Ischemia Reperfusion Injury (IRI) causes Local Release of Free Heme which Aggravates Inflammation and Contributes to Delayed Graft Function
Li Wang1, Vijith Vijayan2, Rongjun Chen2, Anja Thorenz2, Cees van Kooten3, Hermann Haller1, Stephan Immenschuh2, Faikah Gueler1.
1Nephrology, Hannover Medical School, Hannover, Germany; 2Transfusion Medicine, Hannover Medical School, Hannover, Germany; 3Nephrology, Einthoven laboratory of Vascular and Regenerative Medicine, Leiden University Medical Centre, Leiden, Netherlands
Ischemia reperfusion injury (IRI) is relevant in solid organ transplantation and contributes to delayed graft function (DGF). In this study, release of free heme after renal IRI and the consecutive inflammatory response were studied in mice.
Methods: Renal IRI was induced by 15, 35 and 45 min unilateral renal pedicle clamping in mice. Sham surgery served as control. Mice were sacrificed at 2 and 4 and 24 hours after IRI. Free heme was measured in the kidney and systemic complement activation was measured in blood samples. qPCR for pro-inflammatory cytokine expression, histology and immunohistochemistry for acute kidney injury were done.
Results: In correlation with increased duration of ischemia time the free heme generation in the tissue increased and enhanced local pro-inflammatory cytokine release (TNF-alpha, MCP-1, IL-6) was measured. AKI score and inflammatory cell infiltration into the tissue increased as well. Complement activation was higher in correlation with longer ischemia time
Conclusion: Free heme release in ischemic organs aggravates local inflammation. Strategies to reduce free heme production prior to solid organ transplantation would be promising therapeutic approaches to reduce the risk of DGF.
