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The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Supinski, Gerald S. Ji, Xinying Wang, Wenyi Callahan, Leigh A. |
| Copyright Year | 2007 |
| Abstract | The mechanisms by which infections induce diaphragm dysfunction remain poorly understood. The purpose of this study was to determine which caspase pathways (i.e., the extrinsic, death receptor-linked caspase-8 pathway, and/or the intrinsic, mitochondrial-related caspase-9 pathway) are responsible for endotoxin-induced diaphragm contractile dysfunction. We determined 1) whether endotoxin administration (12 mg/kg IP) to mice induces caspase-8 or -9 activation in the diaphragm; 2) whether administration of a caspase-8 inhibitor (N-acetyl-Ile-Glu-Thr-Asp-CHO, 3 mg/kg iv) or a caspase-9 inhibitor (N-acetyl-Leu-Glu-His-Asp-CHO, 3 mg/kg iv) blocks endotoxin-induced diaphragmatic weakness and caspase-3 activation; 3) whether TNF receptor 1-deficient mice have reduced caspase activation and diaphragm dysfunction following endotoxin; and 4) whether cytokines (TNF-alpha or cytomix, a mixture of TNF-alpha, interleukin-1beta, interferon-gamma, and endotoxin) evoke caspase activation in C(2)C(12) myotubes. Endotoxin markedly reduced diaphragm force generation (P < 0.001) and induced increases in caspase-3 and caspase-8 activity (P < 0.03), but failed to increase caspase-9. Inhibitors of caspase-8, but not of caspase-9, prevented endotoxin-induced reductions in diaphragm force and caspase-3 activation (P < 0.01). Mice deficient in TNF receptor 1 also had reduced caspase-8 activation (P < 0.001) and less contractile dysfunction (P < 0.01) after endotoxin. Furthermore, incubation of C(2)C(12) cells with either TNF-alpha or cytomix elicited significant caspase-8 activation. The caspase-8 pathway is strongly activated in the diaphragm following endotoxin and is responsible for caspase-3 activation and diaphragm weakness. |
| Starting Page | 196 |
| Ending Page | 202 |
| Page Count | 7 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://jap.physiology.org/content/jap/102/4/1649.full.pdf |
| PubMed reference number | 17218430v1 |
| Volume Number | 102 |
| Issue Number | 4 |
| Journal | Journal of applied physiology |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acetylcysteine Caspase Activation Diaphragmatic Hernia Glutamic Acid Infection Interferon Type II Interleukin-1 beta Isoleucine Leucine Muscle Weakness Skeletal Myocytes Threonine Tumor Necrosis Factors caspase-3 caspase-8 caspase-9 mg/kg positive regulation of mitotic actomyosin contractile ring assembly type I interferon receptor |
| Content Type | Text |
| Resource Type | Article |
