呼吸机模式对实验兔膈肌细胞凋亡和超微结构影响的研究
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摘要
背景
机械通气是呼吸衰竭患者生命支持的重要手段,但机械通气时间的延长,易出现困难撤机。膈肌是最主要的呼吸肌,在呼吸过程中所起的作用约占全部呼吸肌的60%-80%。膈肌的功能损伤会直接导致呼吸衰竭。临床研究认为机械通气控制模式(Control Mechanical Ventilation,CMV)可导致膈肌放电消失,膈肌纤维废用性萎缩,即呼吸机诱导的膈肌功能下降(Ventilation induced diaphragm disfunction,VIDD)。研究者通过动物实验从不同角度描述VIDD的发生：发现大鼠在CMV6小时后便开始出现横膈膜蛋白质氧化和脂质过氧化产物的持续增多,其氧化修饰发展迅速,在持续控制性机械通气18小时后,膈肌Ⅰ型和Ⅱ型纤维的数量减少,且Ⅱ型纤维出现较大程度的萎缩,大鼠膈肌肌肉萎缩也较外周骨骼肌萎缩更甚；对不同种类动物取完整膈肌测量跨膈压(Pdi)的活体研究表明,行CMV通气后(实验兔1天、实验猪3天),膈神经在最大和次最大刺激频率下,Pdi均进行性下降等。
膈神经冲动发放次数或膈神经冲动发放频率的减少参与造成隔肌功能障碍。Ayas等的研究中提供了有利的证据,他们关于CMV时刺激膈神经防止膈肌萎缩的报道间接提示,机械通气时确实存在膈肌神经刺激的减少。肌肉的正常收缩活动依赖于完整的神经冲动,一旦神经刺激减少或消失,膈肌将发生萎缩和收缩功能下降,进而发展为VIDD。但是,研究中对几种常用模式支持下膈肌肌电活动的变化未做阐述,对其与不同模式对膈肌功能和结构的影响的相关性未进行进一步的研究。
目前认为,由于横膈活动的减弱,导致线粒体损伤,引起氧化应激和蛋白质水解系统的激活等是导致VIDD的主要途径。VIDD废用性肌萎缩时蛋白质流失直接与3种蛋白质水解系统有关,即溶酶体蛋白酶、钙活化蛋白酶(如钙蛋白酶)和蛋白酶体系统。最近研究提示,Caspase-3有助于蛋白质降解和肌萎缩。细胞对Caspase-3活性的控制是复杂的,涉及到许多相互联系的信号通路。钙蛋白酶抑制蛋白(Calpastatin)是Caspase-3和钙蛋白酶的共同底物。增强Caspase-3或钙蛋白酶活性会降低细胞内Calpastatin水平,促进钙蛋白酶活化。另外,增强钙蛋白酶活性能导致Caspase-3活化。因此,Caspase-3和钙蛋白酶之间的交互作用在废用性肌内调节肌丝释放中起着一定作用,在促进CMV膈肌损伤中扮演了极为重要的角色。近期的临床和动物研究中对危重病患者给于抗氧化剂和糖皮质激素进行干预,期望减少VIDD的发生及延缓VIDD进程,研究结果提示可以延缓VIDD的进一步发展,但是研究报告中同时提出这些干预措施的影响因素很多。McClungJM等的研究表明PSV模式可以减少VIDD的发生进程,尝试间断予PSV模式通气来减少VIDD的发生。但是研究中其支持水平与对照组(CMV)模式不同,无法判断是呼吸机模式还是支持水平对VIDD的影响?对于几种常用的呼吸机模式,在相同支持水平下对膈肌的影响,相关的研究目前国内外尚无报道。
目的：
研究三种常用通气模式CMV、A/C和PSV模式,在同样压力支持水平下,呼吸机对实验兔的膈肌肌电活动变化的影响,并观察其对膈肌细胞凋亡和超微结构的影响。
方法：
将16只实验兔(普通级,2.0kg～2.1kg)随机数字表法归入空白对照组、CMV组、A/C组和PSV组,分别行8%水合氯醛4ml/kg腹腔注射麻醉后,进行气管切开插管、连接流量呼吸换能器,并持续观察膈肌肌电图(diaphragm electromyo-gram,EMGdi)变化。右颈总动脉穿刺置管血压监测；行微泵静脉咪唑安定1mg/kg/h静脉注射镇静。CMV组(Rr45bpm,FiO2lL/min, I:El:3,VT8-10ml/kg)、A/C组(PCVmode,Trigger0.1L/min,Rr45bpm, Pi10cmH2O, Ti0.5sec,FiO225%,维持VT8-10ml/kg呼吸机)、PSV组(Spont mode,Trigger0.1L/min, PSV10cmH2O, Esense25%, FiO225%,维持VT8-10m1/kg)分别行三种模式进行机械通气24小时,F102维持正常血气Pa02水平。根据血气调整Fi02、VT和RR。各组实验过程中持续监测膈肌电活动和呼吸运动,监测动脉血压,维持生命体征稳定。空白对照组：不进行机械通气,行气管切开,并监测膈肌肌电活动及呼吸运动30min后,予空气栓塞法处死动物。取膈肌进行免疫组化及western blot分析各组实验兔膈肌肌细胞的Caspase-3活性表达、并电镜下观察膈肌组织超微结构的改变。
结果：
1. EMGDi频谱分析结果：三组低频成分(L)增加,高频成分(H)降低,CMV组、A/C组和PSV组H/L分别下降82.3%,81.8%,80.6%,(p<0.01);中心频率(Fc)与对照组相比分别下降43%,37.1%和34.9%。(P<0.01)。组间比较,Fc值CMV组下降最明显,其次为A/C组(与CMV组比较P<0.05)和PSV组(与CMV和A/C比较p<0.05)
