The role of SDF_1α/CXCR4 axis in non-antibody mediated TRALI in cardiac surgery patients

Abstract Background Acute lung injury (ALI) after extracorporeal circulation can originate from multiple causes, including transfusion. Despite improvements in blood safety policy, transfusion-related lung injury (TRALI) continues to occur, suggesting an incomplete understanding of its pathogenesis. Objectives To evaluate the association between the composition of the red blood cell unit (RBC) and the onset of ALI after transfusion, defined by a ratio between partial pressure of oxygen (PaO 2 ) and the fraction of inspired oxygen (FiO 2 ) ≤ 300 mmHg in the first 3 days postoperatively. Methods Adults undergoing scheduled cardiac surgery at Nantes University Hospital between September 2016 and March 2021 and requiring transfusion of 1–5 RBC during surgery were included. To determine the exposure of each patient (i.e., total amount of inflammatory proteins received during transfusion), we analyzed the composition (panel of 15 proteins) of each RBC received by the participants. After stimulation of peripheral blood mononuclear cells (PBMC) with supernatant RBC (SN-RBC), NK cell cytotoxicity to pulmonary epithelial cells (Calu_3 cells) was assessed. Finally, we determined the association between SN-RBC composition, patient characteristics, and blood donation preparation methods. Results Over the study period, 161 patients were included, of whom 54 (33.5%) developed ALI within the first 3 days. Patients with ALI had a significantly higher median (IQR) exposure to SDF_1α than non-ALI patients 2.0 × 10 4 (0.0 to 4.2 × 10 4 ) vs. 1.0 × 10 4 (0.0 to 2.7 × 10 4 ) picograms, P = 0.02. In vitro, PBMC coculture with SN-RBC containing high levels of SDF_1α enhanced NKG2D-dependant NKG2A + NK cell cytotoxicity to Calu_3 cells. RBC from female donors or donors with platelet counts higher than 300 × 10 9 /L showed the highest concentration of SDF_1α, as well as RBC prepared by "whole blood filtration". Conclusions High exposure to SDF_1α through transfusion may be associated with the onset of ALI following cardiac surgery. The increase in NKG2D-dependent cytotoxicity of NKG2A + NK cells is a possible explanation for this finding. These results advocate for better characterization of the determinants of RBC composition and for developing new immune strategies to mitigate transfusion side effects.