Apocynin improves diaphragmatic function after endotoxin administration.
Free radicals are known to play an important role in modulating the development of respiratory muscle dysfunction during sepsis. Moreover, neutrophil numbers increase in the diaphragm after endotoxin administration. Whether or not superoxide derived from infiltrating white blood cells contributes to muscle dysfunction during sepsis is, however, unknown. The purpose of the present study was to examine the effect of apocynin, an inhibitor of the superoxide-generating neutrophil NADPH complex, on endotoxin-induced diaphragmatic dysfunction. We studied groups of rats given saline, endotoxin, apocynin, or both endotoxin and apocynin. Animals were killed 18 h after injection, a portion of the diaphragm was used to assess force generation, and the remaining diaphragm was used for determination of 4-hydroxynonenal (a marker of lipid peroxidation) and nitrotyrosine levels (a marker of free radical-mediated protein modification). We found that endotoxin reduced diaphragm force generation and that apocynin partially prevented this decrease [e.g., force in response to 20 Hz was 23 +/- 1 (SE), 12 +/- 2, 23 +/- 1, and 19 +/- 1 N/cm(2), respectively, for saline, endotoxin, apocynin, and endotoxin/apocynin groups; P < 0.001]. Apocynin also prevented endotoxin-mediated increases in diaphragm 4-hydroxynonenal and nitrotyrosine levels (P < 0.01). These data suggest that neutrophil-derived free radicals contribute to diaphragmatic dysfunction during sepsis.
Supinski
G
G
Metrohealth Medical Center, Cleveland 44109, Ohio.
Stofan
D
D
Nethery
D
D
Szweda
L
L
DiMarco
A
A
D000098:Acetophenones / Q000627:therapeutic use*; D000447:Aldehydes / Q000032:analysis; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism*; D004731:Endotoxins / Q000494:pharmacology; D006651:Histocytochemistry; D015151:Immunoblotting; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D000098:Acetophenones; D000447:Aldehydes; D000975:Antioxidants; D004731:Endotoxins; C002744:3-nitrotyrosine; D014443:Tyrosine; C056165:acetovanillone; C027576:4-hydroxy-2-nonenal