Gillinov A M, Redmond J M, Zehr K J, Wilson I C, Curtis W E, Bator J M, Burch R M, Reitz B A, Baumgartner W A, Herskowitz A
Department of Cardiac Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Ann Thorac Surg. 1994 Jan;57(1):126-33. doi: 10.1016/0003-4975(94)90380-8.
Blood contact with synthetic surfaces during cardiopulmonary bypass (CPB) causes a diffuse inflammatory reaction that includes neutrophil activation. The purpose of this study was to determine if inhibition of neutrophil adhesion with a new antiinflammatory agent NPC 15669 (N-(9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl)-L-leucine) could reduce pulmonary injury in a porcine model of CPB. NPC 15669 blocks adherence of activated neutrophils by inhibiting upregulation of the Mac-1 (CD11b/CD18) adhesion molecule. Sixteen piglets underwent 2 hours of hypothermic CPB followed by 2 hours of observation; 8 received NPC 15669 (10 mg/kg intravenous bolus followed by 6 mg.kg-1.h-1 intravenous infusion) and 8 received equal volumes of vehicle. After 90 minutes of CPB, expression of neutrophil adhesion molecule subunit CD18 increased 118% in control piglets but only 36% in piglets treated with NPC 15669 (p < 0.01). Although neutropenia developed in all animals during CPB, lung tissue myeloperoxidase content was significantly lower in treated than in control animals 2 hours after CPB (94.9 +/- 10.4 versus 46.9 +/- 5.5 mumol.10 mg-1.min-1; p < 0.002). Free radical-mediated lipid peroxidation (quantitated by spectrophotometric assay of plasma conjugated dienes) was significantly reduced by treatment with NPC 15669 during and after CPB. Pulmonary function was better in NPC 15669-treated animals: 2 hours after CPB, pulmonary vascular resistance increased 477% in control piglets but only 140% in piglets receiving NPC 15669 (p < 0.03); arterial oxygen tension was significantly greater in piglets receiving NPC 15669 (428 +/- 33 mm Hg) than in controls (141 +/- 46; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
在体外循环（CPB）期间，血液与合成表面接触会引发包括中性粒细胞激活在内的弥漫性炎症反应。本研究的目的是确定使用新型抗炎药物NPC 15669（N-(9H-(2,7-二甲基芴基-9-甲氧基)-羰基)-L-亮氨酸）抑制中性粒细胞黏附是否能减轻猪CPB模型中的肺损伤。NPC 15669通过抑制Mac-1（CD11b/CD18）黏附分子的上调来阻止活化中性粒细胞的黏附。16只仔猪接受了2小时的低温CPB，随后观察2小时；8只接受NPC 15669（静脉推注10 mg/kg，随后以6 mg·kg-1·h-1静脉输注），8只接受等量的赋形剂。CPB 90分钟后，对照仔猪中性粒细胞黏附分子亚基CD18的表达增加了118%，而接受NPC 15669治疗的仔猪仅增加了36%（p<0.01）。尽管CPB期间所有动物均出现中性粒细胞减少，但CPB 2小时后，治疗组动物肺组织髓过氧化物酶含量显著低于对照组（94.9±10.4对46.9±5.5 μmol·10 mg-1·min-1；p<0.002）。在CPB期间及之后，用NPC 15669治疗可显著降低自由基介导的脂质过氧化（通过血浆共轭二烯的分光光度法测定）。接受NPC 15669治疗的动物肺功能更好：CPB 2小时后，对照仔猪肺血管阻力增加了477%，而接受NPC 15669的仔猪仅增加了140%（p<0.03）；接受NPC 15669的仔猪动脉血氧张力显著高于对照组（428±33 mmHg对141±46；p<0.0001）。（摘要截短于250字）
