Department of Physiology, Center for Muscle Biology, University of Kentucky, Lexington, 40536-0298, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L225-31. doi: 10.1152/ajplung.00264.2010. Epub 2010 Nov 19.
Doxorubicin, a common chemotherapeutic agent, causes respiratory muscle weakness in both patients and rodents. Tumor necrosis factor-α (TNF), a proinflammatory cytokine that depresses diaphragm force, is elevated following doxorubicin chemotherapy. TNF-induced diaphragm weakness is mediated through TNF type 1 receptor (TNFR1). These findings lead us to hypothesize that TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm muscle weakness. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via intravenous injection. Three days later, we measured contractile properties of muscle fiber bundles isolated from the diaphragm. We tested the involvement of TNF/TNFR1 signaling using pharmaceutical and genetic interventions. Etanercept, a soluble TNF receptor, and TNFR1 deficiency protected against the depression in diaphragm-specific force caused by doxorubicin. Doxorubicin stimulated an increase in TNFR1 mRNA and protein (P < 0.05) in the diaphragm, along with colocalization of TNFR1 to the plasma membrane. These results suggest that doxorubicin increases diaphragm sensitivity to TNF by upregulating TNFR1, thereby causing respiratory muscle weakness.
多柔比星是一种常见的化疗药物，会导致患者和啮齿动物的呼吸肌无力。肿瘤坏死因子-α（TNF）是一种促炎细胞因子，会降低膈肌力量，在多柔比星化疗后会升高。TNF 诱导的膈肌无力是通过 TNF 型 1 受体（TNFR1）介导的。这些发现使我们假设 TNF/TNFR1 信号转导介导多柔比星引起的膈肌肌肉无力。我们通过静脉注射给予 C57BL/6 小鼠临床剂量的多柔比星（20mg/kg）来检验这一假设。三天后，我们测量了从膈肌分离的肌纤维束的收缩特性。我们使用药物和基因干预来测试 TNF/TNFR1 信号转导的参与情况。依那西普，一种可溶性 TNF 受体，和 TNFR1 缺乏症可预防多柔比星引起的膈肌特异性力的下降。多柔比星刺激 TNFR1 mRNA 和蛋白的增加（P<0.05）在膈肌中，同时 TNFR1 与质膜的共定位。这些结果表明，多柔比星通过上调 TNFR1 增加膈肌对 TNF 的敏感性，从而导致呼吸肌无力。