2.Caspase-3蛋白表达：免疫组化显示与对照组相比,CMV、A/C和PSV模式的17-kD active Caspase-3蛋白表达增强。CMV组、A/C组中17-kD active Caspase3表达呈强阳性(积分分别为6.40±0.57,5.98±0.41)；PSV模式呈中等阳性(4.47±0.67分),与CMV组和A/C比较差异有统计学意义(P<0.05)。Western-blot结果显示三种模式与对照组比较,CMV.A/C和PSV模式灰度值依次为2.473±0.431(p<0.01)；2.202±0.213(p<0.01)；1.829±1.001(p<0.05),三组组间两两比较无显著性差异。
3.膈肌超微结构的观察：电镜下可见,三种模式中,CMV组部分肌原纤维溶解断裂,排列疏松且不规则,肌丝出现裂隙,部分z线出现模糊、结构紊乱、排列不整齐,肌原纤维间线粒体肿胀、基质空亮、嵴变形、溶解,有的线粒体呈絮状、髓样或空泡样变；A/C组部分肌原纤维排列疏松,部分z线模糊、结构紊乱；肌原纤维间空泡形成,线粒体肿胀、嵴变形、溶解；PSV组肌纤维间大量空泡及脂质空泡形成；但线粒体无肿胀、嵴致密、丰富。
结论：
①增加机械通气的支持水平可导致膈肌肌电活动下降,但是PSV模式可以减少膈肌电活动的下降幅度。②PSV模式与CMV模式和A/C模式比较,可以减少膈肌细胞Caspase-3蛋白的高表达。③CMV对膈肌肌纤维的结构损伤最明显,PSV模式可以减轻膈肌组织的损伤。因此提示PSV模式可以作为临床预防VIDD的方法之一。
Background:
Mechanical ventilation (MV) is a clinical intervention for patients who are unable to maintain adequate alveolar ventilation.Recent evidence reveals that controlled MV results in a swift progression of diaphragmatic atrophy and weakness.It seems that this diaphragmatic atrophy and weakness contributes to difficulty in weaning patients from the ventilator. Although several factors may contribute to delay weaning, a major determinant appears to be respiratory muscle weakness.Historically, the term "disuse atrophy" has described a situation where in sustained inactivity of the respiratory muscles (ie, passive ventilation) results in deconditioning and weakness.More recently it has been referred to as "ventilator-induced diaphragmatic dysfunction, VIDD."In contrast,"use atrophy" describes a situation where chronic high-tension inspiratory work causes structural damage to the diaphragm and weakness.Both laboratory and clinical studies demonstrated that relatively brief periods of complete respiratory muscle inactivity, as well as intense muscle loading, result in acute inflammation, loss of muscle mass, and weakness.Recent years,studies have shown that PSV mode can reduce the process of VIDD and try to use PSV mode ventilation to reduce the occurrence of VIDD.But it is not confirmed that the effects of the VIDD are modes or the level of support. The aim of this study is to analyse the diaphragm EMGdi activity in the different mode under the same level of ventilation, and observe the impact of diaphragm apoptosis and ultrastructure on healthy rabbits.
