Lymphatic endothelium as a new immunomodulatory target in lung transplantation
Final Report Abstract
The DFG funded project has been accomplished as stated in the timelines of the project. The biggest hurdle in the project management were the general limitations in the research process to the COVID pandemics. Taken together, the scientific findings can be summarized as follows. Allogeneic mouse lung transplantation initiates rapid lymphangiogenesis in our CLAD mouse model. Prolonged cold ischemia time accelerates the development of CLAD phenotype, indicating that deteriorated ischemia-reperfusion injury and indirect allorecognition are fundamental for late stage CLAD development. Furthermore, we have confirmed that pro-inflammatory macrophages and antiinflammatory macrophages are the source of VEGFC after lung transplantation, which is crucial for VEGFR3 signalling and lymphatic activation. Moreover, we have illustrated in cell models that LPS stimulates VEGFC expression in macrophages via NF-kB signalling. TLR4, the receptor for LPS, also plays an important role in ischemia-reperfusion injury, and can be activated by damage associated molecular patterns, including HMGB-1 and low molecular weight hyaluronic acid. IFNg on the other hand regulates VEGFC negatively in macrophages and monocytes. As IFNg is highly released in lung graft by T cells, it might contribute to the regulation of VEGFC release and VEGFR3 signalling. Taken together, our data describe the VEGFC/VEGFR3 signalling pattern and lymphatic endothelial activation after lung transplantation and their significance in the CLAD development.
