivotal role in maintaining epithelial integrity by functioning as a cell adhesion molecule and regulating cell surface stability of the catalytic α-subunit of the transporter, thereby, maintaining optimal alveolar fluid balance. Here, we identified the E3 ubiquitin ligase for the Na,K-ATPase β-subunit, which promoted polyubiquitination, subsequent endocytosis and proteasomal degradation of the protein upon exposure of alveolar epithelial cells to elevated CO levels, thus impairing alveolar integrity. Ubiquitination of the Na,K-ATPase β-subunit required lysine 5 and 7 and mutating these residues (but not other lysines) prevented trafficking of Na,K-ATPase from the plasma membrane and stabilized the protein upon hypercapnia. Furthermore, ubiquitination of the Na,K-ATPase β-subunit was dependent on prior phosphorylation at serine 11 by protein kinase C (PKC)-ζ. Using a protein microarray, we identified the tumor necrosis factor receptor-associated factor 2 (TRAF2) as the E3 ligase driving ubiquitination of the Na,K-ATPase β-subunit upon hypercapnia. Of note, prevention of Na,K-ATPase β-subunit ubiquitination was necessary and sufficient to restore the formation of cell-cell junctions under hypercapnic conditions. These results suggest that a hypercapnic environment in the lung may lead to persistent epithelial dysfunction in affected patients. As such, the identification of the E3 ligase for the Na,K-ATPase may provide a novel therapeutic target, to be employed in patients with acute or chronic hypercapnic respiratory failure, aiming to restore alveolar epithelial integrity.
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http://dx.doi.org/10.3389/fcell.2021.689983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283768PMC
July 2021

Hypercapnia-induces IRE1α-driven Endoplasmic Reticulum-associated Degradation of the Na,K-ATPase β-subunit.

Am J Respir Cell Mol Biol 2021 Jun 30. Epub 2021 Jun 30.

Justus Liebig University, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Department of Internal Medicine, Giessen, Germany.

Acute respiratory distress syndrome (ARDS) is often associated with elevated levels of CO2 (hypercapnia) and impaired alveolar fluid clearance. Misfolding of the Na,K-ATPase (NKA), a key molecule involved in both alveolar epithelial barrier tightness and in resolution of alveolar edema, in the endoplasmic reticulum (ER) may decrease plasma membrane (PM) abundance of the transporter. Here, we investigated how hypercapnia affects the NKA β-subunit (NKA-β) in the ER. Exposing murine precision-cut lung slices (PCLS) and human alveolar epithelial A549 cells to elevated CO2 levels led to a rapid decrease of NKA-β abundance in the ER and at the cell surface. Knockdown of ER alpha-mannosidase I (MAN1B1) and ER degradation enhancing alpha-mannosidase like protein 1 by siRNA or treatment with the MAN1B1 inhibitor, kifunensine rescued loss of NKA-β in the ER, suggesting ER-associated degradation (ERAD) of the enzyme. Furthermore, hypercapnia activated the unfolded protein response (UPR) by promoting phosphorylation of inositol-requiring enzyme 1α (IRE1α) and treatment with a siRNA against IRE1α prevented the decrease of NKA-β in the ER. Of note, the hypercapnia-induced phosphorylation of IRE1α was triggered by a Ca2+-dependent mechanism. Additionally, inhibition of the inositol trisphosphate receptor decreased phosphorylation levels of IRE1α in PCLS and A549 cells, suggesting that Ca2+ efflux from the ER might be responsible for IRE1α activation and ERAD of NKA-β. In conclusion, here we provide evidence that hypercapnia attenuates maturation of the regulatory subunit of NKA by activating IRE1α and promoting ERAD, which may contribute to impaired alveolar epithelial integrity in patients with ARDS and hypercapnia.
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http://dx.doi.org/10.1165/rcmb.2021-0114OCDOI Listing
June 2021

Protocol for the generation of murine bronchiolospheres.

STAR Protoc 2021 Jun 11;2(2):100594. Epub 2021 Jun 11.

Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Cardio-Pulmonary Institute (CPI), Institute for Lung Health (ILH), member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392 Giessen, Hessen, Germany.

Organoid models have been shown to be valuable tools for studying epithelial-mesenchymal crosstalk during biological and pathological settings. Our data identified ACTA2+ PDGFRα+ repair-supportive mesenchymal cells as an important component of the conducting airway niche. Here, we provide a detailed protocol for culturing airway organoids, or bronchiolospheres, which provide an assessment of the ability of mesenchymal cells to support club-cell growth. For complete details on the use and execution of this protocol, please refer to Moiseenko et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209683PMC
June 2021

Evaluation of Diagnostic Accuracy and Radiation Exposure of Dual-Energy Computed Tomography (DECT) in the Course of Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Rofo 2021 Jun 17. Epub 2021 Jun 17.

Department of Diagnostic and Interventional Radiology, University Hospital Gießen, Justus Liebig University, Gießen, Germany.

Purpose:  The purpose of this study was to assess the diagnostic accuracy of computed tomography pulmonary angiogram (CTPA) including dual energy and reconstruction of iodine maps for diagnosing CTEPH. This method for detecting embolisms and perfusion failures was compared with V/Q-SPECT. An additional purpose was to compare the applied radiation dose of both techniques.

Materials And Methods:  71 patients (49 women) with suspected CTEPH were included in this prospective study. The patients received a V/Q-SPECT and a dual-energy CTPA. Iodine maps were reconstructed from the data set. CTPA and the iodine maps were read by an experienced radiologist unaware of the clinical information as well as the results of the V/Q-SPECT. Results were compared to the V/Q-SPECT. DLP and the applied amount of radionuclides (MAA, Technegas) were obtained for comparison of radiation dose.

Results:  For the diagnosis of CTEPH, the sensitivity of DECT was 1.000, specificity 0.966, PPV 0.867 and NPV 1.000, respectively. There was not a considerable difference in the x-ray exposure between the DECT examination and the V/Q-SPECT (1.892 mSv vs. 1.911 mSv; p = 0.6115). Both examination modalities were highly consistent regarding the classification of pathological segments (1177/1278 segments, 92,09 %, κ = 0,5938).

Conclusion:  This study presents the DECT, in combination with reconstructed iodine maps, as a potential alternative to the current imaging technique of first choice, V/Q-SPECT. For creating future prospective diagnostic algorithms, the implementation of DECT screening with iodine maps should be considered.

Key Points: · DECT correctly identified all CTEPH patients.. · There is substantial agreement between DECT and V/Q-SPECT in the classification of pathological segments.. · There is no significant difference in radiation exposure during DECT examination and V/Q-SPECT examination.. · Reduced radiation dose does not negatively impact image quality..

Citation Format: · Schüßler A, Richter M, Tello K et al. Evaluation der diagnostischen Genauigkeit und der Strahlendosis der Dual-Energy-Computertomografie (DECT) bei chronisch thromboembolischer pulmonaler Hypertonie (CTEPH). Fortschr Röntgenstr 2021; DOI: 10.1055/a-1502-7541.
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http://dx.doi.org/10.1055/a-1502-7541DOI Listing
June 2021

Exercise hemodynamics in heart failure patients with preserved and mid-range ejection fraction: key role of the right heart.

Clin Res Cardiol 2021 Jun 10. Epub 2021 Jun 10.

Department of Cardiology, Kerckhoff-Klinik GmbH, Benekestr 2-8, 61231, Bad Nauheim, Germany.

Objective: We sought to explore whether classification of patients with heart failure and mid-range (HFmrEF) or preserved ejection fraction (HFpEF) according to their left ventricular ejection fraction (LVEF) identifies differences in their exercise hemodynamic profile, and whether classification according to an index of right ventricular (RV) function improves differentiation.

Background: Patients with HFmrEF and HFpEF have hemodynamic compromise on exertion. The classification according to LVEF implies a key role of the left ventricle. However, RV involvement in exercise limitation is increasingly recognized. The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/PASP) ratio is an index of RV and pulmonary vascular function. Whether exercise hemodynamics differ more between HFmrEF and HFpEF than between TAPSE/PASP tertiles is unknown.

