Impact of NETs on vascular fibrosis, systemic inflammation and secondary organ injury after venous thrombosis

• Applicant: Dr. Deya Cherpokova
• Subject Area: Hematology, Oncology
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317673989

Neutrophils are key effector cells of the innate immune system, which are rapidly recruited to sites of infection or inflammation. Besides phagocytosis, neutrophils are capable of disarming pathogens in the extracellular environment by the release of neutrophil extracellular traps (NETs), composed of decondensed chromatin lined with histones and granule proteins. Increasing experimental evidence suggests that NET formation is also induced in sterile inflammation, triggers pathological thrombosis and is harmful to the host. NETs have been established as critical components of venous thrombosis. However, their exact activities remain elusive. For instance, it is not known whether NETs induce vessel wall remodeling and distant secondary organ injury as a consequence of the thrombotic event. The primary aims of this grant proposal are (1) to elucidate the contribution of NETs to post-thrombotic vessel wall fibrosis as a consequence of deep vein thrombosis (DVT) and (2) to investigate how DVT-induced systemic inflammation affects the function of tissues and organs distal to the thrombosed vessel. To address these questions, wild-type and genetically modified mice deficient for enzymes critical for NET formation will be subjected to models of DVT in the inferior vena cava (IVC). The IVC will be evaluated for NET formation and fibrosis. Additionally, signs of a systemic pro-coagulant and pro-inflammatory state and of secondary organ damage will be subsequently assessed in the afflicted host by a wide range of biochemical, immunohistochemical and imaging techniques. This research project will advance our understanding of the mechanisms by which NETs may promote vessel wall injury and associated fibrosis and how they may participate in the systemic thrombo-inflammatory conditions in DVT. This work is likely to have important implications for the development of novel thrombolytic therapies, aiming at prevention or degradation of NETs.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Denisa D. Wagner, Ph.D.