Solorzano C C, Ksontini R, Pruitt J H, Auffenberg T, Tannahill C, Galardy R E, Schultz G P, MacKay S L, Copeland E M, Moldawer L L
Department of Surgery, University of Florida College of Medicine, Gainesville 32610, USA.
Shock. 1997 Jun;7(6):427-31. doi: 10.1097/00024382-199706000-00007.
Excessive tumor necrosis factor alpha (TNF alpha) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNF alpha production rely on monoclonal antibodies or immunoadhesins that bind TNF alpha and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNF alpha processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 microgram/mL endotoxin, GM-6001 at concentrations > 5 micrograms/mL blocked release of TNF alpha, but did not affect the release of either IL-1 beta or IL-6. GM-6001 also inhibited the release of soluble TNF receptor (p75) from peripheral blood mononuclear cells stimulated with endotoxin and/or TNF alpha. To confirm the role of secreted TNF alpha in endotoxic shock-induced mortality, C57BL/6 mice were challenged with either endotoxin alone (500 micrograms/mouse) or endotoxin (100 ng/mouse) plus D-galactosamine (8 mg/mouse). GM-6001 pretreatment (100 mg/kg) significantly attenuated the 90-minute plasma TNF alpha response in both models and improved survival in mice treated with low-dose endotoxin plus D-galactosamine. However, plasma IL-1 beta and IL-6 concentrations at 90 min after endotoxin treatment were unaffected by GM-6001 following lethal endotoxin challenge, confirming the in vivo specificity of this matrix metalloproteinase inhibitor for TNF alpha processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNF alpha both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock.
对革兰氏阴性菌血症或内毒素血症产生过度的肿瘤坏死因子α（TNFα）通常会导致低血压、休克和死亡率增加。目前用于阻断TNFα过度产生的有害作用的方法依赖于结合TNFα从而阻止其与细胞受体相互作用的单克隆抗体或免疫粘附素。本报告研究了一种先前描述的基质金属蛋白酶抑制剂GM-6001是否能抑制TNFα的加工和释放，并减轻内毒素诱导的死亡率。在体外以1微克/毫升内毒素刺激的人外周血单核细胞中，浓度>5微克/毫升的GM-6001可阻断TNFα的释放，但不影响IL-1β或IL-6的释放。GM-6001还抑制了用内毒素和/或TNFα刺激的外周血单核细胞中可溶性TNF受体（p75）的释放。为了证实分泌的TNFα在内毒素休克诱导的死亡率中的作用，C57BL/6小鼠分别接受单独的内毒素（500微克/只）或内毒素（100纳克/只）加D-半乳糖胺（8毫克/只）攻击。GM-6001预处理（100毫克/千克）在两种模型中均显著减弱了90分钟时血浆TNFα反应，并提高了低剂量内毒素加D-半乳糖胺处理小鼠的存活率。然而，在致死性内毒素攻击后，内毒素处理90分钟时血浆IL-1β和IL-6浓度不受GM-6001影响，证实了这种基质金属蛋白酶抑制剂对TNFα加工的体内特异性。这些发现表明，一种新型的基质金属蛋白酶抑制剂能够在体外和体内阻止TNFα的释放，并能消除内毒素血症休克的有害后遗症。
