Mathew J P, Rinder C S, Tracey J B, Auszura L A, O'Connor T, Davis E, Smith B R
Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06520-8035.
J Thorac Cardiovasc Surg. 1995 Mar;109(3):448-56. doi: 10.1016/S0022-5223(95)70275-X.
Granulocyte adhesion to ischemic tissue, mediated in large part by beta 2 integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this agent might modulate up-regulation of this adhesion receptor. In vitro, whole blood was incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucyl-phenylalanine, and granulocyte CD11b measured. Acadesine significantly (p < 0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation (p < 0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low- and high-dose treatment groups, there was significant (p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte CD11b in vitro, and acadesine is capable of a similar inhibition during in vivo cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury.
粒细胞与缺血组织的黏附在很大程度上由β2整合素受体介导，在再灌注损伤的病理生理学中起重要作用。阿卡地新是一种调节缺血组织中腺苷水平的药物，已被证明可减轻缺血动物模型中的再灌注损伤。本研究的目的是在体外试验和体外循环期间给予阿卡地新的体内试验中测量粒细胞CD11b/CD18的变化，以确定该药物是否可能调节这种黏附受体的上调。在体外，将全血与阿卡地新或对照稀释剂孵育，用N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸刺激，并测量粒细胞CD11b。阿卡地新显著（p<0.01）抑制N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸诱导的粒细胞CD11b上调，平均抑制率为61%。在类似实验中，腺苷也抑制N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸诱导的粒细胞CD11b上调（p<0.01）。在体内，我们机构参与体外循环期间阿卡地新多中心试验的34例患者在围手术期被随机分为安慰剂组、低剂量组或高剂量阿卡地新输注组。合并低剂量和高剂量治疗组，接受阿卡地新的患者粒细胞CD11b上调有显著（p = 0.05）抑制；阿卡地新组粒细胞CD11b表达在基线的2.8倍达到峰值，而安慰剂组为4.3倍。相比之下，单核细胞CD11b上调（体外循环后在基线的3倍达到峰值）不受阿卡地新影响。阿卡地新和腺苷在体外抑制粒细胞CD11b上调，阿卡地新在体内体外循环期间也能产生类似的抑制作用。这种抑制作用可能有助于这些药物减轻体内再灌注损伤的能力。
