Novel polyisoprenyl phosphates block phospholipase D and human neutrophil activation in vitro and murine peritoneal inflammation in vivo
Novel polyisoprenyl phosphates block phospholipase D and human neutrophil activation in vitro and murine peritoneal inflammation in vivo
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DOI：
10.1038/sj.bjp.0706338
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发表时间：
2005-10-01
影响因子：
7.3
通讯作者：
Serhan, CN
中科院分区：
文献类型：
--
作者：
Levy, BD;Hickey, L;Serhan, CN
1白细胞产生活性氧（ROS）是宿主防御过程中安装的抗菌武器的重要组成部分，但当释放到细胞外环境时，ROS也会损伤宿主组织并引起炎症。聚异戊二烯磷酸盐（PIPPs）是人类白细胞膜的成分，调节关键的细胞内酶，如磷脂酶D（PLD）。我们制备了新的PIPP模拟物，并研究了它们在急性炎症中对白细胞活化（包括ROS生成）的体内影响。2 PIPP模拟物以立体特异性和浓度依赖性方式直接调节色褐链霉菌磷脂酶D（sPLD）的作用。内源性前角鲨烯二磷酸（PSDP）的α（Z）-异构体的IC 50为100 nM。3还确定了PIPP模拟抑制重组人PLD 1b（人白细胞中的一种主要亚型）的结构-活性关系。PLD 1b抑制的PIPP模拟物等级顺序与sPLD不同，尽管（Z）- PSDP异构体仍然是抑制两种酶的最有效的PIPP模拟物。将PLD 1b截短到其催化核心揭示了PSDP的类异戊二烯和二磷酸部分的潜在调节作用。4在酵母聚糖A引发的腹膜炎期间，（Z）- PSDP异构体减少了激活的人白细胞的ROS产生，并减少了小鼠中性粒细胞的积累（65.6%）和体内ROS产生（38.5%）。酵母聚糖A给药后2 h腹腔内给药时，（Z）- PSDP异构体可降低体内中性粒细胞蓄积（72.5%）和6 h后腹膜渗出液中ROS生成（74.4%）。5总之，这些结果为保护和控制许多人类疾病特征的未受抑制的炎症反应提供了新方法。
1 Leukocyte production of reactive oxygen species ( ROS) is an essential component of the antimicrobial armament mounted during host defense, but when released to the extracellular milieu ROS can also injure host tissues and provoke inflammation. Polyisoprenyl phosphates ( PIPPs) are constituents of human leukocyte membranes that regulate pivotal intracellular enzymes, such as phospholipase D ( PLD). We prepared new PIPP mimetics and studied their impact in vivo on leukocyte activation, including ROS generation, in acute inflammation.2 In a stereospecific and concentration- dependent manner, the PIPP mimetics directly regulated Streptomyces chromofuscus phospholipase D ( sPLD) action. The IC50 for a ( Z)- isomer of endogenous presqualene diphosphate ( PSDP) was 100 nM.3 Structure - activity relationships were also determined for PIPP mimetic inhibition of recombinant human PLD1b, a prominent isoform in human leukocytes. The PIPP mimetic rank order for PLD1b inhibition differed from sPLD, although the ( Z)- PSDP isomer remained the most potent PIPP mimetic for inhibition of both enzymes. Truncation of PLD1b to its catalytic core uncovered potential regulatory roles for both PSDP's isoprenoid and diphosphate moieties.4 The ( Z)- PSDP isomer reduced ROS production by activated human leukocytes and decreased murine neutrophil accumulation ( 65.6%) and ROS production ( 38.5%) in vivo during zymosan A- initiated peritonitis. When administered intraperitoneally 2 h after zymosan A, the ( Z)- PSDP isomer decreased in vivo neutrophil accumulation ( 72.5%) and ROS generation ( 74.4%) 6 h later in peritoneal exudates.5 Together, these results provide new means to protect and control unchecked inflammatory responses that characterize many human diseases.