Souza Danielle G, Ferreira Flávio Lopes, Fagundes Caio T, Amaral Flávio A, Vieira Angélica T, Lisboa Rodolfo Assis, Andrade Marcus Vinícius Melo, Trifilieff Alexandre, Teixeira Mauro M
Immunopharmacology, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Eur J Pharmacol. 2007 Sep 24;571(1):72-80. doi: 10.1016/j.ejphar.2007.05.058. Epub 2007 Jun 12.
Tumor necrosis factor (TNF)-alpha plays an important role in the mediation of reperfusion-induced tissue injury and lethality. Here, we assessed the effects of PKF242-484 and PKF241-466, two dual inhibitors of TNF-alpha converting enzyme (TACE) and matrix metalloproteinases (MMPs), in a model of ischemia and reperfusion injury in mice. Reperfused animals that received PKF242-484 or PKF241-466 treatment had a dose-dependent reduction of TNF-alpha concentrations in serum. Both drugs delayed and partially inhibited the reperfusion-associated lethality. Maximal inhibition occurred at 10 mg/kg. At this dose, both inhibitors reduced reperfusion-associated local and remote tissue injury, as assessed by changes in vascular permeability, neutrophil recruitment and hemorrhage. In addition, the compounds markedly reduced production of TNF-alpha, CXCL1 (keratinocyte-derived chemokine, KC) and CCL2 (monocyte chemoattractant protein-1, MCP-1) in intestine and lungs of animals which underwent reperfusion. FN-439, an inhibitor of MMPs which possesses no effect on TACE, decreased MMP-2 and MMP-3 activity, but failed to affect tissue injury, TNF-alpha production or lethality. Thus, combined TACE and MMP inhibitors might be effective co-adjuvants in treatments of injuries that follow reperfusion of an ischemic vascular territory. The effects of these drugs on TNF-alpha production appear to be more relevant than their effects on MMP inhibition.
肿瘤坏死因子（TNF）-α在介导再灌注诱导的组织损伤和致死率方面发挥着重要作用。在此，我们评估了TNF-α转换酶（TACE）和基质金属蛋白酶（MMPs）的双重抑制剂PKF242-484和PKF241-466在小鼠缺血再灌注损伤模型中的作用。接受PKF242-484或PKF241-466治疗的再灌注动物血清中TNF-α浓度呈剂量依赖性降低。两种药物均延迟并部分抑制了再灌注相关的致死率。最大抑制作用出现在10mg/kg。在此剂量下，两种抑制剂均减少了再灌注相关的局部和远处组织损伤，这通过血管通透性、中性粒细胞募集和出血的变化来评估。此外，这些化合物显著降低了经历再灌注的动物肠道和肺部中TNF-α、CXCL1（角质形成细胞衍生趋化因子，KC）和CCL2（单核细胞趋化蛋白-1，MCP-1）的产生。FN-439是一种对TACE无作用的MMPs抑制剂，可降低MMP-2和MMP-3活性，但未能影响组织损伤、TNF-α产生或致死率。因此，联合TACE和MMP抑制剂可能是治疗缺血血管区域再灌注后损伤的有效辅助药物。这些药物对TNF-α产生的影响似乎比它们对MMP抑制的影响更重要。