Methods: We analyzed 166 patients with HFpEF (LVEF ≥ 50%) or HFmrEF (LVEF 40-49%) who underwent basic diagnostics (laboratory testing, echocardiography at rest, and cardiopulmonary exercise testing [CPET]) and exercise with right heart catheterization. Hemodynamics were compared according to echocardiographic left ventricular or RV function.

Results: Exercise hemodynamics (e.g. pulmonary arterial wedge pressure/cardiac output [CO] slope, CO increase during exercise, and maximum total pulmonary resistance) showed no difference between HFpEF and HFmrEF, but significantly differed across TAPSE/PASP tertiles and were associated with CPET results. N-terminal pro-brain natriuretic peptide concentration also differed significantly across TAPSE/PASP tertiles but not between HFpEF and HFmrEF.

Conclusion: In patients with HFpEF or HFmrEF, TAPSE/PASP emerged as a more appropriate stratification parameter than LVEF to predict clinically relevant impairment of exercise hemodynamics. Stratification of exercise hemodynamics in patients with HFpEF or HFmrEF according to LVEF or TAPSE/PASP, showing significant distinctions only with the RV-based strategy. All data are shown as median [upper limit of interquartile range] and were calculated using the independent-samples Mann-Whitney U test or Kruskal-Wallis test. PVR pulmonary vascular resistance; max maximum level during exercise.
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http://dx.doi.org/10.1007/s00392-021-01884-1DOI Listing
June 2021

Validity of echocardiographic tricuspid regurgitation gradient to screen for new definition of pulmonary hypertension.

EClinicalMedicine 2021 Apr 5;34:100822. Epub 2021 Apr 5.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Centre (UGMLC, Member of the German Centre for Lung Research (DZL), Klinikstrasse 32, 35392, Germany.

Background: Currently an echocardiographic threshold for the tricuspid regurgitation gradient (TRG) of > 31 mmHg is recommended for screening for pulmonary hypertension (PH). Invasively diagnosed PH was recently redefined as mean pulmonary arterial pressure (mPAP) > 20 mmHg instead of ≥ 25 mmHg. We investigated the ability of TRG to screen for the new PH-definition.

Methods: Retrospective assessment of echocardiography and right heart catheterisation data from 1572 patients entering the Giessen PH-Registry during 2008-2018. Accuracy of different TRG thresholds and other echocardiographic parameters was evaluated using receiver operating characteristic curves.

Findings: 1264 patients fulfilled the new PH-definition. Positive (PPV) and negative predictive values and accuracy of TRG > 46 mmHg were 95%, 39%, and 73%, respectively, for the new PH-definition. Lowering the TRG cut-off to 31 mmHg and below worsened PPV to ≤ 89%. The PPV of TRG for pre-capillary PH (mPAP > 20 mmHg and pulmonary vascular resistance ≥ 3 Wood Units) was ≤ 85%. In patients with TRG ≤ 46 mmHg, tricuspid annular plane systolic excursion/TRG and TRG/right ventricular outflow tract acceleration time were superior to TRG in screening for newly defined pre-capillary PH.

Interpretation: In patients with suspected PH referred to a tertiary care centre, the PPV of TRG to meet the new PH-definition depended strongly on the TRG cut-off used. Our data do not support lowering the TRG cut-off. Combining TRG with other echocardiographic parameters might improve the validity of echocardiographic screening for PH.
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http://dx.doi.org/10.1016/j.eclinm.2021.100822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102717PMC
April 2021

COVID-19: spot urine rather than bronchoalveolar lavage fluid analysis?

Crit Care 2021 04 30;25(1):162. Epub 2021 Apr 30.

Department of Internal Medicine II, University Hospital Giessen and Marburg, Justus Liebig University Giessen, Klinikstrasse 33, 35392, Giessen, Germany.

