The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-α production
The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-α production
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DOI：
10.1016/j.bbi.2003.12.001
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发表时间：
2004-09-01
影响因子：
15.1
通讯作者：
Shi, YF
中科院分区：
文献类型：
--
作者：
Greeneltch, KM;Haudenschild, CC;Shi, YF
感染性休克被认为是细菌毒素对免疫系统的过度刺激的结果，其导致促炎细胞因子的全身性过度产生，包括肿瘤坏死因子-α（TNF-α、IL-1和IL-6）。各种研究已经表明，TNF-α（败血性休克的主要介质）诱导组织损伤、血压损失、器官衰竭和最终死亡。据报道，阿片类药物拮抗剂纳洛酮的给药可逆转阿片类药物介导的低血压，促进器官灌注并增加患者生存率。在这项研究中，我们研究了阿片受体拮抗剂纳曲酮，调节感染性休克反应后，在BALB/c小鼠注射脂多糖（LPS）或葡萄球菌肠毒素B（SE B）与D-半乳糖胺（D-gal）的组合，或单独与激动性抗Fas抗体（Jo 2）。这些治疗中的每一种都诱导了快速发作、急性休克和最终死亡（注射后6- 9小时），尽管涉及不同的机制。阿片类拮抗剂纳洛酮的管理保护小鼠从LPS + D-gal诱导的休克，但不SEB + Dgal或Jo 2抗体，保护作用，被吗啡逆转。纳洛酮在体内显著抑制LPS诱导的TNF-α的产生，但不抑制SEB。当骨髓来源的，脾或腹腔巨噬细胞在体外用LPS处理时，纳洛酮的给药对TNF-α的产生没有直接影响。这些结果表明，纳洛酮能够通过间接抑制体内TNF-α的产生来预防LPS诱导的败血性休克死亡率。(C)2004年爱思唯尔公司All rights reserved.
dSeptic shock is believed to be a consequence of excessive stimulation of the immune system by bacterial toxins that results in systemic overproduction of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha, IL-1, and IL-6. Various studies have shown that TNF-a, a major mediator of septic shock, induces tissue injury, loss of blood pressure, organ failure, and ultimately death. Administration of the opioid antagonist naloxone has been reported to reverse opiate-mediated hypotension, promote organ perfusion and increase patient survival. In this study, we examined the mechanism by which the opioid receptor antagonist, naltrexone, modulates the septic shock response in BALB/c mice after injection with lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB) in combination with D-galactosamine (D-gal), or with agonistic anti-Fas antibody (Jo2) alone. Each of these treatments induced rapid-onset, acute shock, and ultimately mortality (6-9h after injection), although different mechanisms are involved. Administration of the opioid antagonist naltrexone protected mice from shock induced by LPS + D-gal, but not SEB + Dgal or Jo2 antibody, a protective effect that was reversed by morphine. Naltrexone significantly inhibited the production of TNF-alpha induced by LPS, but not SEB in vivo. When bone marrow-derived, splenic or peritoneal macrophages were treated with LPS in vitro, administration of naltrexone had no direct effect on TNF-alpha production. These results suggest that naltrexone is capable of preventing LPS-induced septic shock mortality by indirect inhibition of TNF-a production in vivo. (C) 2004 Elsevier Inc. All rights reserved.