Eicosapentaenoic acid preserves diaphragm force generation following endotoxin administration.
BACKGROUND
Infections produce severe respiratory muscle weakness, which contributes to the development of respiratory failure. An effective, safe therapy to prevent respiratory muscle dysfunction in infected patients has not been defined. This study examined the effect of eicosapentaenoic acid (EPA), an immunomodulator that can be safely administered to patients, on diaphragm force generation following endotoxin administration.


METHODS
Rats were administered the following (n = 5/group): (a) saline, (b) endotoxin, 12 mg/kg IP, (c) endotoxin + EPA (1.0 g/kg/d), and (d) EPA alone. Diaphragms were removed and measurements made of the diaphragm force-frequency curve, calpain activation, caspase activation, and protein carbonyl levels.


RESULTS
Endotoxin elicited large reductions in diaphragm specific force generation (P < 0.001), and increased diaphragm caspase activation (P < 0.01), calpain activation (P < 0.001) and protein carbonyl levels (P < 0.01). EPA administration attenuated endotoxin-induced reductions in diaphragm specific force, with maximum specific force levels of 27 +/- 1, 14 +/- 1, 23 +/- 1, and 24 +/- 1 N/cm2, respectively, for control, endotoxin, endotoxin + EPA, and EPA treated groups (P < 0.001). EPA did not prevent endotoxin induced caspase activation or protein carbonyl formation but significantly reduced calpain activation (P < 0.02).


CONCLUSIONS
These data indicate that endotoxin-induced reductions in diaphragm specific force generation can be partially prevented by administration of EPA, a nontoxic biopharmaceutical that can be safely given to patients. We speculate that it may be possible to reduce infection-induced skeletal muscle weakness in critically ill patients by administration of EPA.
Division of Pulmonary, Critical Care and Sleep Medicine, University of Kentucky, 740 South Limestone, Lexington, KY 40536-0284, USA. gsupi2@email.uky.edu
Gerald S
GS
Supinski
Jonas
J
Vanags
Leigh Ann
LA
Callahan
D000818:Animals; D053148:Caspase 3 / Q000187:drug effects; D003720:Densitometry; D003964:Diaphragm / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D004731:Endotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D018908:Muscle Weakness / Q000473:pathology; D051381:Rats; D012131:Respiratory Insufficiency / Q000517:prevention & control
D004731:Endotoxins; D015118:Eicosapentaenoic Acid; C505410:Casp3 protein, rat; D053148:Caspase 3