Inactivity-induced diaphragm dysfunction and mitochondria-targeted antioxidants: new concepts in critical care medicine.
Inactivity-induced diaphragm dysfunction and mitochondria-targeted antioxidants: new concepts in critical care medicine.
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不活动引起的膈肌功能障碍和线粒体靶向抗氧化剂：重症监护医学的新概念。
DOI：
10.1097/ccm.0b013e31821e85ca
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发表时间：
2011
影响因子：
8.8
通讯作者：
Singhal,Sunil
中科院分区：
文献类型：
--
作者：
Levine,Sanford;Budak,MuratT;Dierov,Jamil;Singhal,Sunil
在过去的十年中，Powers实验室贡献了一系列引人注目的出版物（1-4），表明大鼠中的受控机械通气（MV）-根据标准化方案进行12-18小时-可预测地引起膈肌不活动，伴随着氧化应激，肌纤维萎缩和收缩功能障碍的三联体。这些研究的临床相关性在2008年变得明显，当时我们（5）报道了18-72小时的MV和人类膈肌失活-在脑死亡器官供体中-引起了一些氧化应激和缓慢和快速膈肌肌纤维显著（即50%）萎缩的证据。此外，我们注意到caspase-3（一种细胞质丝氨酸蛋白酶）的活性增加，以及编码atrogin-1和MuRF-1（泛素-蛋白酶体蛋白水解途径（UPPP）的关键组分）的信使核糖核酸的表达增加，我们认为蛋白水解增加在产生肌纤维萎缩中起主要作用。我们计算出这些膜片的最大跨膜压力将显著降低。我们后来证明肌球蛋白重链蛋白（收缩的分子马达）的浓度降低到对照浓度的50%以下，这为假定的收缩功能障碍提供了一种可能的机制。最近，Jaber等人（7）使用颈部磁膈神经刺激直接证明了长期MV患者的膈肌峰值抽搐张力（通过气道闭塞压评估）进行性降低;此外，他们的活检数据表明肌纤维萎缩，UPPP活性增加，钙蛋白酶（即钙蛋白酶I，II和III）的蛋白表达增加，另一个丝氨酸细胞质蛋白酶家族。我们推测这些钙蛋白酶表达的增加代表了钙蛋白酶活性的增加;这种诱导性飞跃是重要的，因为UPPP不能降解附着在肌纤维晶格上的完整的放线菌球蛋白复合物。事实上，Whidden等人（4）和其他人（8）最近的研究表明，钙蛋白酶和半胱天冬酶-3的活性增加与氧化应激结合，切割结构蛋白，如肌联蛋白（9），从而影响肌动蛋白、肌球蛋白和其他肌原纤维蛋白从晶格中释放，供UPPP进一步降解。
Over the past decade, the Powers lab has contributed a remarkable series of publications (1–4) indicating that controlled mechanical ventilation (MV) in the rat—according to a standardized protocol carried out for 12–18 hrs—predictably elicited diaphragm inactivity that was accompanied by the triad of oxidative stress, myofiber atrophy, and contractile dysfunction. The clinical relevance of these studies became apparent in 2008, when we (5) reported that 18–72 hrs of MV and human diaphragm inactivity—in brain dead organ donors—elicited some evidence of oxidative stress and dramatic (ie, 50%) atrophy of both slow and fast diaphragm myofibers. Furthermore, we noted increased activity of caspase-3, a cytoplasmic serine protease, and increased expression of messenger ribonucleic acid coding for atrogin-1 and MuRF-1, key components of the ubiquitin–proteasome proteolytic pathway (UPPP), and we suggested that increased proteolysis played a major role in producing the myofiber atrophy.Additionally, on the basis of the data in our article, we calculated that maximum transdiaphragmatic pressure of these diaphragms would be dramatically decreased. We (6) later demonstrated that the concentration of myosin heavy chain proteins (the molecular motor of contraction) was decreased to< 50% of control concentrations, and this provides one possible mechanism for the postulated contractile dysfunction. More recently, Jaber et al (7) used cervical magnetic phrenic nerve stimulation to directly demonstrate progressive decreases in diaphragm peak twitch tension (assessed by airway occlusion pressures) in patients on prolonged MV; additionally, their biopsy data indicated myofiber atrophy, increased UPPP activity, and increased protein expression of the calpains (ie, calpains I, II, and III), another family of serine cytoplasmic proteases. We presume that these increases in calpain expression represented an increase in calpain activity; this inductive leap is important since the UPPP cannot degrade intact actinomyosin complexes that are attached to the myofiber lattice. Indeed, recent work by Whidden et al (4) and others (8) indicates that increased activity of both the calpains and caspase-3 in conjunction with oxidative stress cleaves structural proteins such as titin (9) and thereby effects the release of actin, myosin, and other myofibrillar proteins from the lattice for further degradation by the UPPP.