Pneumologie 2024; 78(S 01): S117
DOI: 10.1055/s-0044-1778990
Abstracts
Zellbiologie, Grundlagenforschung in der Pneumologie

Pro-coagulant extracellular vesicles mediate smoking-induced pulmo-vascular inflammation

I Burhorst
1   Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, German Center for Lung Research (Dzl), Marburg, Germany
,
I Beinborn
1   Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, German Center for Lung Research (Dzl), Marburg, Germany
,
C Preußer
2   Institute for Tumor Immunology and Core Facility – Extracellular Vesicles, Philipps-University Marburg, Marburg, Germany
,
E Pogge von Strandmann
2   Institute for Tumor Immunology and Core Facility – Extracellular Vesicles, Philipps-University Marburg, Marburg, Germany
,
T Heimerl
3   Center for Synthetic Microbiology (Synmikro), Philipps-University Marburg, Marburg, Germany
,
B Schmeck
4   Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, German Center for Lung Research (Dzl), Marburg, Germany; Department of Pulmonary and Critical Care Medicine, Philipps-University Marburg, Marburg, Germany
,
B Benedikter
5   University Eye Clinic Maastricht, Maastricht University Medical Center (Mumc+), School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
,
K Laakmann
1   Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, German Center for Lung Research (Dzl), Marburg, Germany
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Background Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, with smoking as major risk factor. Tobacco smoke increases the risk of thrombosis, resulting in dysregulation of tissue factor (TF)-mediated extrinsic coagulation that further impacts downstream intracellular signaling via protease activated receptors (PARs). Here, we investigated the impact of bronchial epithelial cell (BEC)-derived TF+-extracellular vesicles (EVs) on human lung endothelial cell (EC) activation as mediators of pulmo-vascular inflammation.

Results We could show that human BECs secrete pro-coagulant TF+-EVs when stimulated with tobacco smoke extract. Those TF+-EVs are secreted towards the lung lumen and basolateral side by polarized BECs to potentially target PAR1 and PAR2 expressing cells from the lung lumen and tissue side. COPD-specific regulation of TF and PAR1 was further demonstrated by re-analysis of public RNA sequencing data showing upregulation of these factors in lung tissue from COPD patients. With respect to potential TF+-EV target cells, we demonstrated that especially lung ECs express PAR1 and PAR2. Stimulation of these cells with TF+-EVs induced EC activation as monitored by proinflammatory gene expression of IL-8, ICAM-1 and VCAM-1 or intracellular calcium release. Additionally, EC activation can be blocked by PAR1 and PAR1/PAR2 siRNA knockdown as well as the clinically relevant thrombin-inhibiting anti-coagulants Dabigatran and anti-thrombin III.

Conclusion In conclusion, tobacco smoke induces secretion of procoagulant TF+-EVs by BECs to stimulate human lung ECs via PAR1 and PAR2. Stimulated lung ECs express pro-inflammatory mediators, thereby potentially promoting COPD-associated EC dysfunction and thrombotic events.



Publication History

Article published online:
01 March 2024

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