UMR 1148 INSERM, Xavier Bichat Hospital, 46 rue Henri Huchard, Paris, France.
IGMBC, Illkirch, France.
Cardiovasc Res. 2018 Oct 1;114(12):1656-1666. doi: 10.1093/cvr/cvy130.
Both leukotrienes and neutrophils have been linked to plaque destabilization. Despite being evoked, the role of leukotriene B4 (LTB4) in neutrophil recruitment to plaques and the concomitant effects of these two actors on plaque stability remain to be proven. Since both actors are elicited during endotoxaemia, a condition associated with the risk of cardiovascular events, we investigated whether endotoxaemia promotes LTB4-mediated neutrophil infiltration in plaques and explored the roles of LTB4 and neutrophils in plaque destabilization.
Endotoxaemia induced by repeated peritoneal endotoxin injections at a non-lethal dose (1.5 mg/kg, 5 days) in chow-fed aged Apoe-/- mice (over 45 weeks old) resulted in neutrophil infiltration and activation in plaques. Subsequently to neutrophil invasion, plaques exhibited increased features of vulnerability: reduced collagen content, expanded necrotic cores, and thinned fibrous caps. These plaque features were reproduced by direct deposition of isolated neutrophils onto murine atheromatous carotid arteries in an in vivo assay. In endotoxemic mice, plaques produced increased amounts of LTB4. Genomic or pharmacological impairments of this production reduced neutrophil infiltration, collagenolysis, and apoptosis of smooth muscle cells in plaques of endotoxemic mice. Furthermore, conditioned media of human culprit plaques (CPs) contained more LTB4 than non-CPs and levels of LTB4 correlated to both neutrophil activation markers and endotoxin releases in CPs.
These results show that the increased neutrophil recruitment elicited by LTB4 contributes to increase features of plaque destabilization in endotoxemic contexts and point out LTB4 as a potential therapeutic target in atherosclerosis.
白三烯和中性粒细胞都与斑块不稳定有关。尽管已经被诱发，但白三烯 B4（LTB4）在中性粒细胞向斑块募集中的作用以及这两种因子对斑块稳定性的共同影响仍有待证实。由于这两种因子都在内毒素血症中被激发，而内毒素血症与心血管事件的风险相关，因此我们研究了内毒素血症是否促进 LTB4 介导的斑块内中性粒细胞浸润，并探讨了 LTB4 和中性粒细胞在斑块不稳定中的作用。
用非致死剂量（1.5mg/kg，5 天）的重复腹腔内内毒素注射在普通饮食喂养的年龄 Apoe-/- 小鼠（超过 45 周龄）中诱导内毒素血症，导致中性粒细胞浸润和斑块激活。随后，中性粒细胞入侵后，斑块表现出增加的脆弱性特征：胶原含量减少、扩大的坏死核心和变薄的纤维帽。这些斑块特征可以通过将分离的中性粒细胞直接沉积到体内实验中的鼠动脉粥样硬化颈动脉上来重现。在内毒素血症小鼠中，斑块产生的 LTB4 增加。该产生的基因或药物损伤减少了内毒素血症小鼠斑块中的中性粒细胞浸润、胶原溶解和平滑肌细胞凋亡。此外，人罪犯斑块（CPs）的条件培养基中含有比非 CPs 更多的 LTB4，并且 LTB4 的水平与 CPs 中的中性粒细胞激活标志物和内毒素释放相关。
这些结果表明，LTB4 诱发的中性粒细胞募集增加导致内毒素血症背景下斑块不稳定特征增加，并指出 LTB4 是动脉粥样硬化的潜在治疗靶点。
