Abstract
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 neither significant nor dose dependent. The actual CL response was significantly higher in the peritoneal fluid of rats subjected to peritonitis, which was significantly and dose-dependently attenuated by FLZ treatment (ANOVA F4.45 = 11.048, P < .001). Normalization of CL response for 1000 PMNs revealed that FLZ dose-dependently albeit insignificantly reduced the activity of PMNs. The high dose of FLZ caused 2.29-fold decrement in the area under curve (AUC) pertaining to cumulative CL response. The findings of this study suggest that FLZ protects rats against septic shock by inhibiting PMN-mediated inflammatory cascade without compromising their phagocytic activity.
Highlights
Sepsis and its sequelae are often lethal and considered to be the leading causes of mortality in intensive care units [1, 2]
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)
The findings of this study suggest that FLZ protects rats against septic shock by inhibiting PMN-mediated inflammatory cascade without compromising their phagocytic activity
Summary
Sepsis and its sequelae are often lethal and considered to be the leading causes of mortality in intensive care units [1, 2]. Effective host defense against bacterial infection depends on the recruitment and activation of PMNs that localize, kill, and clear the pathogens [3, 4]. Massive inflammatory reaction resulting from uncontrolled sequestration and prolonged activation of PMNs could be potentially deleterious and has largely been implicated in sepsis-mediated multiorgan dysfunction [5, 6, 7, 8]. PMNs (neutrophils and macrophages) could be regarded as dual-edged weapons, their controlled migration and optimal activity being essential for beneficial effects [4, 9, 10]. Therapeutic strategies to attenuate excessive acute inflammatory responses without compromising essential host defense mechanisms would logically benefit in preventing neutrophil-mediated organ damage in septic shock [11, 12]
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