Blood transfusion and the two-insult model of post-injury multiple organ failure

Neutrophils (PMNs) have been implicated in the pathogenesis of multiple org an failure (MOF). The two-insult model of MOF is based on the fundamental c oncept that two sequential and independent insults that are individually in nocuous against the host can cause overwhelming inflammation. The in vitro PMN priming/activation sequence simulates the two-insult model. Our work ha s demonstrated that transfusion is an early consistent risk factor for post -injury MOF and lysophosphatidylcholines (lyso-PCs) are generated in stored blood components. Additionally, platelet-activating factor (PAF) is a key inflammatory agent produced in severely injured patients. We therefore hypo thesize that two events, trauma and transfusion, enhance PMN cytotoxicity i rrespective of the sequence. Superoxide (O-2(-)) production was measured by reduction of cytochrome c, adherence to fibrinogen was assessed by the rad ioactivity of adherent (Na2CrO4)-Cr-51 (Cr-51)-labeled PMNs, and endothelia l cell (EC) damage by measuring the radioactivity released from Cr-51-label ed human umbilical vein endothelial cells monolayers. Isolated PMNs were pr imed with buffer, PAF (2 muM), or lyso-PCs (4.5, 15, and 30 muM) followed b y activation with buffer, N-formyl-methionyl-leucyl-phenylalanine (fMLP)(1 muM), PAF (2 CIM), or lyso-PCs (4.5, 15, and 30 muM). Neither PAF nor lyso- PCs alone stimulated O-2(-) production. While PAF alone caused PMN adherenc e, lyso-PCs alone did not allowed PMNs to adhere to fibrinogen. However, bo th combinations of PAF/lyso-PCs and lyso-PCs/PAF significantly augmented O- 2(-) production and PMN adherence. Furthermore, these enhanced PMN cytotoxi c responses significantly caused EC damage. These findings suggest that in the scenario of the two-insult model, early or late transfusion administere d following trauma can provoke PMN cytotoxicity via priming or activation, thereby increasing the risk of post-injury MOF.