Apocynin improves diaphragmatic function after endotoxin administration

Free radicals are known to play an important role in modulating the develop ment of respiratory muscle dysfunction during sepsis. Moreover, neutrophil numbers increase in the diaphragm after endotoxin administration. Whether o r 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 su peroxide-generating neutrophil NADPH complex, on endotoxin-induced diaphrag matic dysfunction. We studied groups of rats given saline, endotoxin, apocy nin, or both endotoxin and apocynin. Animals were killed 18 h after injecti on, a portion of the diaphragm was used to assess force generation, and the remaining diaphragm was used for determination of 4-hydroxynonenal fa mark er of lipid peroxidation) and nitrotyrosine levels (a marker of free radica l-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 in creases in diaphragm 4-hydroxynonenal and nitrotyrosine levels (P < 0.01). These data suggest that neutrophil-derived free radicals contribute to diap hragmatic dysfunction during sepsis.