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http://dx.doi.org/10.1186/s13054-021-03579-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086224PMC
April 2021

Impact of the new definition for pulmonary hypertension in patients with lung disease: an analysis of the United Network for Organ Sharing database.

Pulm Circ 2021 Apr-Jun;11(2):2045894021999960. Epub 2021 Mar 30.

University of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University Giessen, Giessen, Germany.

The implications of the recent change in the definition of pulmonary hypertension on epidemiology and outcomes are not known. We sought to determine the percentage of patients with the two most common lung diseases that would be reclassified regarding the presence/absence of pulmonary hypertension with the revised definition. A query of the United Network for Organ Sharing database was performed. The percentage of patients meeting the current and previous definition of pulmonary hypertension was described. Outcomes of patients stratified by the current and previous definitions were compared. There were 15,563 patients with right heart catheterization data analyzed. Pulmonary hypertension was more prevalent in both chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis under the new definition at 52.4% versus 82.4%, and 47.6% versus 73.6%, respectively. "Pre-capillary" pulmonary hypertension by the new definition was lower at 28.1% for chronic obstructive pulmonary disease and 36.8% for idiopathic pulmonary fibrosis. Of the patients with pulmonary hypertension by the old definition, 23.9% of chronic obstructive pulmonary disease patients and 18.7% of idiopathic pulmonary fibrosis patients were not classified as pulmonary hypertension by the new definition. Conversely, 15.9% of chronic obstructive pulmonary disease patients and 15.1% of idiopathic pulmonary fibrosis patients who did not meet diagnostic criteria for pulmonary hypertension by the old definition did have pulmonary hypertension by the new definition. Patients in both disease categories had shorter transplant-free waitlist survival in the presence of pulmonary hypertension by both the new and old definitions. There was a trend toward the new definition of pre-capillary pulmonary hypertension better discerning outcomes compared to the old definition of pulmonary hypertension in idiopathic pulmonary fibrosis patients. Most patients with advanced lung disease who are listed for lung transplantation have pulmonary hypertension, but fewer have pre-capillary pulmonary hypertension than pulmonary hypertension by the old definition. Both the old and new definition of precapillary pulmonary hypertension appear to discern outcomes among the two groups of lung disease analyzed, with some evidence to suggest that the new definition performs slightly better in the idiopathic pulmonary fibrosis population.
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http://dx.doi.org/10.1177/2045894021999960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020109PMC
March 2021

Utilising biomarkers to predict right heart maladaptive phenotype: a step toward precision medicine.

Eur Respir J 2021 04 8;57(4). Epub 2021 Apr 8.

Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, Germany.

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http://dx.doi.org/10.1183/13993003.04506-2020DOI Listing
April 2021

The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension.

Am J Physiol Lung Cell Mol Physiol 2021 05 24;320(5):L903-L915. Epub 2021 Mar 24.

Cardiopulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.

Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, patients with COPD can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to cigarette smoke (CS) for 8 mo and then subsequently treated with doxycycline for additional 3 mo in room air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline and use of a Tet-On/Tet-Off system when evaluating those parameters should be interpreted with caution.
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http://dx.doi.org/10.1152/ajplung.00048.2021DOI Listing
May 2021

A novel non-invasive and echocardiography-derived method for quantification of right ventricular pressure-volume loops.

Eur Heart J Cardiovasc Imaging 2021 Feb 28. Epub 2021 Feb 28.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Klinikstrasse 32, Giessen 35392, Germany.

Aims: We sought to assess the feasibility of constructing right ventricular (RV) pressure-volume (PV) loops solely by echocardiography.

