This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The acute chest syndrome (ACS) is a form of acute lung injury (ALI) unique to sickle cell disease (SCD). For children > 10 years, ACS is the major cause of morbidity and mortality. The pathogenesis of ACS is unknown; however, recent studies have documented an increase in secretory phospholipase A2 (sPLA2) activity (100% of children) 24 hours prior to development of ACS. ALI is PMN-mediated, though the PMN's role in ACS remains undefined. Because sPLA2 may indirectly, through cleavage of membrane phospholipids or directly, through activation of a membrane receptor, affect PMNs, we hypothesize that the acute chest syndrome in SCD is secondary to sPLA2 activation of PMNs resulting in PMN-mediated ALI. This hypothesis will be tested by completion of the following specific aims: 1. examine if sPLA2 causes cleavage of lipids from sickled red blood cells (RBC) membranes; 2. test the plasma from sickle cell patients when ill and compare to their 'baseline' plasma to determine if lipid mediators accumulate during vaso-occlusive crisis (VOC) or ACS; 3. determine if sPLA2 incubation of the sickled RBCs during VOC causes release of lipid mediators; 4. employ these lipid mediators in a two-event model of PMN-mediated in vitro pulmonary endothelial injury
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