Fluconazole attenuates lung injury and mortality in a rat peritonitis model.
OBJECTIVE
Acute lung injury following peritonitis constitutes an enigmatic clinical problem with no specific therapy. Recently, immunomodulators such as azole compounds have been shown to attenuate shock-related tissue injury. The present investigation was undertaken to study the effect of fluconazole on acute lung injury and survival following faecal peritonitis in rats.


METHODS
Male Wistar rats weighing 225-235 g.


METHODS
Faecal peritonitis (Fp) was produced in four groups of adult male Wistar rats by intraperitoneal administration of non-sterile faecal suspension (1:1 w/v saline). A fifth group of rats was given sterile faecal material (SFM), which served as control.


METHODS
Rats in Fp groups were given fluconazole in doses of 0 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg by gavage 30 min before induction of peritonitis. The control animals received an equal volume of distilled water.


RESULTS
Survival over a period of 72 h, oxidative stress, neutrophil activity, and lung injury were measured. This study showed a 90% survival in the fluconazole-treated group compared to only 20% survival in untreated rats (P<0.008 log-rank test). The lungs of animals with Fp showed massive pathological changes including intraalveolar oedema, fibrosis, and mixed inflammatory cell infiltrate. These changes were dose-dependently attenuated by fluconazole. Enhanced oxidative stress (P<0.001) and neutrophil activity in the peritoneal fluid and lung (P<0.001) in Fp animals was dose-dependently reduced by fluconazole.


CONCLUSIONS
This study clearly suggests the role of neutrophils in Fp-induced tissue injury/mortality, which may be dose-dependently, attenuated by fluconazole.
D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001202:Ascitic Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D015725:Fluconazole / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation; D007274:Injections, Intraperitoneal; D007416:Intestinal Perforation / Q000150:complications; D008168:Lung / Q000737:chemistry; D008297:Male; D018375:Neutrophil Activation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010538:Peritonitis / Q000150:complications*; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D013482:Superoxide Dismutase / Q000097:blood; D015996:Survival Rate; D013997:Time Factors
D000276:Adjuvants, Immunologic; D015725:Fluconazole; D009195:Peroxidase; D013482:Superoxide Dismutase