Methods:
Sixteen New Zealand rabbits (conventional animal,2.0kg～2.1kg) were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive24hours of CMV or AJC or PSV mode. After intubated with tracheostomy, connection flow transducer, continuous observation of the diaphragmatic EMGdi (diaphragm electromyo-gram, EMGdi).CMV group:Rr45bpm, FiO21L/min, and the I:E1:3, VT8-10ml/kg);A/C group: PCVmode, Trigger O.1L/min, Rr45bpm,Pi10cmH2O, Ti0.5sec, FiO225%, to maintain VT8-10ml/kg; PSV group the (Spont mode, Trigger0.1L/min, PSV10cmH2O, Esense25%, FiO225%to maintain VT8-10ml/kg). According to ABG, adjust the FiO2, VT and RR. Control group:animals were sacrificed by air embolism after monitor the EMGdi for30min, no mechanical ventilation. Ventilator support for24hours, whichever is analysed of the diaphragm immune histochemistry and western blot expression of Caspase-3activity of diaphragm of each group,and observed the ultrastructural changes of the diaphragm by electron microscopy.
Result:
1.Three ventilation modes significantly reduce the diaphragm electrical activity under the same level of support.
EMGDi spectrum analysis result:Compared with the control group, low frequency components (L) of three groups increased, high frequency components (H) decreased,H/L decresed of82.3%,81.8%,80.6%(p<0.01) in CMVgroup, A/C group and PSV group respectively. Center frequency (Fc) decreased by43%,37.1%and34.9%, respectively (P<0.01).Significant statistics difference of Fc was found in multiple comparisons (CMV vs A/C, P<0.05; CMV vs PSV, P0.05;A/C vs PSV, P0.05).
2.Caspase-3activity induced significantly by three ventilation modes,PSV mode attenuated changes in Caspase-3.
Compared with control animals, the expression of17kD Acti-Caspase3of diaphragm in three modes was increased. CMV group Active-caspase3expression was strongly positive,the same as A/C mode(6.40±0.57vs5.98±0.41,P>0.05).The gray value of Western blot are2.473±0.431(p<0.01);2.202±0.213(p<0.01);1.829±1.001(p<0.05),respectively.
3.PSV mode inhibited the damage of diaphragm structure.
Observed through the electron microscope:The ultrastructure of diaphragm was normaL in control group.Different among the three groups,abnormal uhrastructure was observed in CMV group,including disrupted myofibrils,swollen mitoehondria, structural disorder, irregular arrangement of myofibrillar swelling of mitochondria; A/C group shows Myofibrils arranged in neat rows (some loosely arranged), part of the z line is fuzzy, the structural disorder; myofibrillar vacuolization, mitochondrial swelling, cristae deformation, dissolution; PSV group muscle fibril arranged in neat, sarcomere integrity, clear, no significant swelling of the Z line neat and clear; formation of a large number of vacuoles and lipid vacuoles in the muscle fibers mitochondrial swelling, cristae dense and rich.
Conclusion:
The main effection of diaphragm electrical activity is the level of ventilation support. The three modes were significantly induced the expression of Caspase-3protein, but PSV mode can reduce the diaphragm of the level of caspase-3.CMV leads to structural injury, PSV can reduce the damage of the diaphragm.
