LPS EFFLUX HOST CELLS TO PLASMA LIPOPROTEINS

描述(摘自申请者摘要)：细菌脂多糖 (脂多糖)是一种有效的免疫调节化合物，在革兰氏过程中 阴性感染，可能在脓毒症的诱导中起主要作用 令人震惊。因此，要全面了解 这些强效物质对免疫调节的运输、解毒和减弱作用 细菌膜成分将是形成有效的 感染性休克的干预策略。之前的工作来自几个 实验室已经表明，内毒素从革兰氏阴性菌表面释放出来 细菌似乎有两种命运：脂蛋白可能与白细胞结合，启动一种 炎症反应，或者它们与血浆脂蛋白结合，后者 减弱内毒素的生物活性，促进清除。最近在Dr。 厨房的实验室表明，宿主中还有一个额外的成分 对内毒素的反应。内毒素可以从白细胞表面去除，并 与血浆脂蛋白或纯化的高密度脂蛋白混合物复合 脂蛋白(Hdl)。这种现象被称为内毒素外流。归纳法 炎症时急性期反应物的减少可能会增加内毒素的外流。最后， 内毒素的外流可能是下调宿主炎症的原因 对内毒素的反应。提出了四个具体的目标来解决这一假设 内毒素外流可降低细胞对内毒素的反应。 特异性目标1：确定细胞表面蛋白在内毒素中的作用 细胞和脂蛋白之间的交通。 特定目标2：确定可溶性脂转移所起的作用 内毒素外流和对已感染内毒素的细胞的反应中的蛋白质。 具体目标3：评估天然脂蛋白的相对重要性 作为细胞相关受体的正常和急性期血浆类 LP。特定目标4：研究内毒素外流对细胞反应的影响 LP。

Description (adapted from applicant's abstract): Bacterial lipopolysaccharides (LPS) are potent immunomodulatory compounds which, during the course of Gram negative infections, probably play a major role in the induction of septic shock. Therefore, a complete understanding of host mechanisms involved in the transport, detoxification, and attenuation of immune modulation by these potent bacterial membrane constituents will be necessary to formulate effective interventional strategies for septic shock. Previous work from several laboratories has shown that LPS released from the surface of Gram negative bacteria appear to have two fates: LPS may bind to leukocytes to initiate an inflammatory responses, or they made bind to plasma lipoproteins which attenuates LPS bioactivity and facilitates clearance. Recent work in Dr. Kitchens' laboratory suggests that there is an additional component in the host response to LPS. LPS may be removed from the surface of leukocytes and complexed with plasma lipoproteins or mixtures of purified high-density lipoproteins (HDL). This phenomenon is referred to as LPS efflux. The induction of acute phase reactants during inflammation may enhance LPS efflux. Finally, LPS efflux may be responsible for down-regulation of the host inflammatory response to LPS. Four specific aims are offered to address the hypothesis that LPS efflux reduces cellular responses to LPS. Specific aim 1: To determine the roles played by cell surface proteins in LPS traffic between cells and lipoproteins. Specific aim 2: To determine the roles played by soluble lipid transfer proteins in LPS efflux and in responses to cells that have acquired LPS. Specific aim 3: To evaluate the relative importance of natural lipoprotein classes from normal and acute phase plasma as acceptors for cell-associated LPS. Specific aim 4: To study the impact of LPS efflux on cellular responses to LPS.