Chiang N, Gronert K, Clish C B, O'Brien J A, Freeman M W, Serhan C N
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
J Clin Invest. 1999 Aug;104(3):309-16. doi: 10.1172/JCI7016.
Polymorphonuclear neutrophil (PMN) activation is pivotal in acute inflammation and injury from reperfusion. To elucidate components controlling PMNs in vivo, we prepared novel transgenic mice with the human leukotriene (LT) B4 receptor (BLTR) for functional characterization. Overexpression of BLTR in leukocytes dramatically increased PMN trafficking to skin microabscesses and lungs after ischemia-reperfusion, whereas mice deficient in 5-lipoxygenase (5-LO) showed diminished PMN accumulation in reperfused lungs. Hence, both BLTR expression and LT biosynthesis are critical for PMN infiltration in reperfusion-initiated second-organ injury. Also, in BLTR transgenic mice, 5-LO expression and product formation were selectively increased in exudates, demonstrating that receptor overexpression amplifies proinflammatory circuits. Endogenous lipoxin (LX) A4 was produced in ischemic lungs and elevated by reperfusion. Because LXA4 and aspirin-triggered 15-epimeric LXA4 (ATL) selectively regulate leukocyte responses, they were tested in BLTR transgenic mice. Despite excessive PMN recruitment in BLTR transgenic mice, intravenous injection of ATL sharply diminished reperfusion-initiated PMN trafficking to remote organs, and topical application of LX was protective in acute dermal inflammation. These results demonstrate a direct role for BLTR with positive feedback, involving BLTR and 5-LO signaling in controlling PMNs. Moreover, LXA4 and ATL counter BLTR-amplified networks, revealing a novel protective role for LX and ATL in stress responses that has applications in perioperative medicine.
多形核中性粒细胞（PMN）的激活在急性炎症和再灌注损伤中起关键作用。为了阐明体内控制PMN的成分，我们制备了具有人白三烯（LT）B4受体（BLTR）的新型转基因小鼠以进行功能表征。白细胞中BLTR的过表达显著增加了缺血再灌注后PMN向皮肤微脓肿和肺的迁移，而缺乏5-脂氧合酶（5-LO）的小鼠在再灌注肺中PMN的积累减少。因此，BLTR表达和LT生物合成对于再灌注引发的第二器官损伤中PMN的浸润都至关重要。此外，在BLTR转基因小鼠中，渗出液中5-LO的表达和产物形成选择性增加，表明受体过表达放大了促炎回路。内源性脂氧素（LX）A4在缺血肺中产生并因再灌注而升高。由于LXA4和阿司匹林触发的15-表异构LXA4（ATL）选择性调节白细胞反应，因此在BLTR转基因小鼠中对它们进行了测试。尽管BLTR转基因小鼠中PMN募集过多，但静脉注射ATL可显著减少再灌注引发的PMN向远处器官的迁移，局部应用LX对急性皮肤炎症具有保护作用。这些结果证明了BLTR具有正反馈的直接作用，涉及BLTR和5-LO信号传导来控制PMN。此外，LXA4和ATL对抗BLTR放大的网络，揭示了LX和ATL在应激反应中的新保护作用，这在围手术期医学中有应用价值。