机械通气是呼吸衰竭患者生命支持的重要手段,但机械通气时间的延长,易出现困难撤机。膈肌是最主要的呼吸肌,在呼吸过程中所起的作用约占全部呼吸肌的60%-80%。膈肌的功能损伤会直接导致呼吸衰竭。临床研究认为机械通气控制模式(Control Mechanical Ventilation,CMV)可导致膈肌放电消失,膈肌纤维废用性萎缩,即呼吸机诱导的膈肌功能下降(Ventilation induced diaphragm disfunction,VIDD)。研究者通过动物实验从不同角度描述VIDD的发生：发现大鼠在CMV6小时后便开始出现横膈膜蛋白质氧化和脂质过氧化产物的持续增多,其氧化修饰发展迅速,在持续控制性机械通气18小时后,膈肌Ⅰ型和Ⅱ型纤维的数量减少,且Ⅱ型纤维出现较大程度的萎缩,大鼠膈肌肌肉萎缩也较外周骨骼肌萎缩更甚；对不同种类动物取完整膈肌测量跨膈压(Pdi)的活体研究表明,行CMV通气后(实验兔1天、实验猪3天),膈神经在最大和次最大刺激频率下,Pdi均进行性下降等。
膈神经冲动发放次数或膈神经冲动发放频率的减少参与造成隔肌功能障碍。Ayas等的研究中提供了有利的证据,他们关于CMV时刺激膈神经防止膈肌萎缩的报道间接提示,机械通气时确实存在膈肌神经刺激的减少。肌肉的正常收缩活动依赖于完整的神经冲动,一旦神经刺激减少或消失,膈肌将发生萎缩和收缩功能下降,进而发展为VIDD。但是,研究中对几种常用模式支持下膈肌肌电活动的变化未做阐述,对其与不同模式对膈肌功能和结构的影响的相关性未进行进一步的研究。
目前认为,由于横膈活动的减弱,导致线粒体损伤,引起氧化应激和蛋白质水解系统的激活等是导致VIDD的主要途径。VIDD废用性肌萎缩时蛋白质流失直接与3种蛋白质水解系统有关,即溶酶体蛋白酶、钙活化蛋白酶(如钙蛋白酶)和蛋白酶体系统。最近研究提示,Caspase-3有助于蛋白质降解和肌萎缩。细胞对Caspase-3活性的控制是复杂的,涉及到许多相互联系的信号通路。钙蛋白酶抑制蛋白(Calpastatin)是Caspase-3和钙蛋白酶的共同底物。增强Caspase-3或钙蛋白酶活性会降低细胞内Calpastatin水平,促进钙蛋白酶活化。另外,增强钙蛋白酶活性能导致Caspase-3活化。因此,Caspase-3和钙蛋白酶之间的交互作用在废用性肌内调节肌丝释放中起着一定作用,在促进CMV膈肌损伤中扮演了极为重要的角色。近期的临床和动物研究中对危重病患者给于抗氧化剂和糖皮质激素进行干预,期望减少VIDD的发生及延缓VIDD进程,研究结果提示可以延缓VIDD的进一步发展,但是研究报告中同时提出这些干预措施的影响因素很多。McClungJM等的研究表明PSV模式可以减少VIDD的发生进程,尝试间断予PSV模式通气来减少VIDD的发生。但是研究中其支持水平与对照组(CMV)模式不同,无法判断是呼吸机模式还是支持水平对VIDD的影响?对于几种常用的呼吸机模式,在相同支持水平下对膈肌的影响,相关的研究目前国内外尚无报道。
目的：
研究三种常用通气模式CMV、A/C和PSV模式,在同样压力支持水平下,呼吸机对实验兔的膈肌肌电活动变化的影响,并观察其对膈肌细胞凋亡和超微结构的影响。
方法：
将16只实验兔(普通级,2.0kg～2.1kg)随机数字表法归入空白对照组、CMV组、A/C组和PSV组,分别行8%水合氯醛4ml/kg腹腔注射麻醉后,进行气管切开插管、连接流量呼吸换能器,并持续观察膈肌肌电图(diaphragm electromyo-gram,EMGdi)变化。右颈总动脉穿刺置管血压监测；行微泵静脉咪唑安定1mg/kg/h静脉注射镇静。CMV组(Rr45bpm,FiO2lL/min, I:El:3,VT8-10ml/kg)、A/C组(PCVmode,Trigger0.1L/min,Rr45bpm, Pi10cmH2O, Ti0.5sec,FiO225%,维持VT8-10ml/kg呼吸机)、PSV组(Spont mode,Trigger0.1L/min, PSV10cmH2O, Esense25%, FiO225%,维持VT8-10m1/kg)分别行三种模式进行机械通气24小时,F102维持正常血气Pa02水平。根据血气调整Fi02、VT和RR。各组实验过程中持续监测膈肌电活动和呼吸运动,监测动脉血压,维持生命体征稳定。空白对照组：不进行机械通气,行气管切开,并监测膈肌肌电活动及呼吸运动30min后,予空气栓塞法处死动物。取膈肌进行免疫组化及western blot分析各组实验兔膈肌肌细胞的Caspase-3活性表达、并电镜下观察膈肌组织超微结构的改变。
结果：
1. EMGDi频谱分析结果：三组低频成分(L)增加,高频成分(H)降低,CMV组、A/C组和PSV组H/L分别下降82.3%,81.8%,80.6%,(p<0.01);中心频率(Fc)与对照组相比分别下降43%,37.1%和34.9%。(P<0.01)。组间比较,Fc值CMV组下降最明显,其次为A/C组(与CMV组比较P<0.05)和PSV组(与CMV和A/C比较p<0.05)
