title: The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction.
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.
authors.affiliation: Department of Medicine, Medical College of Georgia, Augusta, Georgia, USA. gsupi2@email.uky.edu
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Supinski
authors.forename: Xinying
authors.initials: X
authors.lastname: Ji
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wang
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Callahan
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology*; D004731:Endotoxins; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects*; D018908:Muscle Weakness / Q000139:chemically induced* / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D053181:Caspase 8; D053453:Caspase 9