Cytokines, IL-1beta, IL-6, IL-8, and TNFalpha, and lipids, lysophosphatidy1cholines (lyso-PCs), are generated during blood storage and may cause deleterious effects in the transfused host. One of these life-threatening complications is transfusion related acute lung injury (TRALI). Previous work has shown that lipids generated during routine blood storage are involved in the pathogenesis of TRALI. Lyso-PCs rapidly prime neutrophils (PMNs) in vitro for maximal cytotoxic potential and increased adherence to vascular endothelium (EC). Moreover, IL-6, IL-8 and TNFalpha also prime PMNs in vitro. Therefore, lipids and cytokines produced during blood storage may prime the PMNs of transfused hosts predisposing them to TRALI. PMN priming involves augmentation of both degranulation and the respiratory burst in response to a second agonist as well as increased adhesion of PMNs to EC, which results in the indiscriminate adherence to EC of PMNs with maximal cytotoxic potential. Priming agents cause acute lung injury in animal models; however, two agents must be administered. Furthermore, many of the agents used in these animal models also activate EC causing upregulation of adhesion molecules. We have hypothesized that a similar two event model exists for TRALI with each patient having an underlying clinical condition, which could act as the first event, followed by the infusion of lipids and cytokines in stored blood components representing the second event. We will test this hypothesis in by completing the following specific aims.
Specific Aim 1 : we have developed an animal model of TRALI to investigate the role of cytokines and lipids from stored blood as the second, of the two insults required in the pathogenesis of TRALI.
Specific Aim 2 will examine the clinical entities associated with the first event of this two event model including recent surgery, massive transfusion and cytokine therapy. In addition, the ability of the mediators involved with these clinical entities to activate pulmonary endothelium and to alter the PMN:EC physiology will be tested. Completion of these specific aims will provide information to target areas for clinical intervention to make transfusions safer.
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