Kadokami T, McTiernan C F, Kubota T, Frye C S, Bounoutas G S, Robbins P D, Watkins S C, Feldman A M
Cardiovascular Institute of the University of Pittsburgh Medical Center Health System, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2281-91. doi: 10.1152/ajpheart.2001.280.5.H2281.
Tumor necrosis factor (TNF)-alpha plays a key role in the pathogenesis of septic shock syndrome, and myocardial TNF-alpha expression may contribute to this pathophysiology. We examined the myocardial expression of TNF-alpha-related cytokines and chemokines in mice exposed to lipopolysaccharide (LPS) and tested the effects of anti-TNF therapy on myocardial cytokine expression. Cytokine mRNA levels were measured by RNase protection assay, and protein levels in the plasma and myocardium were assessed by enzyme-linked immunosorbent assays. LPS (4 microg/g body wt ip) induced marked cytokine expression, including TNF-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein (MCP)-1, in both the plasma and myocardium. Pretreatment with adenovirus-mediated TNF receptor fusion protein (AdTNFR1; 10(9) plaque-forming units iv) decreased plasma cytokine levels. In contrast, whereas myocardial IL-1beta expression was also suppressed, expression of IL-6 and MCP-1 was not inhibited by AdTNFR1. In summary, anti-TNF treatment differentially altered the cytokine expression in the plasma and myocardium during endotoxemia. Inability to block myocardial expression of IL-6 and MCP-1 suggests a possible mechanism for the failure of anti-TNF therapies in the treatment of endotoxin shock.
肿瘤坏死因子（TNF）-α在脓毒性休克综合征的发病机制中起关键作用，心肌TNF-α的表达可能促成这种病理生理过程。我们检测了暴露于脂多糖（LPS）的小鼠心肌中TNF-α相关细胞因子和趋化因子的表达，并测试了抗TNF治疗对心肌细胞因子表达的影响。通过核糖核酸酶保护试验测量细胞因子mRNA水平，通过酶联免疫吸附试验评估血浆和心肌中的蛋白水平。LPS（4微克/克体重，腹腔注射）在血浆和心肌中均诱导显著的细胞因子表达，包括TNF-α、白细胞介素（IL）-1β、IL-6和单核细胞趋化蛋白（MCP）-1。用腺病毒介导的TNF受体融合蛋白（AdTNFR1；10⁹ 噬斑形成单位，静脉注射）预处理可降低血浆细胞因子水平。相比之下，虽然心肌IL-1β的表达也受到抑制，但AdTNFR1并未抑制IL-6和MCP-1的表达。总之，抗TNF治疗在内毒素血症期间对血浆和心肌中的细胞因子表达产生了不同的影响。无法阻断心肌中IL-6和MCP-1的表达提示了抗TNF治疗在内毒素休克治疗中失败的一种可能机制。
