THE ACUTE CHEST SYNDROME IN SICKLE CELL ANEMIA: THE ROLE OF THE NEUTROPHIL

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。急性胸部综合征（ACS）是镰状细胞病（SCD）特有的一种急性肺损伤（ALI）。对于> 10岁的儿童，ACS是发病和死亡的主要原因。ACS的发病机制尚不清楚;然而，最近的研究记录了ACS发生前24小时分泌型磷脂酶A2（sPLA 2）活性增加（100%的儿童）。ALI是由PMN介导的，尽管PMN在ACS中的作用尚不清楚。由于sPLA 2可以通过膜磷脂的裂解间接地或通过膜受体的激活直接地影响PMN，我们假设SCD中的急性胸部综合征继发于sPLA 2激活PMN，导致PMN介导的ALI。这一假设将通过完成以下具体目标进行检验：1。检查sPLA 2是否引起脂质从镰状红细胞（RBC）膜裂解; 2.测试镰状细胞病患者患病时的血浆，并与他们的“基线”血浆进行比较，以确定脂质介质是否在血管闭塞危象（VOC）或ACS期间积聚; 3.确定在VOC期间镰状RBC的sPLA 2孵育是否导致脂质介质的释放; 4.在PMN介导的体外肺内皮损伤的两事件模型中使用这些脂质介质

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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