Rolipram plus Sivelestat inhibits bone marrow-derived leukocytic lung recruitment after cardiopulmonary bypass in a primate model
Rolipram plus Sivelestat inhibits bone marrow-derived leukocytic lung recruitment after cardiopulmonary bypass in a primate model
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DOI：
10.1007/s10047-018-1071-0
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发表时间：
2019-03-01
影响因子：
1.3
通讯作者：
Sato, Yukio
中科院分区：
文献类型：
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作者：
Goto, Yukinobu;Hiramatsu, Yuji;Sato, Yukio
心肺转流（CPB）恢复因骨髓（BM）来源的多形核白细胞（PMNs）和单核细胞（MO）引起的肺部炎症而变得复杂。尽管西维来司他减少炎症介质，咯利普兰抑制PMN和MO活化，但体内改善CPB恢复的任何动力学效应尚不清楚。我们假设，术中联合使用这些化合物将通过下调PMN和MO募集来减少CPB诱导的肺部炎症。在食蟹猴（n=13）中通过手术建立2小时CPB，并通过流式细胞术用5-溴-2-脱氧尿苷（BrdU）和细胞因子ELISA监测术后BM白细胞释放和肺募集。术中给予西维来司、西维来司加咯利普兰或生理盐水（对照），外周和灌注取样过程均显示BrdU标记的细胞代表活化的白细胞浸润。细胞因子CD 11b和CD 18水平是白细胞活化标志物。西维来司联合咯利普兰减弱了CPB相关循环带细胞的增加，延长了BM通过时间（PMN：121.0 +/- 3.7至96.2 +/-4.3 h [对照]，p=0.012; MO：84.4 +/- 4.1至61.4 +/-3.0 h [对照]，p=0.003），并减少了肺泡外观。CPB期间CD 11b介导的PMN和MO变化以及术后支气管肺泡灌洗液中白细胞介素（IL）-6和IL-8的升高均受到抑制。单独使用西维来司可使PMN通过时间增加至115.8 +/-6.6 h，但单核细胞不受影响。因此，咯利普兰与西维来司他对CPB诱导的BM源性PMN和MO的活化和释放及其向肺的募集具有相加的抑制作用。因此，这些化合物的联合给药可能具有预防CPB诱导的肺损伤的价值。
Cardiopulmonary bypass (CPB) recovery is complicated by lung inflammation from bone marrow (BM)-derived polymorphonuclear leukocytes (PMNs) and monocytes (MO). Although Sivelestat reduces inflammatory mediators and Rolipram inhibits PMN and MO activation, any kinetic effects to improve CPB recovery in vivo are unknown. We hypothesized that intraoperative co-administration of these compounds would reduce CPB-induced lung inflammation through downregulation of PMN and MO recruitment. A 2-h CPB was surgically established in cynomolgus monkeys (n=13), and BM leukocyte release and lung recruitment were monitored postoperatively by flow cytometry with 5-bromo-2-deoxyuridine (BrdU) and cytokine ELISA. Either Sivelestat, Sivelestat plus Rolipram, or saline (control) was administered intraoperatively and both peripheral and perfusion sampling courses revealed BrdU-labeled cells representative of activated leukocyte infiltration. Levels of cytokines CD11b and CD18 were leukocytic activation markers. Sivelestat plus Rolipram attenuated increases in CPB-associated circulating band cells, prolonged BM-transit time (PMN: 121.0 +/- 3.7 to 96.2 +/- 4.3h [control], p=0.012; MO: 84.4 +/- 4.1 to 61.4 +/- 3.0h [control], p=0.003), and reduced their alveolar appearance. CD11b-mediated PMN and MO changes during CPB and the post-surgical increases of Interleukin (IL)-6 and IL-8 in the bronchoalveolar lavage fluid were suppressed. Sivelestat alone increased PMN transit time to 115.8 +/- 6.6h, but monocytes were unaffected. Therefore, Rolipram has additive inhibitory effects with Sivelestat on the CPB-induced activation and release of BM-derived PMNs and MO and their recruitment to the lungs. Co-administration of these compounds could, therefore, hold value for preventing CPB-induced lung injury.