Effect of Fluconazole on Phagocytic Response of Polymorphonuclear Leukocytes ina Rat Model of Acute Sepsis

摘要

Recently, fluconazole (FLZ) has been shown to improve survival and reduce multiorgan failure in experimental and clinical septic shock. The mechanism by which FLZ affords protection against sepsis remains obscure. This study examines the effect of FLZ on phagocytic activity of polymorphonuclear leukocytes (PMNs) in a rat model of septic shock by inducing fecal peritonitis in male Wistar rats using intraperitoneal instillation (1 mL/kg) of fecal suspension in saline (1:1 w/v). Sham control rats received sterile fecal suspension and vehicle treatment. FLZ was administered in the doses of 0, 3, 10, and 30 mg/kg by gavage 30 minutes before fecal instillation. The samples of peritoneal fluid were collected 8 hours following fecal inoculation for the evaluation of phagocytic response of PMNs using zymosan-induced luminol-dependent chemiluminescence (CL). Fecal peritonitis caused massive infiltration of PMNs in the peritoneal cavity (ANOVA F4.45 = 6.322, P < .001). Although FLZ reduced the infiltration of PMNs, this effect was neithersignificant nor dose dependent. The actual CL response wassignificantly higher in the peritoneal fluid of rats subjected toperitonitis, which was significantly and dose-dependentlyattenuated by FLZ treatment (ANOVA F4.45 = 11.048, P < .001). Normalization of CL response for 1000 PMNs revealedthat FLZ dose-dependently albeit insignificantly reduced theactivity of PMNs. The high dose of FLZ caused 2.29-folddecrement in the area under curve (AUC) pertaining to cumulativeCL response. The findings of this study suggest that FLZ protectsrats against septic shock by inhibiting PMN-mediated inflammatorycascade without compromising their phagocytic activity.