The purpose of our proposal is to investigate the clinical relevance of elevated secretory phospholipase A2(sPLA2) in acute chest syndrome (ACS) in sickle cell disease (SCD), and to define the molecular and cellular mechanisms by which increased sPLA2 levels results in the acute lung injury of ACS. Our preliminary data suggest that elevated sPLA2 occurs in patients prior to the diagnosis of ACS and that an elevated value might be used to initiate therapy prior to the diagnosis of pulmonary disease. Our studies furthermore suggest that sPLA2 is not only a marker for impending ACS but also plays a key role in the pathogenesis of ACS. A better understanding of the role of this enzyme in ACS is important because acute chest syndrome is the leading cause of death in SCD. To investigate the mechanism by which sPLA2 is upregulated and results in lung damage in SCD, we propose to combine a clinical and laboratory effort with the following specific aims: 1. To determine the relationship between the degree of sPLA2 elevation and the etiology (infectious and non-infectious) of ACS, 2. To initiate a limited phase II clinical trial to determine is sPLA2 levels can be used to initiate effective therapy prior to the development of ACS and 3. To define the substrates and products of sPLA2 that result in the acute lung injury of ACS. We will explore our hypothesis that the dramatic increase in sPLA2 in severe ACS is related to pulmonary fat embolism. The research plan outlined in this application includes formal collaborations with other institutions to generate adequate patient numbers for the limited clinical trial and to evaluate the applicability and feasibility of a future multi- institution phase III trial. We will identify the substrate(s) used by sPLA2, determine the products formed and their relation to lung injury in ACS. Ultimately, the findings of this work could be used in design and evaluation of clinical trials utilizing novel inhibitors of sPLA2. The successful accomplishment of these three objectives should enable us to develop a detailed mechanistic understanding of the pathophysiology of an important complication in sickle cell disease. The insights generate are also likely to further our understanding of the mechanism of lung damage induced by pulmonary fat embolism.
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