p38 mitogen-activated protein kinase modulates endotoxin-induced diaphragm caspase activation

Gerry S. Supinski, Xin Ying Ji, Leigh Ann Callahan

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


We postulated that the p38 pathway is activated in the diaphragm during sepsis and contributes to sepsis-induced diaphragm caspase activation and contractile dysfunction. This study determined whether: (1) endotoxin administration elicits p38 activation in the diaphragm; (2) cytokines activate p38 in isolated muscle cells; (3) activation of p38 is accompanied by caspase 8 activation; (4) inhibition of p38 prevents caspase 8 activation and; (5) inhibition of p38 prevents diaphragm dysfunction in endotoxin-treated animals. Wefirst evaluated the time course of diaphragm p38 activation after endotoxin in mice. We then determined if p38 inhibitor administration could prevent caspase 8 activation in endotoxin-treated mice. We also assessed p38 and caspase 8 activation in C2C12 muscle cells treated with control media or a cytokine mixture, with or without concomitant chemical inhibition of p38 (using SB203580, 25 μM) or loss of p38 function due to cell transfection with a dominant negative p38 genetic construct. Endotoxin administration activated diaphragm p38 (P < 0.001), and cytokines activated p38 in C2C12 cells (P < 0.05). In both the diaphragm and cells, p38 activation was accompanied by increases in active caspase 8 (P < 0.01). Inhibition of p38 with either SB203580 or with a dominant negative p38 construct prevented caspase activation (P < 0.001). p38 inhibitors also prevented endotoxin-induced diaphragm weakness (P < 0.001). p38 modulates cytokine-induced skeletal muscle caspase activation.

Original languageEnglish
Pages (from-to)121-127
Number of pages7
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Issue number1
StatePublished - Jul 1 2010


  • Caspase
  • Diaphragm
  • Endotoxin
  • Proteolysis
  • Sepsis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology


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