Methods And Results: We performed RV conductance and pressure wire (PW) catheterization with simultaneous echocardiography in 35 patients with pulmonary hypertension. To generate echocardiographic PV loops, a reference RV pressure curve was constructed using pooled PW data from the first 20 patients (initial cohort). Individual pressure curves were then generated by adjusting the reference curve according to RV isovolumic and ejection phase duration and estimated RV systolic pressure. The pressure curves were synchronized with echocardiographic volume curves. We validated the reference curve in the remaining 15 patients (validation cohort). Methods were compared with correlation and Bland-Altman analysis. In the initial cohort, echocardiographic and conductance-derived PV loop parameters were significantly correlated {rho = 0.8053 [end-systolic elastance (Ees)], 0.8261 [Ees/arterial elastance (Ea)], and 0.697 (stroke work); all P < 0.001}, with low bias [-0.016 mmHg/mL (Ees), 0.1225 (Ees/Ea), and -39.0 mmHg mL (stroke work)] and acceptable limits of agreement. Echocardiographic and PW-derived Ees were also tightly correlated, with low bias (-0.009 mmHg/mL) and small limits of agreement. Echocardiographic and conductance-derived Ees, Ees/Ea, and stroke work were also tightly correlated in the validation cohort (rho = 0.9014, 0.9812, and 0.9491, respectively; all P < 0.001), with low bias (0.0173 mmHg/mL, 0.0153, and 255.1 mmHg mL, respectively) and acceptable limits.

Conclusion: The novel echocardiographic method is an acceptable alternative to invasively measured PV loops to assess contractility, RV-arterial coupling, and RV myocardial work. Further validation is warranted.
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http://dx.doi.org/10.1093/ehjci/jeab038DOI Listing
February 2021

Right ventricular pressure-volume loop shape and systolic pressure change in pulmonary hypertension.

Am J Physiol Lung Cell Mol Physiol 2021 05 3;320(5):L715-L725. Epub 2021 Mar 3.

Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.

Right ventricular (RV) function determines outcome in pulmonary arterial hypertension (PAH). RV pressure-volume loops, the gold standard for measuring RV function, are difficult to analyze. Our aim was to investigate whether simple assessments of RV pressure-volume loop morphology and RV systolic pressure differential reflect PAH severity and RV function. We analyzed multibeat RV pressure-volume loops (obtained by conductance catheterization with preload reduction) in 77 patients with PAH and 15 patients without pulmonary hypertension in two centers. Patients were categorized according to their pressure-volume loop shape (triangular, quadratic, trapezoid, or notched). RV systolic pressure differential was defined as end-systolic minus beginning-systolic pressure (ESP - BSP), augmentation index as ESP - BSP/pulse pressure, pulmonary arterial capacitance (PAC) as stroke volume/pulse pressure, and RV-arterial coupling as end-systolic/arterial elastance (Ees/Ea). Trapezoid and notched pressure-volume loops were associated with the highest afterload (Ea), augmentation index, pulmonary vascular resistance (PVR), mean pulmonary arterial pressure, stroke work, B-type natriuretic peptide, and the lowest Ees/Ea and PAC. Multivariate linear regression identified Ea, PVR, and stroke work as the main determinants of ESP - BSP. ESP - BSP also significantly correlated with multibeat Ees/Ea (Spearman's ρ: -0.518, < 0.001). A separate retrospective analysis of 113 patients with PAH showed that ESP - BSP obtained by routine right heart catheterization significantly correlated with a noninvasive surrogate of RV-arterial coupling (tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio; ρ: -0.376, < 0.001). In conclusion, pressure-volume loop shape and RV systolic pressure differential predominately depend on afterload and PAH severity and reflect RV-arterial coupling in PAH.
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http://dx.doi.org/10.1152/ajplung.00583.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174826PMC
May 2021

The Lung Vasculature: A Driver or Passenger in Lung Branching Morphogenesis?

Front Cell Dev Biol 2020 14;8:623868. Epub 2021 Jan 14.

Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Institute for Lung Health (ILH), Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, Giessen, Germany.

