Squadrito F, Saitta A, Altavilla D, Campo G M, Ioculano M, Squadrito G, Caputi A P
Istituto di Farmacologia, Università degli Studi, Messina.
Cardiologia. 1993 Jan;38(1):45-51.
The role of tumor necrosis factor (TNF-alpha) was investigated in an anaesthetized rat model of coronary artery ligation (60 min) followed by reperfusion (60 min; MI/R). Sham operated rats were used as controls (Sham MI/R). Myocardial necrosis, myocardial myeloperoxidase activity (MPO; investigated as an index of leukocyte adhesion and accumulation), serum creatinphosphokinase (CPK) activity and serum and macrophage TNF-alpha were studied. Ischemia and reperfusion produced a marked myocardial injury, with enhancement of serum CPK levels and myocardial MPO activity in the area at risk and in the necrotic area. Furthermore, serum TNF-alpha was undetectable during the occlusion period, but increased significantly after release of the coronary artery. At the end of reperfusion, macrophage TNF-alpha was also enhanced. A passive immunization with a hyperimmune serum containing antibodies against murine TNF-alpha or administration of an inhibitor of TNF-alpha synthesis, such as cloricromene, significantly lowered myocardial necrosis, reduced the increase in serum CPK and decreased MPO activity in the area at risk and in the necrotic area. Finally, the administration of the specific anti-TNF-alpha antibodies neutralized the serum levels of TNF-alpha and the injection of cloricromene reduced both serum and macrophage TNF-alpha. These data are consistent with an involvement of TNF-alpha in myocardial ischemia-reperfusion injury and suggest that drugs capable of reducing TNF-alpha might represent a novel therapeutic approach to the treatment of myocardial reperfusion injury.
在冠状动脉结扎（60分钟）后再灌注（60分钟；心肌梗死/再灌注）的麻醉大鼠模型中研究了肿瘤坏死因子（TNF-α）的作用。假手术大鼠用作对照（假心肌梗死/再灌注）。研究了心肌坏死、心肌髓过氧化物酶活性（MPO；作为白细胞黏附和聚集的指标进行研究）、血清肌酸磷酸激酶（CPK）活性以及血清和巨噬细胞TNF-α。缺血和再灌注导致明显的心肌损伤，危险区域和坏死区域的血清CPK水平升高以及心肌MPO活性增强。此外，在冠状动脉闭塞期间未检测到血清TNF-α，但在冠状动脉松开后显著增加。再灌注结束时，巨噬细胞TNF-α也增强。用含有抗鼠TNF-α抗体的超免疫血清进行被动免疫或给予TNF-α合成抑制剂（如氯克罗孟）可显著降低心肌坏死，减少危险区域和坏死区域血清CPK的升高并降低MPO活性。最后，给予特异性抗TNF-α抗体可中和血清TNF-α水平，注射氯克罗孟可降低血清和巨噬细胞TNF-α。这些数据表明TNF-α参与了心肌缺血-再灌注损伤，并提示能够降低TNF-α的药物可能代表一种治疗心肌再灌注损伤的新治疗方法。