2.Caspase-3蛋白表达：免疫组化显示与对照组相比,CMV、A/C和PSV模式的17-kD active Caspase-3蛋白表达增强。CMV组、A/C组中17-kD active Caspase3表达呈强阳性(积分分别为6.40±0.57,5.98±0.41)；PSV模式呈中等阳性(4.47±0.67分),与CMV组和A/C比较差异有统计学意义(P<0.05)。Western-blot结果显示三种模式与对照组比较,CMV.A/C和PSV模式灰度值依次为2.473±0.431(p<0.01)；2.202±0.213(p<0.01)；1.829±1.001(p<0.05),三组组间两两比较无显著性差异。
3.膈肌超微结构的观察：电镜下可见,三种模式中,CMV组部分肌原纤维溶解断裂,排列疏松且不规则,肌丝出现裂隙,部分z线出现模糊、结构紊乱、排列不整齐,肌原纤维间线粒体肿胀、基质空亮、嵴变形、溶解,有的线粒体呈絮状、髓样或空泡样变；A/C组部分肌原纤维排列疏松,部分z线模糊、结构紊乱；肌原纤维间空泡形成,线粒体肿胀、嵴变形、溶解；PSV组肌纤维间大量空泡及脂质空泡形成；但线粒体无肿胀、嵴致密、丰富。
结论：
①增加机械通气的支持水平可导致膈肌肌电活动下降,但是PSV模式可以减少膈肌电活动的下降幅度。②PSV模式与CMV模式和A/C模式比较,可以减少膈肌细胞Caspase-3蛋白的高表达。③CMV对膈肌肌纤维的结构损伤最明显,PSV模式可以减轻膈肌组织的损伤。因此提示PSV模式可以作为临床预防VIDD的方法之一。
Background:
Mechanical ventilation (MV) is a clinical intervention for patients who are unable to maintain adequate alveolar ventilation.Recent evidence reveals that controlled MV results in a swift progression of diaphragmatic atrophy and weakness.It seems that this diaphragmatic atrophy and weakness contributes to difficulty in weaning patients from the ventilator. Although several factors may contribute to delay weaning, a major determinant appears to be respiratory muscle weakness.Historically, the term "disuse atrophy" has described a situation where in sustained inactivity of the respiratory muscles (ie, passive ventilation) results in deconditioning and weakness.More recently it has been referred to as "ventilator-induced diaphragmatic dysfunction, VIDD."In contrast,"use atrophy" describes a situation where chronic high-tension inspiratory work causes structural damage to the diaphragm and weakness.Both laboratory and clinical studies demonstrated that relatively brief periods of complete respiratory muscle inactivity, as well as intense muscle loading, result in acute inflammation, loss of muscle mass, and weakness.Recent years,studies have shown that PSV mode can reduce the process of VIDD and try to use PSV mode ventilation to reduce the occurrence of VIDD.But it is not confirmed that the effects of the VIDD are modes or the level of support. The aim of this study is to analyse the diaphragm EMGdi activity in the different mode under the same level of ventilation, and observe the impact of diaphragm apoptosis and ultrastructure on healthy rabbits.