Multiple cellular, biochemical, and physical factors converge to coordinate organogenesis. During embryonic development, several organs such as the lung, salivary glands, mammary glands, and kidneys undergo rapid, but intricate, iterative branching. This biological process not only determines the overall architecture, size and shape of such organs but is also a pre-requisite for optimal organ function. The lung, in particular, relies on a vast surface area to carry out efficient gas exchange, and it is logical to suggest that airway branching during lung development represents a rate-limiting step in this context. Against this background, the vascular network develops in parallel to the airway tree and reciprocal interaction between these two compartments is critical for their patterning, branching, and co-alignment. In this mini review, we present an overview of the branching process in the developing mouse lung and discuss whether the vasculature plays a leading role in the process of airway epithelial branching.
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http://dx.doi.org/10.3389/fcell.2020.623868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873988PMC
January 2021

Therapeutic Potential of Regorafenib-A Multikinase Inhibitor in Pulmonary Hypertension.

Int J Mol Sci 2021 Feb 2;22(3). Epub 2021 Feb 2.

Universities of Giessen and Marburg Lung Center (UGMLC), Excellence Cluster Cardio-Pulmonary Institute (CPI), Member of the German Center for Lung Research (DZL), Justus-Liebig University, 35392 Giessen, Germany.

Pulmonary hypertension (PH) is characterized by a progressive elevation of mean arterial pressure followed by right ventricular failure and death. Previous studies have indicated that numerous inhibitors of receptor tyrosine kinase signaling could be either beneficial or detrimental for the treatment of PH. Here we investigated the therapeutic potential of the multi-kinase inhibitor regorafenib (BAY 73-4506) for the treatment of PH. A peptide-based kinase activity assay was performed using the PamStation12 platform. The 5-bromo-2'-deoxyuridine proliferation and transwell migration assays were utilized in pulmonary arterial smooth muscle cells (PASMCs). Regorafenib was administered to monocrotaline- and hypoxia-induced PH in rats and mice, respectively. Functional parameters were analyzed by hemodynamic and echocardiographic measurements. The kinase activity assay revealed upregulation of twenty-nine kinases in PASMCs from patients with idiopathic PAH (IPAH), of which fifteen were established as potential targets of regorafenib. Regorafenib showed strong anti-proliferative and anti-migratory effects in IPAH-PASMCs compared to the control PASMCs. Both experimental models indicated improved cardiac function and reduced pulmonary vascular remodeling upon regorafenib treatment. In lungs from monocrotaline (MCT) rats, regorafenib reduced the phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2. Overall, our data indicated that regorafenib plays a beneficial role in experimental PH.
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http://dx.doi.org/10.3390/ijms22031502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867319PMC
February 2021

Genetic Delivery and Gene Therapy in Pulmonary Hypertension.

Int J Mol Sci 2021 Jan 25;22(3). Epub 2021 Jan 25.

Excellence Cluster Cardio-Pulmonary Institute (CPI), Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus Liebig University of Giessen, Aulweg 130, 35392 Giessen, Germany.

Pulmonary hypertension (PH) is a progressive complex fatal disease of multiple etiologies. Hyperproliferation and resistance to apoptosis of vascular cells of intimal, medial, and adventitial layers of pulmonary vessels trigger excessive pulmonary vascular remodeling and vasoconstriction in the course of pulmonary arterial hypertension (PAH), a subgroup of PH. Multiple gene mutation/s or dysregulated gene expression contribute to the pathogenesis of PAH by endorsing the proliferation and promoting the resistance to apoptosis of pulmonary vascular cells. Given the vital role of these cells in PAH progression, the development of safe and efficient-gene therapeutic approaches that lead to restoration or down-regulation of gene expression, generally involved in the etiology of the disease is the need of the hour. Currently, none of the FDA-approved drugs provides a cure against PH, hence innovative tools may offer a novel treatment paradigm for this progressive and lethal disorder by silencing pathological genes, expressing therapeutic proteins, or through gene-editing applications. Here, we review the effectiveness and limitations of the presently available gene therapy approaches for PH. We provide a brief survey of commonly existing and currently applicable gene transfer methods for pulmonary vascular cells in vitro and describe some more recent developments for gene delivery existing in the field of PH in vivo.
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http://dx.doi.org/10.3390/ijms22031179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865388PMC
January 2021

Evaluation of Regional Pulmonary Ventilation in Spontaneously Breathing Patients with Idiopathic Pulmonary Fibrosis (IPF) Employing Electrical Impedance Tomography (EIT): A Pilot Study from the European IPF Registry (eurIPFreg).

