Anthrax Toxins Induce Shock in Rats by Depressed Cardiac Ventricular Function
Anthrax Toxins Induce Shock in Rats by Depressed Cardiac Ventricular Function
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DOI：
10.1371/journal.pone.0000466
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发表时间：
2007-05-23
期刊：
影响因子：
3.7
通讯作者：
Frankel, Arthur E.
中科院分区：
文献类型：
--
作者：
Watson, Linley E.;Kuo, Shu-ru;Frankel, Arthur E.
炭疽感染常伴有严重的、往往是不可逆的休克。炭疽杆菌的分离的毒性蛋白通过未知的机制在大鼠中产生非细胞因子介导的低血压。这些观察结果表明炭疽毒素有直接的心血管影响。在这里，我们描述这些影响。作为第一步，我们以不同剂量向3至12只大鼠的队列全身施用炭疽致死毒素（LeTx）和水肿毒素（EdTx），并确定发作时间、低血压程度和死亡率。我们在输注后的不同时间点测量了保护性抗原（PA）毒素组分的血清浓度。PA的峰值血清水平在mg/mL范围内，半衰期为10-20分钟。剂量，产生低血压与延迟致死，然后我们给推注静脉注射毒素的四到六个仪表大鼠组，并通过遥测连续监测血压。最后，将遥测实验中使用的相同剂量给予另外四组大鼠，并在治疗前和治疗后1、2、3和24小时进行超声心动图检查。LeTx和EdTx均产生低血压。我们观察到的传播速度增加了一倍，20%的增加，左心室舒张和收缩面积在LeTx治疗的大鼠，但不是在EdTx治疗的大鼠。EdTx处理的大鼠心率显著增加，而LeTx处理的大鼠心率则没有显著增加。这些结果表明，LeTx降低左心室收缩功能和EdTx减少前负荷。毒素很容易被吸收到组织中，在血清毒素浓度在μ g/mL范围内的数分钟至数小时内发生生物效应。LeTx和EdTx产生不可逆的休克，随后死亡。这些发现应该为合理设计药物干预措施提供依据，以减少系统性炭疽感染的不良预后。
Anthrax infections are frequently associated with severe and often irreversible hypotensive shock. The isolated toxic proteins of Bacillus anthracis produce a non-cytokine-mediated hypotension in rats by unknown mechanisms. These observations suggest the anthrax toxins have direct cardiovascular effects. Here, we characterize these effects. As a first step, we administered systemically anthrax lethal toxin (LeTx) and edema toxin (EdTx) to cohorts of three to twelve rats at different doses and determined the time of onset, degree of hypotension and mortality. We measured serum concentrations of the protective antigen (PA) toxin component at various time points after infusion. Peak serum levels of PA were in the mg/mL range with half-lives of 10-20 minutes. With doses that produced hypotension with delayed lethality, we then gave bolus intravenous infusions of toxins to groups of four to six instrumented rats and continuously monitored blood pressure by telemetry. Finally, the same doses used in the telemetry experiments were given to additional groups of four rats, and echocardiography was performed pretreatment and one, two, three and twenty-four hours post-treatment. LeTx and EdTx each produced hypotension. We observed a doubling of the velocity of propagation and 20% increases in left ventricular diastolic and systolic areas in LeTx-treated rats, but not in EdTx-treated rats. EdTx-but not LeTx-treated rats showed a significant increase in heart rate. These results indicate that LeTx reduced left ventricular systolic function and EdTx reduced preload. Uptake of toxins occurs readily into tissues with biological effects occurring within minutes to hours of serum toxin concentrations in the mu g/mL range. LeTx and EdTx yield an irreversible shock with subsequent death. These findings should provide a basis for the rational design of drug interventions to reduce the dismal prognosis of systemic anthrax infections.