Methods:
Sixteen New Zealand rabbits (conventional animal,2.0kg～2.1kg) were included in this prospective randomized animal study. After intraperitoneal anesthesia, animals were randomly assigned to the control group or to receive24hours of CMV or AJC or PSV mode. After intubated with tracheostomy, connection flow transducer, continuous observation of the diaphragmatic EMGdi (diaphragm electromyo-gram, EMGdi).CMV group:Rr45bpm, FiO21L/min, and the I:E1:3, VT8-10ml/kg);A/C group: PCVmode, Trigger O.1L/min, Rr45bpm,Pi10cmH2O, Ti0.5sec, FiO225%, to maintain VT8-10ml/kg; PSV group the (Spont mode, Trigger0.1L/min, PSV10cmH2O, Esense25%, FiO225%to maintain VT8-10ml/kg). According to ABG, adjust the FiO2, VT and RR. Control group:animals were sacrificed by air embolism after monitor the EMGdi for30min, no mechanical ventilation. Ventilator support for24hours, whichever is analysed of the diaphragm immune histochemistry and western blot expression of Caspase-3activity of diaphragm of each group,and observed the ultrastructural changes of the diaphragm by electron microscopy.
Result:
1.Three ventilation modes significantly reduce the diaphragm electrical activity under the same level of support.
EMGDi spectrum analysis result:Compared with the control group, low frequency components (L) of three groups increased, high frequency components (H) decreased,H/L decresed of82.3%,81.8%,80.6%(p<0.01) in CMVgroup, A/C group and PSV group respectively. Center frequency (Fc) decreased by43%,37.1%and34.9%, respectively (P<0.01).Significant statistics difference of Fc was found in multiple comparisons (CMV vs A/C, P<0.05; CMV vs PSV, P0.05;A/C vs PSV, P0.05).
2.Caspase-3activity induced significantly by three ventilation modes,PSV mode attenuated changes in Caspase-3.
Compared with control animals, the expression of17kD Acti-Caspase3of diaphragm in three modes was increased. CMV group Active-caspase3expression was strongly positive,the same as A/C mode(6.40±0.57vs5.98±0.41,P>0.05).The gray value of Western blot are2.473±0.431(p<0.01);2.202±0.213(p<0.01);1.829±1.001(p<0.05),respectively.
3.PSV mode inhibited the damage of diaphragm structure.
Observed through the electron microscope:The ultrastructure of diaphragm was normaL in control group.Different among the three groups,abnormal uhrastructure was observed in CMV group,including disrupted myofibrils,swollen mitoehondria, structural disorder, irregular arrangement of myofibrillar swelling of mitochondria; A/C group shows Myofibrils arranged in neat rows (some loosely arranged), part of the z line is fuzzy, the structural disorder; myofibrillar vacuolization, mitochondrial swelling, cristae deformation, dissolution; PSV group muscle fibril arranged in neat, sarcomere integrity, clear, no significant swelling of the Z line neat and clear; formation of a large number of vacuoles and lipid vacuoles in the muscle fibers mitochondrial swelling, cristae dense and rich.
Conclusion:
The main effection of diaphragm electrical activity is the level of ventilation support. The three modes were significantly induced the expression of Caspase-3protein, but PSV mode can reduce the diaphragm of the level of caspase-3.CMV leads to structural injury, PSV can reduce the damage of the diaphragm.
引文
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2.Khan J, Harrison TB, Rich MM.Mechanisms of neuromuscular dysfunction in critical illness.Crit Care Clin 24:165-177,2008
3.Multz AS,Aldrich TK, Prezant DJ, Karpel JP, Hendler JM. Maximal inspiratory pressure is not a reliable test of inspiratory muscle strength in mechanically ventilated patients.Am Rev Respir Dis 142:529-532,1990.
4. Laghi F, Cattapan SE, Jubran A, Parthasarathy S,Warshawsky P,Choi YS,Tobin MJ. Is weaning failure caused by low-frequency fatigue of the diaphragm?Am J Respir Crit Care Med 167:120-127,2003.
