Diaphragm dysfunction in chronic obstructive pulmonary disease
Diaphragm dysfunction in chronic obstructive pulmonary disease
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DOI：
10.1164/rccm.200502-262oc
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发表时间：
2005-07-15
影响因子：
24.7
通讯作者：
Dekhuijzen, PNR
中科院分区：
文献类型：
--
作者：
Ottenheijm, CAC;Heunks, LMA;Dekhuijzen, PNR
基本原理：由于吸气肌无力引起的高碳酸血症性呼吸衰竭是慢性阻塞性肺疾病（COPD）最重要的死亡原因。然而，在COPD中横膈膜不能产生力的病理生理学尚不清楚。目的：本研究观察了慢性阻塞性肺疾病（COPD）患者膈肌单纤维的收缩功能和肌球蛋白重链含量。研究方法：从8例轻度至中度COPD患者和5例非COPD患者（平均FEV1%预测值，分别为70%和100%）的膈肌肌肉活检中分离出皮肤肌纤维。单纤维的收缩功能进行了评估，然后，肌球蛋白重链含量测定在这些纤维。在膈肌匀浆中，测定泛素-蛋白质结合的水平。结果如下：COPD患者的膈肌纤维显示单位横截面积产生的力减少，每半肌节的肌球蛋白重链含量减少。此外，这些纤维具有降低的力产生的Ca 2+敏感性和较慢的跨桥循环动力学。我们的观察结果存在于肌球蛋白重链的慢和2A亚型表达的纤维。轻中度COPD患者膈肌匀浆中泛素-蛋白结合增加。结论：COPD早期膈肌纤维收缩功能受损。我们的数据表明，通过泛素-蛋白酶体途径增强的隔膜蛋白降解在收缩蛋白的损失中起作用，因此，隔膜不能产生力。
Rationale: Hypercapnic respiratory failure because of inspiratory muscle weakness is the most important cause of death in chronic obstructive pulmonary disease (COPD). However, the pathophysiology of failure of the diaphragm to generate force in COPD is in part unclear. Objectives: The present study investigated contractile function and myosin heavy chain content of diaphragm muscle single fibers from patients with COPD. Methods: Skinned muscle fibers were isolated from muscle biopsies from the diaphragm of eight patients with mild to moderate COPD and five patients without COPD (mean FEV1 % predicted, 70 and 100%, respectively). Contractile function of single fibers was assessed, and afterwards, myosin heavy chain content was determined in these fibers. In diaphragm muscle homogenates, the level of ubiquitin-protein conjugation was determined. Results: Diaphragm muscle fibers from patients with COPD showed reduced force generation per cross-sectional area, and reduced myosin heavy chain content per half sarcomere. In addition, these fibers had decreased Ca2+ sensitivity of force generation, and slower cross-bridge cycling kinetics. Our observations were present in fibers expressing slow and 2A isoforms of myosin heavy chain. Ubiquitin-protein conjugation was increased in diaphragm muscle homogenates of patients with mild to moderate COPD. Conclusions: Early in the development of COPD, diaphragm fiber contractile function is impaired. Our data suggest that enhanced diaphragm protein degradation through the ubiquitin-proteasome pathway plays a role in loss of contractile protein and, consequently, failure of the diaphragm to generate force.