TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness
TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness
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DOI：
10.1152/ajplung.00264.2010
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发表时间：
2011-02-01
影响因子：
4.9
通讯作者：
Reid, Michael B.
中科院分区：
文献类型：
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作者：
Gilliam, Laura A. A.;Moylan, Jennifer S.;Reid, Michael B.
Gilliam LA，Moylan JS，Ferreira LF，Reid MB. TNF/TNFR 1信号转导介导阿霉素诱导的膈肌无力美国生理学杂志肺细胞分子生理学300：L225-L231，2011年。首次发表于2010年11月19日; doi：10.1152/ajplung.00264.2010.-多柔比星是一种常见的化疗药物，可引起患者和啮齿动物的呼吸肌无力。肿瘤坏死因子-α（TNF），一种抑制膈肌力量的促炎细胞因子，在多柔比星化疗后升高。TNF诱导的膈肌无力通过TNF 1型受体（TNFR 1）介导。这些发现使我们假设TNF/TNFR 1信号介导阿霉素诱导的膈肌无力。我们通过静脉注射临床剂量的多柔比星（20 mg/kg）治疗C57 BL/6小鼠来验证这一假设。三天后，我们测量了从膈肌分离的肌纤维束的收缩特性。我们使用药物和遗传干预测试了TNF/TNFR 1信号的参与。依那西普，一种可溶性TNF受体，和TNFR 1缺陷可防止阿霉素引起的细胞特异性力的抑制。阿霉素刺激膈肌TNFR 1 mRNA和蛋白表达增加（P < 0.05），并沿着TNFR 1与质膜共定位。这些结果表明，阿霉素通过上调TNFR 1增加膈肌对TNF的敏感性，从而引起呼吸肌无力。
Gilliam LA, Moylan JS, Ferreira LF, Reid MB. TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness. Am J Physiol Lung Cell Mol Physiol 300: L225-L231, 2011. First published November 19, 2010; doi:10.1152/ajplung.00264.2010.-Doxorubicin, a common chemotherapeutic agent, causes respiratory muscle weakness in both patients and rodents. Tumor necrosis factor-alpha (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.