Respiratory survival mechanisms in acetylcholinesterase knockout mouse
Respiratory survival mechanisms in acetylcholinesterase knockout mouse
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DOI：
10.1046/j.1460-9568.2003.02867.x
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发表时间：
2003-09-01
影响因子：
3.4
通讯作者：
Foutz, AS
中科院分区：
文献类型：
--
作者：
Chatonnet, F;Boudinot, É;Foutz, AS
胆碱能神经传递确保肌肉收缩，并在脑干呼吸模式的调节中发挥作用。有机磷酸酯使乙酰胆碱酯酶 (ACNE) 失活会导致呼吸衰竭，但 ACNE 基因敲除小鼠能够存活到成年。通过全身体积描记术在体内检查确保这些小鼠存活的呼吸适应机制，并在新生儿离体脑干制剂中进行体外检查。 ACNE(-/-) 小鼠没有表现出 ACNE 活性，但丁酰胆碱酯酶 (BChE) 活性不受影响。在体内，班布特罗 (50-500 mug/kg s.c.) 降低外周 BChE 活性，但不降低脑组织中的 BChE 活性，并诱导成年和新生 ACNE(-/-) 小鼠呼吸暂停和死亡，而不影响同窝 ACNE(+/+) 和 (+/-) 动物。在体外，沐浴应用的班布特罗（1-100μM）和四异丙基焦磷酰胺（10-100μM）降低了脑干中的BChE活性，但不干扰脊神经根记录的中枢呼吸活动。在体外，胆碱能激动剂毒蕈碱（50-100μM）和尼古丁（0.5-10μM）诱导呼吸运动神经元的强直活动，并增加AChE（+/+）和（+/-）动物的吸气爆发频率。这些效应在 AChE(-/-) 动物中大大减弱。结果表明，在缺乏 ACNE 的小鼠中，（i）BChE 对于外周生存至关重要，但在中枢节律生成结构中不起关键作用；（ii）呼吸生存的主要适应性机制是中枢呼吸相关神经元和运动神经元对毒蕈碱和烟碱激动剂的下调反应。
Cholinergic neurotransmission ensures muscle contraction and plays a role in the regulation of respiratory pattern in the brainstem. Inactivation of acetylcholinesterase (ACNE) by organophosphates produces respiratory failure but ACNE knockout mice survive to adulthood. Respiratory adaptation mechanisms which ensure survival of these mice were examined in vivo by whole body plethysmography and in vitro in the neonatal isolated brainstem preparation. ACNE(-/-) mice presented no ACNE activity but unaffected butyrylcholinesterase (BChE) activity. In vivo, bambuterol (50-500 mug/kg s.c.) decreased BChE activity peripherally but not in brain tissue and induced apnea and death in adult and neonate ACNE(-/-) mice without affecting littermate ACNE(+/+) and (+/-) animals. In vitro, bath-applied bambuterol (1-100 muM) and tetraisopropylpyrophosphoramide (10-100 muM) decreased BChE activity in the brainstem but did not perturb central respiratory activity recorded from spinal nerve rootlets. In vitro, the cholinergic agonists muscarine (50-100 muM) and nicotine (0.5-10 muM) induced tonic activity in respiratory motoneurons and increased the frequency of inspiratory bursts in AChE(+/+) and (+/-) animals. These effects were greatly attenuated in AChE(-/-) animals. The results suggest that, in mice lacking ACNE, (i) BChE becomes essential for survival peripherally but plays no critical role in central rhythm-generating structures and (ii) a major adaptive mechanism for respiratory survival is the down-regulated response of central respiratory-related neurons and motoneurons to muscarinic and nicotinic agonists.