Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Alabama, USA.
J Leukoc Biol. 2018 Dec;104(6):1173-1186. doi: 10.1002/JLB.3A0618-223R. Epub 2018 Aug 26.
Inflammation-limiting nonsteroidal pain relievers magnify myocardial infarction (MI) incidences and increase re-admission events in heart failure (HF) patients. However, the molecular and cellular mechanism of this provocative adverse effect is unclear. Our goal was to determine whether carprofen (CAP) impedes splenic leukocyte-directed acute inflammation-resolving response in cardiac injury. After subacute CAP treatment, mice were subjected to permanent coronary ligation maintaining MI- and naïve-controls. Spleen and left ventricle (LV) leukocytes were quantitated using flow cytometry pre- and 24 h post-MI. The inflammation resolution mediators were quantified using mass spectrometry while splenocardiac apoptosis and leukocyte phagocytosis were measured by immunofluorescence and ImageStream, respectively. Subacute CAP treatment promoted strain and cardiac dysfunction before MI and coronary occlusion showed signs of acute HF in CAP and MI-controls. Subacute CAP-injected mice had pre-activated splenic neutrophils, an over activated "don't eat me" signal (CD47) with reduced total Mϕs (F4/80 ) and reparative Mϕs (F4/80/Ly6C /CD206) compared with control in LV and spleen. Post-MI, CAP pre-activated neutrophils (Ly6G ) were intensified and reduced reparative neutrophils (Ly6G /CD206 ) and Mϕs (F4/80/Ly6C ) in LV was indicative of non-resolving inflammation compared with MI-control. Subacute CAP treatment deferred neutrophil phagocytosis functions in the spleen and LV and was more evident post-MI compared with MI-control. CAP pre-activated splenic neutrophils that tailored the Mϕ phagocytosis thereby increased splenocardiac leukocyte death. CAP over amplified COX-1 and COX-2 compared with MI-control and failed to limit prostaglandins and thromboxane in post-MI setting. Further, CAP reduced cardiac-protective epoxyeicosatrienoic acids and over amplified pyrogenic inflammatory cytokines and reduced reparative cytokines, thereby non-resolving inflammation.
炎症限制型非甾体类抗炎药会增加心肌梗死（MI）的发生率，并增加心力衰竭（HF）患者的再入院事件。然而，这种刺激性不良反应的分子和细胞机制尚不清楚。我们的目标是确定卡洛芬（CAP）是否会阻碍心脏损伤中脾脏白细胞定向的急性炎症消退反应。在亚急性 CAP 治疗后，将小鼠进行永久冠状动脉结扎，维持 MI 和对照。使用流式细胞术在 MI 前和 24 小时后定量检测脾脏和左心室（LV）白细胞。使用质谱法定量炎症消退介质，同时通过免疫荧光和 ImageStream 分别测量脾-心细胞凋亡和白细胞吞噬作用。亚急性 CAP 处理在 MI 前促进了菌株和心脏功能障碍，而冠状动脉闭塞在 CAP 和 MI 对照组中显示出急性 HF 的迹象。与对照组相比，亚急性 CAP 注射小鼠的脾脏中性粒细胞预先激活，“不要吃我”信号（CD47）过度激活，总巨噬细胞（F4/80）减少，修复性巨噬细胞（F4/80/Ly6C / CD206）减少，LV 和脾脏。MI 后，与 MI 对照组相比，CAP 预先激活的中性粒细胞（Ly6G）增加，修复性中性粒细胞（Ly6G / CD206）和巨噬细胞（F4/80/Ly6C）减少，表明炎症未得到解决。与 MI 对照组相比，亚急性 CAP 治疗延迟了脾脏和 LV 中的中性粒细胞吞噬功能，并且在 MI 后更为明显。CAP 预先激活的脾脏中性粒细胞调整了巨噬细胞的吞噬作用，从而增加了脾-心白细胞死亡。与 MI 对照组相比，CAP 过度扩增 COX-1 和 COX-2，并且在 MI 后未能限制前列腺素和血栓素。此外，CAP 减少了心脏保护性环氧二十碳三烯酸，并过度放大了致热炎症细胞因子，减少了修复性细胞因子，从而导致炎症未得到解决。
