The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction.

The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. Research Abstract Details 

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The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. Abstract Text:

Gerald S Supinski,Xinying Ji,Wenyi Wang,Leigh A Callahan,

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.

The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. Publishing Authors By Initials

GS Supinski,X Ji,W Wang,LA Callahan,

For similar biological phenomena, cell phenomena, and immunity: cell physiology: cell communication: signal transduction research abstracts see: biological phenomena, cell phenomena, and immunity: cell physiology: cell communication: signal transduction research

PUBMED ID PMID:

MEDLINE DATE:

The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of applied physiology (Bethesda, Md. : 198

VOLUME: 102

Page Numbers: 1649-57

Journal Abbreviation:

ISSN: 8750-7587

DAY: 11

MONTH: 01

YEAR: 2007

The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8502536

The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. Keywords Mesh Terms:

KEYWORDS: Signal Transduction

MESH TERMS: drug effects

Chemical & Substance for Abstract: The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction. Information

Substance Name: Caspase 9

Registry Number: EC 3.4.22.-

Grant and Affiliation Information for The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction.

AFFILIATION: Department of Medicine, Medical College of Georgia, Augusta, Georgia, USA. gsupi2@email.uky.edu

Country: United States

AGENCY: United States PHS

GRANT: 80429

ACRONYM:

MEDLINETA: J Appl Physiol

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