J Clin Med 2021 Jan 7;10(2). Epub 2021 Jan 7.

Member of the German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), Klinikstr. 33, 35392 Giessen, Germany.

Objectives: In idiopathic pulmonary fibrosis (IPF), alterations in the pulmonary surfactant system result in an increased alveolar surface tension and favor repetitive alveolar collapse. This study aimed to assess the usefulness of electrical impedance tomography (EIT) in characterization of regional ventilation in IPF.

Materials And Methods: We investigated 17 patients with IPF and 15 healthy controls from the University of Giessen and Marburg Lung Center (UGMLC), Germany, for differences in the following EIT parameters: distribution of ventilation (TID), global inhomogeneity index (GI), regional impedance differences through the delta of end-expiratory lung impedance (dEELI), differences in surface of ventilated area (SURF), as well as center of ventilation (CG) and intratidal gas distribution (ITV). These parameters were assessed under spontaneous breathing and following a predefined escalation protocol of the positive end-expiratory pressure (PEEP), applied through a face mask by an intensive care respirator (EVITA, Draeger, Germany).

Results: Individual slopes of dEELI over the PEEP increment protocol were found to be highly significantly increased in both groups ( < 0.001) but were not found to be significantly different between groups. Similarly, dTID slopes were increasing in response to PEEP, but this did not reach statistical significance within or between groups. Individual breathing patterns were very heterogeneous. There were no relevant differences of SURF, GI or CGVD over the PEEP escalation range. A correlation of dEELI to FVC, BMI, age, or weight did not forward significant results.

Conclusions: In this study, we did see a significant increase in dEELI and a non-significant increase in dTID in IPF patients as well as in healthy controls in response to an increase of PEEP under spontaneous breathing. We propose the combined measurements of EIT and lung function to assess regional lung ventilation in spontaneously breathing subjects.
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http://dx.doi.org/10.3390/jcm10020192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827956PMC
January 2021

Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican.

Cancers (Basel) 2021 Jan 8;13(2). Epub 2021 Jan 8.

Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany.

Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown . Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican () as a novel downstream target of IRF9. Indeed, and expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
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http://dx.doi.org/10.3390/cancers13020208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827113PMC
January 2021

A comparison of airway pressures for inflation fixation of developing mouse lungs for stereological analyses.

Histochem Cell Biol 2021 Feb 29;155(2):203-214. Epub 2020 Dec 29.

Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, member of the German Center for Lung Research (DZL), Parkstrasse 1, 60231, Bad Nauheim, Germany.

The morphometric analysis of lung structure using the principles of stereology has emerged as a powerful tool to describe the structural changes in lung architecture that accompany the development of lung disease that is experimentally modelled in adult mice. These stereological principles are now being applied to the study of the evolution of the lung architecture over the course of prenatal and postnatal lung development in mouse neonates and adolescents. The immature lung is structurally and functionally distinct from the adult lung, and has a smaller volume than does the adult lung. These differences have raised concerns about whether the inflation fixation of neonatal mouse lungs with the airway pressure (P) used for the inflation fixation of adult mouse lungs may cause distortion of the neonatal mouse lung structure, leading to the generation of artefacts in subsequent analyses. The objective of this study was to examine the impact of a P of 10, 20 and 30 cmHO on the estimation of lung volumes and stereologically assessed parameters that describe the lung structure in developing mouse lungs. The data presented demonstrate that low P (10 cmHO) leads to heterogeneity in the unfolding of alveolar structures within the lungs, and that high P (30 cmHO) leads to an overestimation of the lung volume, and thus, affects the estimation of volume-dependent parameters, such as total alveoli number and gas-exchange surface area. Thus, these data support the use of a P of 20 cmHO for inflation fixation in morphometric studies on neonatal mouse lungs.
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http://dx.doi.org/10.1007/s00418-020-01951-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910376PMC
February 2021
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