Shames B D, Meldrum D R, Selzman C H, Pulido E J, Cain B S, Banerjee A, Harken A H, Meng X
Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Am J Physiol. 1998 Sep;275(3):H1084-91. doi: 10.1152/ajpheart.1998.275.3.H1084.
Endotoxin [lipopolysaccharide (LPS)] causes tumor necrosis factor-alpha (TNF-alpha)-mediated myocardial contractile depression. Tolerance to the cardiac toxicity of LPS can be induced by a prior exposure to LPS or by pretreatment with glucocorticoids. The mechanisms by which the myocardium acquires tolerance to LPS remain unknown. LPS causes phosphorylation and degradation of inhibitory kappaB-alpha (IkappaB-alpha), releasing nuclear factor-kappaB (NF-kappaB) to activate TNF-alpha gene transcription. We hypothesized that LPS induces supranormal synthesis of myocardial IkappaB-alpha protein and thus renders the myocardium tolerant to subsequent LPS. Rats were challenged with LPS after pretreatment with LPS, dexamethasone, or saline. In saline-pretreated rats, LPS caused a rapid decrease in myocardial IkappaB-alpha protein levels, activation of NF-kappaB, and increased TNF-alpha production. These events were followed by myocardial contractile depression. After the initial decrease in myocardial IkappaB-alpha, IkappaB-alpha protein levels rebounded to a level greater than control levels by 24 h. Dexamethasone pretreatment similarly increased myocardial IkappaB-alpha protein levels. In rats pretreated with either LPS or dexamethasone, myocardial IkappaB-alpha protein levels remained similar to control levels after LPS challenge. The preserved level of myocardial IkappaB-alpha protein was associated with diminished NF-kappaB activation, attenuated myocardial TNF-alpha production, and improved cardiac contractility. We conclude that LPS and dexamethasone upregulate myocardial IkappaB-alpha protein expression and that an increased level of myocardial IkappaB-alpha protein may promote cardiac tolerance to LPS by inhibition of NF-kappaB intranuclear translocation and myocardial TNF-alpha production.
内毒素[脂多糖（LPS）]可导致肿瘤坏死因子-α（TNF-α）介导的心肌收缩力下降。预先接触LPS或用糖皮质激素预处理可诱导对LPS心脏毒性的耐受性。心肌获得对LPS耐受性的机制尚不清楚。LPS可导致抑制性κB-α（IkappaB-α）磷酸化和降解，释放核因子-κB（NF-κB）以激活TNF-α基因转录。我们假设LPS诱导心肌IkappaB-α蛋白超常合成，从而使心肌对随后的LPS产生耐受性。用LPS、地塞米松或生理盐水预处理大鼠后，再用LPS攻击。在生理盐水预处理的大鼠中，LPS导致心肌IkappaB-α蛋白水平迅速下降、NF-κB激活以及TNF-α产生增加。这些事件随后导致心肌收缩力下降。心肌IkappaB-α最初下降后，IkappaB-α蛋白水平在24小时内反弹至高于对照水平。地塞米松预处理同样增加了心肌IkappaB-α蛋白水平。在用LPS或地塞米松预处理的大鼠中，LPS攻击后心肌IkappaB-α蛋白水平仍与对照水平相似。心肌IkappaB-α蛋白的保留水平与NF-κB激活减弱、心肌TNF-α产生减弱以及心脏收缩力改善有关。我们得出结论，LPS和地塞米松上调心肌IkappaB-α蛋白表达，并且心肌IkappaB-α蛋白水平升高可能通过抑制NF-κB核内转位和心肌TNF-α产生来促进心脏对LPS的耐受性。
