Investigation of the influence of obesity on ischemia-reperfusion effects in the lung and involved signaling pathways in a murine model

• Applicant: Dr. Manuel Sollmann
• Subject Area: Anaesthesiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 569327064

In the context of lung transplantation (LuTx), ischemia-reperfusion injury (IR injury) occurs due to the stop of blood flow to the lungs after removal of the donor and before implantation of the organ into the host. This reduces the function and half-life of the organ, which is a problem concerning the shortage of donor lungs. One factor that could be relevant in the context of IR injury of the lung is the so-called obesity-induced metainflammation. This is a condition comparable to chronic inflammation triggered by chronic metabolic stress due to a high-calorie and high-fat diet. Among other things, this condition is accompanied by a pro-inflammatory polarization of macrophages and an increased release of proinflammatory cytokines. The present project investigates the influence of metainflammation on IR injury of the lung in a mouse model. The first objective is to investigate whether obesity aggravates IR injury in the lung and involved signaling pathways. One potentially involved pathway is the “adenosine monophosphate-activated protein kinase” (AMPK) pathway. Studies have shown that AMPK protects against hypoxic conditions by increasing the supply of energy carriers and reducing the metabolism of the cell. Interestingly, AMPK is downregulated in the context of obesity. The second objective is to evaluate therapeutic options for enhanced IR injury in the context of metainflammation. Specifically, the glucagon-like protein 1 (GLP-1) analogue liraglutide and the dipeptidyl peptidase 4 inhibitor (DPP4) vildagliptin will be evaluated and an optimal treatment regimen outlined. Relevant is the influence of obesity on the quantity and phenotype of leukocytes in the lungs as well as the influence of GLP-1 analogs / DPP4 inhibitors on the leukocytes in the lungs. The third objective is to investigate the influence of lipocalin-2 on pulmonal IR injury. Lipocalin-2 is a so-called adipokine. Adipokines are cytokines secreted by adipose tissue. Obesity causes an increase in secretion of lipocalin-2. In IR experiments of the brain and heart, depletion of lipocalin-2 had a protective effect. In summary, the aim of this project is to investigate the significance of obesity and the associated metainflammation on IR injury to the lungs, to identify involved signaling pathways and to evaluate therapeutic strategies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Jeffrey Dodd-o, Ph.D.