Cuzzocrea S, Zingarelli B, Costantino G, Caputi A P
Institute of Pharmacology, University of Messina, Italy.
Free Radic Biol Med. 1999 Jan;26(1-2):25-33. doi: 10.1016/s0891-5849(98)00142-7.
Peroxynitrite, a potent cytotoxic oxidant formed by the reaction of NO with superoxide anion, has been proposed to have major pathogenetic role in inflammatory process. Here we have investigated the therapeutic efficacy of Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), a novel superoxide dismutase mimetic that possesses peroxynitrite scavenging effect, in rats subjected to carrageenan-induced pleurisy. In vivo treatment with MnTBAP (3 and 10 mg/kg 5 min before carrageenan) prevented in a dose-dependent manner the carrageenan-induced the degree of pleural exudation, polymorphonuclear migration in rats subjected to carrageenan-induced pleurisy. Lung myeloperoxidase (MPO) activity and histological organ injury was significantly reduced by MnTBAP. However, MnTBAP did not inhibit the inducible NO synthase in lung samples. Immunohistochemical analysis for nitrotyrosine, a footprint of peroxynitrite, revealed a positive staining in lungs from carrageenan-treated rats. No positive nitrotyrosine staining was found in the lungs of the carrageenan-treated rats that received MnTBAP (10 mg/kg) treatment. In addition, in vivo MnTBAP treatment significantly reduced in a dose-dependent manner peroxynitrite formation as measured by the oxidation of the fluorescent dye dihydrorhodamine 123, prevented the appearance of DNA damage, the decrease in mitochondrial respiration and partially restored the cellular level of NAD+ in ex vivo macrophages harvested from the pleural cavity of rats subjected to carrageenan-induced pleurisy. Our study demonstrates that the MnTBAP exerts multiple protective effects in carrageenan-induced pleurisy. We suggest peroxynitrite produced during the inflammatory process trigger DNA strand breakage and subsequent cellular dysfunction. Part of these anti-inflammatory effects may be related to: (1) reduction of superoxide formation due to the superoxide dismutase-like activity of the compound and (2) scavenging of peroxynitrite.
过氧亚硝酸盐是由一氧化氮与超氧阴离子反应形成的一种强效细胞毒性氧化剂，有人提出它在炎症过程中具有主要的致病作用。在此，我们研究了四（4-苯甲酸）锰卟啉（MnTBAP）的治疗效果，MnTBAP是一种新型的超氧化物歧化酶模拟物，具有清除过氧亚硝酸盐的作用，用于角叉菜胶诱导胸膜炎的大鼠。用MnTBAP（角叉菜胶注射前5分钟，剂量为3和10mg/kg）进行体内治疗，以剂量依赖的方式预防了角叉菜胶诱导的大鼠胸膜炎的胸腔渗出程度、多形核白细胞迁移。MnTBAP显著降低了肺髓过氧化物酶（MPO）活性和组织器官损伤。然而，MnTBAP并未抑制肺组织样本中的诱导型一氧化氮合酶。对过氧亚硝酸盐痕迹硝基酪氨酸的免疫组织化学分析显示，角叉菜胶处理的大鼠肺组织呈阳性染色。在接受MnTBAP（10mg/kg）治疗的角叉菜胶处理大鼠的肺组织中未发现硝基酪氨酸阳性染色。此外，体内MnTBAP治疗以剂量依赖的方式显著降低了通过荧光染料二氢罗丹明123氧化测定的过氧亚硝酸盐形成，预防了DNA损伤的出现、线粒体呼吸的降低，并部分恢复了从角叉菜胶诱导胸膜炎大鼠胸腔采集的离体巨噬细胞中NAD+的细胞水平。我们的研究表明，MnTBAP在角叉菜胶诱导的胸膜炎中发挥多种保护作用。我们认为炎症过程中产生的过氧亚硝酸盐触发了DNA链断裂及随后的细胞功能障碍。这些抗炎作用部分可能与：（1）由于该化合物的超氧化物歧化酶样活性而减少超氧化物形成，以及（2）清除过氧亚硝酸盐有关。