5.Watson AC,Hughes PD,Louise Harris M, Hart N, Ware RJ, Wendon J, Green M, Moxham J. Measurement of twitch transdiaphragmatic,esophageal,and endotracheal tube pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients in the intensive care unit.Crit Care Med 29:1325-1331,2001.
6. Betters JL, Criswell DS,Shanely RA, Van Gammeren D, Falk D,Deruisseau KC, Deering M, Yimlamai T, Powers SK. Trolox attenuates mechanical ventilation-induced diaphragmatic dysfunction and proteolysis.Am J Respir Crit Care Med 170:1179-1184, 2004
7.Whidden MA, McClung JM, Falk DJ,Hudson MB,Smuder AJ,Nelson WB,Powers SK. Xanthine oxidase contributes to mechanical ventilation-induced diaphragmatic oxidative stress and contractile dysfunction. J Appl Physiol. First published November 20,2008;doi:10.1152/japplphysiol.91477.2008
8.McClung JM, Kavazis AN, DeRuisseau KC, Falk DJ, Deering MA,Lee Y, Sugiura T, Powers SK. Caspase-3 regulation of diaphragm myonuclear domain during mechanical ventilation-induced atrophy. Am J Respir Crit Care Med 175:150-159, 2007.
9. Maes K, Testelmans D, Powers S,Decramer M, Gayan-Ramirez GLeupeptin inhibits ventilator-induced diaphragm dysfunction in rats.Am J Respir Crit Care Med 175:1134-1138,2007.
10. DeRuisseau KC,Kavazis AN,Deering MA, Falk DJ, Van Gammeren D, Yimlamai T, Ordway GA, Powers SK. Mechanical ventilation induces alterations of the ubiquitin proteasome pathway in the diaphragm.J Appl Physiol 98:1314-1321,2005
11.Shanely RA,Van Gammeren D,Deruisseau KC,Zergeroglu AM,McKenzie MJ, Yarasheski KE,Powers SK. Mechanical ventilation depresses protein synthesis in the rat diaphragm.Am J Respir Crit Care Med 170:994-999,2004
12.Capdevila X, Lopez S,Bernard N, Rabischong E, Ramonatxo M, Martinazzo G, Prefaut C Effects of controlled mechanical ventilation on respiratory muscle contractile properties in rabbits.Intensive Care Med 2003;29:103-110
13. 焦光宇等,呼气末正压对机械通气大鼠膈肌结构与功能的影响。解放军医学杂志2008年6月,第33卷第6期：676-680
14. Catherine S.H.Sassoon, Ercheng Zhu, etc Assist-Control Mechanical Ventilation Attenuates Ventilator-Induced Diaphragmatic Dysfunction. Am. J Respir Crit Care Med 2004;170(6):626-632
15. Kenneth M, Baldwin, Fadia H. Plasticity in Skeletal,Cardiac,and Smooth Muscle Invited Review:Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle. J Appl Physiol 2001;90:345-357.
16.Danialou G Ebihara S,Hussain SN,et al.Mechanical ventilation protects against diaphragm injury in sepsis. Am J Resp ir Crit Care Med,2002,165(2):221.228.
17.Roussos C,Koutsoukou A. Respiratory failure[J].Eur Respir J,2003,47(Supp 1):3214.
18. Radell P J,Remahl S, Nicholsd G et al。Effects of prolongedmechanical ventilation and inactivity on pigletdiaphragm function [J].Intensive CareMed,2002, 28(3):358-364.
19.Zergeroglu MA, McKenzie MJ, Shanely RA, Van Gammeren D, DeRuisseau KC,Powers SK. Mechanical ventilation-induced oxidative stress in the diaphragm. J Appl Physiol 2003;95(3):1116-1124.
20. Shanely RA, Zergeroglu MA, Lennon SL, Sugiura T, Yimlamai T, Enns D, et al. Mechanical ventilation-induced diaphragmatic atrophy is associated with oxidative injury and increased proteolytic activity. Am J Respir Crit Care Med 2002;166(10):1369-1374.
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