Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction

Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, Kentucky Submitted 30 July 2008 ; accepted in final form 14 April 2009 Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system is activated in skeletal mu...

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Bibliographic Details
Published in:American journal of physiology. Lung cellular and molecular physiology 2009-06, Vol.296 (6), p.L994-L1001
Main Authors: Supinski, G. S, Vanags, J, Callahan, L. A
Format: Article
Language:English
Subjects:
Animals
Atrophy
Boronic Acids - pharmacology
Bortezomib
Caspase 3 - metabolism
Cysteine Proteinase Inhibitors - pharmacology
Diaphragm - drug effects
Diaphragm - enzymology
Diaphragm - pathology
Endotoxemia - complications
Enzyme Activation - drug effects
Leupeptins - pharmacology
Lungs
Male
Muscle Contraction - drug effects
Muscle Contraction - physiology
Muscle Weakness - drug therapy
Muscle Weakness - etiology
Muscle Weakness - pathology
Musculoskeletal system
Oligopeptides - pharmacology
Organ Size
Protease Inhibitors - pharmacology
Proteases
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors
Proteomics
Pyrazines - pharmacology
Rats
Rats, Sprague-Dawley
Sepsis
Sepsis - complications
Studies
Toxins
Tyrosine - metabolism
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Summary:Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, Kentucky Submitted 30 July 2008 ; accepted in final form 14 April 2009 Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system is activated in skeletal muscle in sepsis, and it has been postulated that this degradative pathway is responsible for inducing skeletal muscle weakness and wasting. The objective of this study was to determine if administration of proteasomal inhibitors (MG132, epoxomicin, bortezomib) can prevent sepsis-induced diaphragm weakness. Rats were given either 1 ) saline (0.5 ml ip), 2 ) endotoxin (12 mg/kg ip), 3 ) endotoxin plus MG132 (2.5 mg/kg), 4 ) endotoxin plus epoxomicin (1 µmol/kg), or 5 ) endotoxin plus bortezomib (0.05 mg/kg). Animals were killed either 48 or 96 h after injections, and assessments were made of diaphragm proteolysis, force-frequency relationships, mass, protein content, and caspase activation. Endotoxin increased proteolysis ( P
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.90404.2008