Role of oxidants, eicosanoids, and neutrophils in amphotericin B lung injury in rats.
Administration of the antifungal antibiotic amphotericin B (AmB, 1 mg/kg) to intact rats produced acute lung injury as indicated by the extravascular leakage of protein and water and histological examination. The injury was neutrophil independent because it occurred in neutropenic rats. AmB produced vasoconstriction and injury in isolated lungs perfused with a cell- and plasma-free physiological solution, and this injury was independent of pulmonary perfusion pressure. In vivo administration of AmB produced an increase in lung tissue and plasma-oxidized glutathione disulfide (GSSG) indicative of oxidant stress. In the isolated lung, the radical scavengers p-hydroxybenzoate (methylparaben) and catalase attenuated AmB lung injury as did 1-phenyl-3-pyrazolidone (Phenidone), a combined radical scavenger and lipoxygenase/cyclooxygenase inhibitor, and the leukotriene antagonist CGP 35949B. Methylparaben and CGP 35949B prevented the elevation in lung tissue leukotriene C4 and B4 levels noted after AmB. We conclude that AmB in the rat produces neutrophil-independent lung injury, which is associated with oxidant stress and eicosanoid production.
McDonnell
T J
TJ
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Chang
S W
SW
Westcott
J Y
JY
Voelkel
N F
NF
D000418:Albumins / Q000378:metabolism; D000666:Amphotericin B / Q000633:toxicity*; D000818:Animals; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D015289:Leukotrienes / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D055370:Lung Injury; D008297:Male; D009504:Neutrophils / Q000502:physiology; D010084:Oxidation-Reduction; D010477:Perfusion; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D000418:Albumins; D015289:Leukotrienes; D011453:Prostaglandins; D000666:Amphotericin B; D005978:Glutathione