Putting the spice in weaning*.
Putting the spice in weaning*.
复制标题
在断奶时加入香料*。
DOI：
10.1097/ccm.0b013e31823e96c2
复制
发表时间：
2012
影响因子：
8.8
通讯作者：
Judge,AndrewR
中科院分区：
文献类型：
--
作者：
Falk,DarinJ;Judge,AndrewR
In this issue of Critical Care Med-icine, Dr. Smuder and colleagues (1) determined the extent to which nuclear factor kappa B (NF-κB) contributes to diaphragm atrophy and weakness induced by mechanical ventilation (MV). Clinically, MV provides adequate ventilation in patients with ventilatory insufficiency. Although this may be a life-saving intervention, there is a high probability of weaning difficulties and this is attributable, in part, to ventilator-induced diaphragmatic dysfunction (2). Pivotal studies performed in small animal models uncovered a rapid loss of contractile function and significant atrophy in diaphragm myofibers during MV (3, 4). These events have been attributed to an overall increase in oxidant production, depletion of antioxidant buffering capacity, and modification of key contractile proteins (5, 6). These investigations have been critical to increase our fundamental understanding of the mechanisms leading to weaning difficulties observed in the intensive care unit and have since been validated as we now know that similar events occur in the human diaphragm. In a brain-dead organ donor model, a significant increase in atrophicrelated gene and protease expression, autophagy, and decrease in myofiber crosssectional area have been observed in the diaphragm (7, 8). Furthermore, a progressive increase in nuclear localization of NF-κB from mechanically ventilated diaphragm biopsy samples was observed by Jaber et al (9) and provides a basis for contribution of this transcriptional activator to the unique and rapid rate of disuse atrophy and contractile dysfunction observed in the diaphragm.The rationale for this study is strong in that NF-κB transcriptional activity is increased in locomotor skeletal muscles during disuse (10–12), sufficient to cause skeletal muscle atrophy in locomotor muscles (13), and required for locomotor skeletal muscle atrophy associated with disuse (11, 13, 14). In 2001, Hunter et al showed an increase in NF-κB transcriptional activity in locomotor muscles in response to disuse that was associated with increased nuclear levels of the NF-κB family member p50 and the nuclear inhibitor of κB (IκB) family member, Bcl-3. Subsequent supershift assays confirmed the presence of κB-binding complexes containing p50 and Bcl-3. Importantly, p50–Bcl-3 complexes can activate transcription. Follow-up work by Hunter et al in 2004, using knockout mice, demonstrated that both the Nfkb1 (encodes for p105/p50) and Bcl-3 genes are required for disuse skeletal muscle fiber atrophy in locomotor muscles (11). Also in 2004, Cai et al demonstrated that skeletal musclespecific transgenic mice overexpressing a constitutively active IκB kinase β activates NF-κB and causes significant skeletal muscle atrophy in locomotor muscles. These findings clearly demonstrated that an increase in NF-κB activation by IκB kinase β is sufficient to cause locomotor skeletal muscle atrophy. In the same study, Cai et al used muscle-specific transgenic mice overexpressing a mutant form of the endogenous inhibitor of κB, IκBα, which cannot be degraded, and subjected these mice to muscle denervation. Compared to wild-type mice, the transgenic mice showed blunted NF-κB activation and only half the locomotor skeletal muscle fiber atrophy. These findings demonstrate that NF-κB activation by IκBα degradation is required for disuse muscle atrophy in locomotor muscles. Despite the clear genetic evidence that NF-κB activation is required for disuse muscle atrophy in locomotor muscles, the study by Smuder and colleagues is the first to our knowledge to determine whether NF-κB activation is required for disuse muscle atrophy in the diaphragm
