Immunoferroptosis: a novel mechanism and promising therapeutic strategy in lung transplantation.

• Applicants: Privatdozent Alexey Dashkevich, Ph.D.; Professor Ali Önder Yildirim, Ph.D.
• Subject Area: Cardiac and Vascular Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505756743

Lung transplantation is the last resort for patients with end-stage lung diseases. The lung transplant recipients benefit from this procedure with health improvement. Unfortunately, lung transplantation displays the worst long-term survival in all solid organ transplantation. Although surgical technique, donor selection, lung preservation, and immunosuppressive therapies have been advanced, the median survival after lung transplantation has increased only slightly, to just 6.7 years in adults. The greatest threat to long-term survival for lung recipients who have survived more than one year post-transplantation is the onset and progression of chronic lung allograft dysfunction (CLAD), which includes three phenotypes: bronchiolitis obliterans syndrome (BOS), neutrophilic reversible allograft dysfunction, and restrictive allograft syndrome, and each of them is characterized either by airway obstruction or restriction, and is largely unresponsive to immunosuppression.Among various cell death pathways described, ferroptosis is a ROS-dependent form of cell death associated with two main biochemical characteristics, namely iron accumulation and lipid peroxidation, leading to caspase- and necrosome-independent cell death. Ischemia-reperfusion injury (IRI) is one of the risk factors for developing chronic lung allograft rejection and recent publications are linking the severity of IRI with the phenomenon of ferroptosis. However, the molecular mechanisms underlying the induction of ferroptotic cell death in the chronically rejecting lung and its contribution to BOS development remains unknown along with its potential as a much-needed therapeutic target. Here, we aim to elucidate the contribution of specific mechanisms of immunoferroptotis as the primary cell death in orchestrating CLAD and BOS development in the chronically rejecting lung allografts and to delineate their potential as BOS biomarkers in patient to improve an early diagnosis.The mutual application of Dr. Alexey Dashkevich as a clinician and Dr. Ali Önder Yildirim as a basic researcher should enforce the implication of the bench findings to the clinically relevant questions.

• DFG Programme: Research Grants