Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Lyso-PCs activate PMNs and endothelium via PKC

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Lipids accumulate during the routine storage of blood and stimulate multiple neutrophil (PMN) functions as well as causing activation of human pulmonary microvascular endothelial cells (HMVECs). Epidemiologic studies have demonstrated that older packed red blood cells are independently associated with the development of acute lung iinjury and multiple organ failure in injured aptients. Moreover, we have implicated these lipids in human transfusion related acute lung injury (TRALI) and have proposed a two event model for this life threatening illness, similar to the pathophysiology of the acute respiratory distress syndrome. In this two event model the clinical status of the patient is the first event and the infusion of biologically active lipids in stored blood components is the second event. An animal model of TRALI has verified that the plasma and lipids from stored, but not fresh, blood and blood components cause TRALI and an in vitro model has demonstrated much of the cellular physiology required for this two event lung model. These events include the requirements of 1) endothelial activation (increase in adhesion molecules and chemokine release) resulting in PMN priming and adherence followed by 2) activation of these adherent "hyperresponsive" PMNs, culminating in lung injury. Lysophosphatidylcholines (lyso-PCs) are the major biologically active species that accumulate in cellular blood components, and these compounds stimulate both PMNs and HMVECs through rapid increases in cytosolic calcium and activation of protein kinase C (PKC). We hypothesize that lipids from stored blood stimulate human PMNs and HMVECs through activation of specific PKC isoforms that stimulate endothelial beds and/or activate sequestered PMNs resulting in acute lung injury. This hypothesis will be tested through completion of the following specific aims: 1) to determine the signaling pathways of lyso-PCs from its receptor to its effector kinases; 2) to confirm the that PKC gamma is the effector kinase in lyso-PC mediated signaling; 3) to determine the role of PKC activation in PMNs and HMVECs, and 4) to investigate the effects of PKC inhibition in a well-described animal model of TRALI using a clinically tested PKC inhibitor. Completion of these specific aims will likely result in targets for in vitro, and possibly clinical, intervention to develop methods to inhibit or to attenuate the effects of these lipids and ultimately make transfusion safer.
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