Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fließer, E; Jandl, K; Lins, T; Birnhuber, A; Valzano, F; Kolb, D; Foris, V; Heinemann, A; Olschewski, H; Evermann, M; Hoetzenecker, K; Kreuter, M; Voelkel, NF; Marsh, LM; Wygrecka, M; Kwapiszewska, G.
Lung Fibrosis Is Linked to Increased Endothelial Cell Activation and Dysfunctional Vascular Barrier Integrity.
Am J Respir Cell Mol Biol. 2024; 71(3):318-331
Doi: 10.1165/rcmb.2024-0046OC
Web of Science
PubMed
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FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Fließer Elisabeth
- Kwapiszewska-Marsh Grazyna
- Co-Autor*innen der Med Uni Graz
- Birnhuber Anna
- Foris Vasile
- Heinemann Akos
- Jandl Katharina
- Kolb Dagmar
- Lins Thomas
- Marsh Leigh
- Olschewski Horst
- Valzano Francesco
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- Abstract:
- Pulmonary fibrosis (PF) can be a fatal disease characterized by progressive lung scarring. It is still poorly understood how the pulmonary endothelium is involved in the disease pathogenesis. Differences of the pulmonary vasculature between patients and donors were analyzed using transmission electron microscopy, immunohistochemistry, and single-cell RNA sequencing. Vascular barrier resistance, endothelial-immune cell adhesion, and sensitivity to an inflammatory milieu were studied in vitro. Integrity and activation markers were measured by ELISA in human plasma. Transmission electron microscopy demonstrated abnormally swollen endothelial cells (ECs) in fibrotic lungs compared with donors. A more intense CD31 and von Willebrand Factor (vWF) and patchy vascular endothelial (VE)-Cadherin staining in fibrotic lungs supported the presence of a dysregulated endothelium. Integrity markers CD31, VE-Cadherin, Thrombomodulin, and VEGFR-2 (vascular endothelial growth factor receptor-2) and activation marker vWF gene expression was increased in different endothelial subpopulations (e.g., arterial, venous, general capillary, aerocytes) in PF. This was associated with a heightened sensitivity of fibrotic ECs to TNF-α or IFN-γ and elevated immune cell adhesion. The barrier strength was overall reduced in ECs from fibrotic lungs. vWF and IL-8 were increased in the plasma of patients, whereas VE-Cadherin, Thrombomodulin, and VEGFR-2 were decreased. VE-Cadherin staining was also patchy in biopsy tissue and was decreased in plasma samples of patients with PF 6 months after the initial diagnosis. Our data demonstrate highly abnormal ECs in PF. The vascular compartment is characterized by hyperactivation and increased immune cell adhesion, as well as dysfunctional endothelial barrier function. Reestablishing EC homeostasis and function might represent a new therapeutic option for fibrotic lung diseases.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Endothelial Cells - metabolism, pathology
- Lung - pathology, metabolism, blood supply
- Male - administration & dosage
- Pulmonary Fibrosis - pathology, metabolism
- Female - administration & dosage
- Middle Aged - administration & dosage
- von Willebrand Factor - metabolism
- Aged - administration & dosage
- Cadherins - metabolism
- Endothelium, Vascular - metabolism, pathology
- Cell Adhesion - administration & dosage
- Thrombomodulin - metabolism
- Antigens, CD - metabolism
- Find related publications in this database (Keywords)
- endothelial dysfunction
- lung fibrosis
- endothelial activation
- vascular barrier