Neural mechanisms of cardiotoxicity of novel cytotoxins produced by methicillin-resistant Staphylococcus aureus

近年来，院内老年患者、患癌患者、手术患者严重机会性感染病例不断增加，可能与抗生素的过度使用有关。其中，耐甲氧西林金黄色葡萄球菌（MRSA）感染严重，有时甚至致命。然而，MRSA中毒患者的药物治疗策略尚未建立。野田教授和他在千叶大学医学院的同事从重症监护病房住院的病人身上分离并纯化了MRSA的两种新型细胞毒素（hl -细胞毒素和hs -细胞毒素）。我们研究了新型MRSA细胞毒素在小鼠和豚鼠心脏组织中引起的电生理变化。静脉注射MRSA毒素可使小鼠心电图发生明显变化，如PR间期延长、QRS复合体增宽、心动过缓和心律失常。利用常规微电极技术对豚鼠离体乳头肌进行电生理实验，发现mrsa毒素灌注可引起静息膜电位和动作电位持续时间的减少以及发达张力（DT）的增加。通过α和β肾上腺素能拮抗剂预处理可以阻断DT的增加，并通过重复使用毒素来减弱。这些结果提示MRSA毒素的心脏毒性与神经机制有关。我们观察到假单胞菌毒素和分子生物学技术产生的MRSA毒素（gst - hs -细胞毒素）对小鼠的心脏毒性作用相似。因此，MRSA毒素可能通过神经机制产生致死性心脏毒性。然而，需要进一步的研究来阐明MRSA毒素心脏毒性的确切细胞机制。

Recently, number of severe opportunistic infections in aged, cancer-bearing or operated patients in hospital is increasing probubly due to excessive use of antibiotics. Among them, methicillin-resistant Staphylococcus aureus (MRSA) infection is sever and sometimes lethal. However, strategy for the medical treatmant of patients suffering from MRSA intoxication has not been established. Professor Noda and his colleagues, Chiba University School of Medicine, have isolated and purified two novel cytotoxins (HL-cytotoxin and HS-cytotoxin) of MRSA from patient hospitalized at an intensive care unit. We studied electrophysiological changes in cardiac tissue induced by the novel MRSA cytotoxins in mice and guinea pigs. Intravenous injection of the MRSA toxins produced marked ECG changes, such as prolongation of PR interval, widening in QRS complex, bradycardia and arrhythmias, in mice. Electrophysiological experiments using cnventional microelectrode techniques in isolated guinea-pig papillary muscles revealed that decreases in resting membrane potential and action potential duration and an indcrease in developed tensions (DT) were inuced by supefusion of the MRSA-toxins. The increase in DT was blocked by pre-treatment with alpha and beta adrenergic antagonists and was attenuated by repeated application of the toxins. These results imply the involvement of neural mechanism in cardiotoxicity of the MRSA toxins. We observed similar cardiotoxic effects with Pseudomonas toxin and MRSA toxin produced by molecular biological techniques (GST-HS-cytotoxin) in mice. Thus, MRSA toxin may produce lethal cardiotixicity through neural mechanisms. However, further studies are needed to clarify precise cellular mechanism (s) of the cardiotoxicity of MRSA toxins.