Bonnans Caroline, Levy Bruce D
Department of Respiratory Disease, Arnaud de Villeneuve Hospital, Montpellier, France.
Am J Respir Cell Mol Biol. 2007 Feb;36(2):201-5. doi: 10.1165/rcmb.2006-0269TR. Epub 2006 Sep 21.
Resolution of acute lung inflammation and injury is an active process; it is not merely the absence of proinflammatory signals. Restoration of homeostasis is coordinated by specific mediators and cellular events. In response to injury and inflammatory stimuli, infiltrating leukocytes and tissue-resident cells interact to generate lipoxins (LXs), which are bioactive eicosanoids derived from arachidonic acid. In contrast to proinflammatory leukotrienes and prostaglandins, LXs display potent antiinflammatory actions. LXA(4) interacts with a G protein-coupled receptor, termed ALX, that transduces counter-regulatory signals in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate (PSDP) is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to presqualene monophosphate (PSMP) upon cell activation. PSDP, but not PSMP, directly inhibits phospholipase D, phosphoinositol-3 kinase, and superoxide anion generation. LXs block PSDP turnover in neutrophil membranes to prevent proinflammatory responses. Hence, LX and polyisoprenyl phosphate signaling provide a counter-regulatory circuit to promote resolution of acute lung inflammation. LXA(4) and PSDP mimetics have been prepared with potent protective actions in murine models of asthma and acute lung injury.
急性肺炎症和损伤的消退是一个活跃的过程；它不仅仅是缺乏促炎信号。内环境稳态的恢复是由特定的介质和细胞事件协调的。响应损伤和炎症刺激，浸润的白细胞和组织驻留细胞相互作用产生脂氧素（LXs），脂氧素是源自花生四烯酸的生物活性类二十烷酸。与促炎白三烯和前列腺素相反，脂氧素具有强大的抗炎作用。LXA(4)与一种称为ALX的G蛋白偶联受体相互作用，该受体部分通过细胞内聚异戊二烯磷酸重塑转导反调节信号。法呢基焦磷酸（PSDP）是人类中性粒细胞中的一种聚异戊二烯磷酸，细胞激活后会迅速转化为法呢基单磷酸（PSMP）。PSDP而非PSMP直接抑制磷脂酶D、磷酸肌醇-3激酶和超氧阴离子的产生。脂氧素阻断中性粒细胞膜中PSDP的周转以防止促炎反应。因此，脂氧素和聚异戊二烯磷酸信号传导提供了一个反调节回路，以促进急性肺炎症的消退。在哮喘和急性肺损伤的小鼠模型中，已经制备出具有强大保护作用的LXA(4)和PSDP模拟物。
