The Extrinsic Caspase Pathway Modulates Endotoxin-induced Diaphragm Contractile Dysfunction.
From: Department of Medicine, Medical College of Georgia, Augusta, Georgia, USA. gsupi2@email.uky.edu
Journal of applied physiology (Bethesda, Md. : 1985)
- Publish Date: Apr 2007
- ISSN: 8750-7587
- Volume: 102
- Issue: 4
- Pages: 1649-57
- Medium: Print
- Language: English
- Citation (JAMA): Supinski Gerald S, Ji Xinying, Wang Wenyi, et al. The Extrinsic Caspase Pathway Modulates Endotoxin-induced Diaphragm Contractile Dysfunction.. J. Appl. Physiol. Apr 2007;102:1649-57
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.
Mesh Headings (Keywords): Animals, Caspase 8, Caspase 9, Diaphragm, Endotoxins, Lipopolysaccharides, Male, Mice, Mice, Inbred ICR, Muscle Contraction, Muscle Weakness, Signal Transduction
Check for Full Text / PubMed Unique Identifier (PMID): 17218430
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.