Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy.
Respiratory dysfunction progresses with age in Kcna1-null mice, a model of sudden unexpected death in epilepsy.
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DOI：
10.1111/epi.13971
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发表时间：
2018-03
期刊：
影响因子：
5.6
通讯作者：
Simeone TA
中科院分区：
文献类型：
--
作者：
Simeone KA;Hallgren J;Bockman CS;Aggarwal A;Kansal V;Netzel L;Iyer SH;Matthews SA;Deodhar M;Oldenburg PJ;Abel PW;Simeone TA
呼吸频率增加、呼吸暂停和呼吸衰竭与癫痫猝死(SUDEP)有关。我们最近在KcNA1−/−小鼠身上证明了癫痫的进行性和死亡率，KcnA1是颞叶癫痫和SUDEP的模型。在这里，我们测试了KcnA1−/−小鼠的呼吸功能障碍随年龄增长而进展的假设，从而增加了呼吸衰竭和猝死(SD)的风险。使用非侵入性呼吸道力学(NAM)系统测定清醒小鼠在基线和增加乙酰甲胆碱(MCH)剂量后的呼吸参数。KcNA1+/+、KcNA1+/−和KcnA1−/−分别在出生后32-36天、P40-46和P48-56三个年龄段死亡，死亡率分别为~30%、~55%和~90%。脉搏血氧饱和度(SaO2)测定。分离肺和脑组织，用RT-qPCR和Western印迹技术检测KcNA1基因和蛋白的表达。在暴露于MCH的离体气管中评估呼吸道平滑肌的反应性。KcnA1−/−小鼠出现基础呼吸驱动增加、慢性氧减饱和、频繁的呼吸暂停低通气(A-H)、A-H-呼吸急促-A-H的非典型呼吸顺序、潮气量增加和甲基甲烷所致的过度换气。MCH引起的过度换气随着年龄的增长而显著减弱。有趣的是，只有Kcna1−/−小鼠在接触甲基环己烷后出现癫痫发作。当KcnA1−/−小鼠接近猝死(SD)时，较低浓度的甲基环己烷引发癫痫发作。年轻的Kcna1−/−小鼠的子集经历了甲基环己烷诱导的癫痫发作，引发了死亡。这些较年轻的KcNA1−/−小鼠的呼吸参数类似于较年长的接近SD的KcNA1−/−小鼠。KcNA1基因和蛋白在KcNA1+/+和KcNA1+/−肺中均不表达，在KcNA1+/+和KcNA1+/−/−气管中，MCH介导的气道平滑肌收缩表现出相似的EC50‘S效应。SUDEP的KcNA1−/−模型显示出进行性呼吸功能障碍，这表明在可能导致猝死的严重癫痫发作期间，呼吸衰竭的易感性增加。
Increased breathing rate, apnea and respiratory failure is associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice a model of temporal lobe epilepsy and SUDEP. Here, we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thus increasing risk of respiratory failure and sudden death (SD). Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using non-invasive airway mechanics (NAM) systems. Kcna1+/+, Kcna1+/− and Kcna1−/− littermates were assessed during three age ranges when up to ~30%, ~55% and ~90%of Kcna1−/− mice have succumbed to SUDEP: postnatal day (P) 32-36, P40-46 and P48-56, respectively. Saturated arterial O2 (SaO2) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by RT-qPCR and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. Kcna1−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea-hypopnea (A-H), an atypical breathing sequence of A-H-tachypnea-A-H, increased tidal volume and hyperventilation induced by MCh. The MCh-provoked hyperventilation was dramatically attenuated with age. Interestingly, only Kcna1−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1−/− mice approached sudden death (SD). MCh-induced seizures experienced by a subset of younger Kcna1−/− mice triggered death. Respiratory parameters of these younger Kcna1−/− mice resembled older near-SD Kcna1−/− mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/− lungs and MCh-mediated airway smooth muscle contractions exhibited similar EC50’s in isolated Kcna1+/+ and Kcna1−/− trachea. The Kcna1−/− model of SUDEP exhibits progressive respiratory dysfunction which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.
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2.1
作者：
Munemoto T;Masuda A;Nagai N;Tanaka M;Yuji S
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