Downs T R, Dage R C, French J F
Marion Merrell Dow Research Institute, Cincinnati, OH 45215, USA.
Int J Immunopharmacol. 1995 Jul;17(7):571-80. doi: 10.1016/0192-0561(95)00042-z.
Multiple organ dysfunction (MOD) is the leading cause of mortality in septic patients with circulatory shock. Recent evidence suggests that the overproduction of the cytokine, tumor necrosis factor-alpha(TNF), and oxygen free radical molecules may mediate the progression of sepsis to MOD and death. In this study, we have examined the ability of MDL 101,002, a free radical scavenger, to reduce organ dysfunction and cytokine secretion induced by lipopolysaccharide (LPS) administration in rats. Treatment with MDL 101,002(10-60 ng/kg, i.p.) 30 min prior to an LPS challenge resulted in a dose-dependent reduction in several markers indicative of organ dysfunction and mortality. MDL 101,002 markedly decreased LPS-induced liver and kidney damage as indicated by serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or urea and creatinine, respectively. MDL 101,002 also prevented LPS-induced pulmonary edema, but did not prevent leukopenia and only partially reduced thrombocytopenia. Associated with these improvements in organ dysfunction and survival was a modest decrease in LPS-stimulated interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) secretion and a marked ( > 90%) inhibition of TNF secretion by MDL 101,002. The data are consistent with a role for oxygen free radicals in the development of endotoxin-induced organ dysfunction and shock and suggest that free radical scavengers could reduce the mortality consequent to sepsis by decreasing organ dysfunction, at least in part, through a reduction in free radical stimulated cytokine secretion.
多器官功能障碍（MOD）是感染性休克患者死亡的主要原因。最近的证据表明，细胞因子肿瘤坏死因子-α（TNF）和氧自由基分子的过度产生可能介导脓毒症进展为MOD及导致死亡。在本研究中，我们检测了自由基清除剂MDL 101,002减轻脂多糖（LPS）诱导的大鼠器官功能障碍和细胞因子分泌的能力。在LPS攻击前30分钟腹腔注射MDL 101,002（10 - 60 ng/kg）可导致几种指示器官功能障碍和死亡率的指标呈剂量依赖性降低。MDL 101,002显著减轻了LPS诱导的肝损伤和肾损伤，分别表现为血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平，或尿素和肌酐水平降低。MDL 101,002还预防了LPS诱导的肺水肿，但未预防白细胞减少，仅部分减轻了血小板减少。与这些器官功能障碍和生存率的改善相关的是，LPS刺激的白细胞介素-1α（IL-1α）和白细胞介素-1β（IL-1β）分泌略有减少，而MDL 101,002对TNF分泌有显著（> 90%）抑制作用。这些数据与氧自由基在内毒素诱导的器官功能障碍和休克发生中的作用一致，并表明自由基清除剂至少部分通过减少自由基刺激的细胞因子分泌来减轻器官功能障碍，从而降低脓毒症导致的死亡率。
