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Am J Physiol Regul Integr Comp Physiol. 2009 Sep;297(3):R825-34. doi: 10.1152/ajpregu.90849.2008. Epub 2009 Jul 15.

The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation.

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Division of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, Lexington, Kentucky, USA.


We previously demonstrated that endotoxin-induced sepsis results in caspase 8-mediated diaphragmatic dysfunction. The upstream signaling pathways modulating diaphragm caspase 8 activation in response to endotoxin administration are, however, unknown. The purpose of the present study was to test the hypothesis that the JNK (Jun N-terminal Kinase) pathway is activated in the diaphragm during sepsis and contributes to sepsis-induced diaphragm caspase 8 activation. Endotoxin was administered to intact animals to model the effects of sepsis. We first assessed the time course of JNK activation after endotoxin (12 mg/kg i.p.) administration to mice. We then determined whether JNK inhibitor administration (30 microm/kg i.p. SP600125) could prevent caspase 8 activation and diaphragm weakness in endotoxin-treated mice. Experiments were then repeated comparing the effects of endotoxin on control and transgenic JNK knockout mice. We finally determined whether cytomix (LPS, TNFalpha, IL1beta, and IFN-gamma) exposure activated caspase 8 in C2C12 muscle cells and whether caspase 8 activation was attenuated by either chemical inhibition of JNK (30 microM SP600125) or transfection with a dominant negative JNK construct. We found that endotoxin activated diaphragm JNK (P < 0.001) and increased active caspase 8 (P < 0.01). Inhibition of JNK with SP600125 or by use of JNK-deficient animals prevented diaphragm caspase 8 activation (P < 0.01) and prevented diaphragm weakness (P < 0.05). JNK inhibition also prevented caspase 8 activation in cytokine-treated muscle cells (P < 0.001). These data implicate JNK activation as a major factor mediating inflammation-induced skeletal muscle caspase 8 activation and weakness.

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