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TNF/TNFR1 signaling mediates doxorubicin-induced diaphragm weakness.

Authors: Gilliam, LA  Moylan, JS  Ferreira, LF  Reid, MB 
Citation: Gilliam LA, etal., Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L225-31. Epub 2010 Nov 19.
Pubmed: (View Article at PubMed) PMID:21097524
DOI: Full-text: 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.


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RGD Object Information
RGD ID: 5130943
Created: 2011-04-15
Species: All species
Last Modified: 2011-04-15
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.