Wang Meijng, Meng Xianzhong, Tsai Ben, Wang Ju-Feng, Turrentine Mark, Brown John W, Meldrum Daniel R
Department of Surgery, Indiana University Medical Center, 545 Barnhill Drive, Indianapolis, IN 46202, USA.
J Surg Res. 2004 Sep;121(1):20-4. doi: 10.1016/j.jss.2004.02.017.
Sepsis and endotoxemia frequently complicate the care of surgical patients. Basic and clinical investigations have correlated tumor necrosis factor alpha (TNF) levels with myocardial suppression and lethality after sepsis. Soluble TNF receptor 1 (sTNFRI) is an endogenous mechanism of clearing serum TNF. Elucidating mechanisms of endogenous adaptation may allow the development of novel therapeutic strategies. Endotoxin tolerance (LPS-preconditioning) is associated with a down-regulation of proinflammatory monokine production; thus, similar down-regulation of sTNFRI may be expected. However, it may be equally plausible to hypothesize that the processes which lead to enhanced shedding of these receptors are up-regulated during tolerance.
To study this, sublethal LPS was administered to male rats (Salmonella typhimurium, 500 microg/kg IP in 1 ml bacteriostatic normal saline IP) or an equivalent volume of bacteriostatic normal saline IP (sham) 24 h prior to subsequent LPS challenge. Rats were sacrificed at 0, 1, 2, 4, 6, and 24 h following LPS and serum TNF and TNFRI were measured by ELISAs.
LPS induced a significant increase in sTNFRI at 1, 2, 4, and 6 h following LPS. sTNFRI levels returned to baseline by 24 h following LPS treatment. LPS induced a parallel increase in TNF. LPS pretreatment (preconditioning) resulted in a significant increase in TNFRI and a significant decrease in TNF.
This study constitutes the initial demonstration that tolerance mechanisms: (1) up-regulate sTNFRI, which binds and clears TNF; and (2) reverses the TNF-to-sTNFRI ratio. Safe pharmacologic methods of up-regulating endogenous TNF-clearance mechanisms may ultimately have therapeutic value.
脓毒症和内毒素血症常使外科患者的护理变得复杂。基础和临床研究已将肿瘤坏死因子α（TNF）水平与脓毒症后的心肌抑制和致死率联系起来。可溶性TNF受体1（sTNFRI）是清除血清TNF的一种内源性机制。阐明内源性适应机制可能有助于开发新的治疗策略。内毒素耐受（脂多糖预处理）与促炎单核因子产生的下调有关；因此，sTNFRI可能会有类似的下调。然而，也有同样合理的假设，即在耐受过程中，导致这些受体脱落增加的过程会被上调。
为研究这一问题，在随后进行脂多糖攻击前24小时，给雄性大鼠腹腔注射亚致死剂量的脂多糖（鼠伤寒沙门氏菌，500微克/千克，溶于1毫升抑菌生理盐水腹腔注射）或等量的抑菌生理盐水（假手术组）。在脂多糖攻击后的0、1、2、4、6和24小时处死大鼠，通过酶联免疫吸附测定法测量血清TNF和TNFRI。
脂多糖攻击后1、2、4和6小时，sTNFRI显著增加。脂多糖处理后24小时，sTNFRI水平恢复到基线。脂多糖使TNF平行增加。脂多糖预处理（预适应）导致TNFRI显著增加，TNF显著降低。
本研究首次证明耐受机制：（1）上调结合并清除TNF的sTNFRI；（2）逆转TNF与sTNFRI的比例。上调内源性TNF清除机制的安全药理学方法最终可能具有治疗价值。
