Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Fliesser, E.
Dissecting the role of endothelium in COVID-19 and progressive pulmonary fibrosis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp. 82
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Biasin Valentina
- Birnhuber Anna
- Kwapiszewska-Marsh Grazyna
- Altmetrics:
- Abstract:
- Endothelial cells, the inner lining of all blood vessels, are heavily affected in COVID-19. The ongoing endothelial dysfunction, a hallmark of long-COVID, has been linked to the progression to pulmonary fibrosis, affecting approximately 25% of severe COVID-19 cases. Progressive pulmonary fibrosis (PPF) is also associated with numerous other chronic lung diseases, such as idiopathic pulmonary fibrosis, systemic sclerosis or hypersensitivity pneumonitis. All of these fibrosing interstitial lung diseases (ILDs) share endothelial maladaptations, which can manifest for example as vascular remodeling and pulmonary hypertension, coagulopathy, integrity loss, hyper-activation and inflammation and/or elevated angiogenesis or vessel loss. So far, research in the field has focused mainly on the role of epithelial cells and fibroblast to myofibroblast differentiation in the pathogenesis of progressive pulmonary fibrosis. The vascular endothelium however remains an under-investigated cellular compartment in the disease. Based on the compelling evidence from COVID-19, which suggests endothelial cells as crucial drivers of fibrogenesis, we hypothesized that the vascular endothelium is also involved in the pathogenesis of PPF. Through examination of lung tissue as well as plasma samples from severely ill COVID-19 patients, we confirmed that the endothelium is significantly impacted by SARS-CoV-2. This was manifested as strong upregulation of several endothelium-related integrity and activation markers (e.g. ICAM-1, vWF, VEGFR-2, VCAM-1, E-selectin, CD31 IL-6 or MCP-1) in COVID-19 lungs as well as plasma of infected individuals. Our subsequent analysis of the endothelium in PPF showed similar results. Collectively, through the utilization of human lung transplant samples, patients' plasma, isolated pulmonary artery endothelial cells, and a publicly available transcriptomic dataset of PPF, we demonstrate that endothelial cells (ECs) are significantly altered in structure and function in PPF. On the structural level, we observed swollen, misshaped ECs, which gave the impression of hyper-activation. The endothelial hyper-activation was further corroborated by our in-vitro analysis, which uncovered increased sensitivity to a pro-inflammatory milieu and simultaneous elevated immune cell adhesion to fibrotic ECs. This was associated with a pronounced dysfunction of endothelial integrity, which was represented in a reduced barrier strength as well as loss of the typical endothelial cobblestone structure in-vitro. Furthermore, the incorporation of the bleomycin mouse model of lung fibrosis revealed that these changes are already evident at the onset of the disease. Our findings corroborate a vascular component in PF pathogenesis and suggest that the re-establishment of vascular homeostasis might become a novel therapy strategy.