Functional role of prothrombin expressing cells in the lung

• Applicant: Professor Dr. Sven Danckwardt
• Subject Area: Pneumology, Thoracic Surgery ; Anatomy and Physiology ; Toxicology, Laboratory Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563561081

The serine protease thrombin is involved in a number of physiological functions beyond hemostasis including angiogenesis, embryogenesis, tumorigenesis and inflammation. Recently thrombin has been implicated to play a key role in lung pathologies, including acute lung injuries, pulmonary fibrosis and other inflammatory (allergic) lung disorders. Serum levels of prothrombin derive from protein synthesis in the liver, yet expression of the prothrombin (F2) gene in a variety of other tissues has been demonstrated to occur during embryogenesis. While considerable insights have been obtained on how thrombin exerts its crucial function in several pathologies, little is known about the (patho)physiological functions of extrahepatic prothrombin expression. To systematically profile organs and cell type(s) expressing prothrombin we generated a newly designed conditional transgenic mouse model (termed ‘D-Insight’) in which endogenous prothrombin expression is tagged by luciferase reporters. Unexpectedly, using this system, we uncovered significant prothrombin expression in the lung. In further preliminary studies, we obtained evidence that lung-derived prothrombin-expression can be assigned to luminal cell populations in the airways, an anatomical site where liver-derived circulating proteins are not normally found. We now want to systematically study prothrombin-expressing cells in the lung and disentangle the functional role of lung-derived prothrombin expression. To this end, we will make use of cells obtained from inducible prothrombin knockdown animals and tissue-specific prothrombin knockout mice and combine this with functional studies in vivo and in vitro, omics and pharmacological approaches. Illuminating non-canonical functions of coagulation components beyond their hemostatic role is central to uncover potentially relevant novel therapeutic targets in prevalent disease entities. This may include disease entities with high morbidity and mortality such as acute or chronic respiratory disorders.

• DFG Programme: Research Grants