MITIGATION OF NITROFURANTOIN-INDUCED TOXICITY IN THE PERFUSED RAT LUNG

1 Nitrofurantoin is an antimicrobial agent which produces pulmonary to xicity via the redox cycling of the nitro group and its radical anion. This futile cycling triggers a complex series of events known collect ively as oxidative stress. 2 In the isolated perfused rat lung, nitrof urantoin induced a decrease in tissue levels of glutathione but not pr otein thiols by the end of the 180 min experiment. There was no declin e in tissue levels of angiotensin converting enzyme (a marker of cell disruption). However, edema was extensive as monitored in real time by weight gain (2.71 +/- 0.56 g vs 0.63 +/- 0.53 g in control, P < 0.05, n=4) and lung mechanical functioning. The edema was matched by an inc rease in lavage proteins (85 +/- 15 mg vs 16 +/- 9 mg in controls, P < 0.05, n=4). Electron microscopic examination of tissue indicated that the endothelial cells were detached from the basement membrane which would account for the edema. 3 Co-infusion of penicillamine, N-acetylc ysteine or N-(2-mercaptopropionyl)-glycine which can protect tissue fr om oxidative stress failed to mitigate NFT-induced edema. Allopurinol, an inhibitor of xanthine oxidase and a metal chelator, significantly decreased weight gain but did not prevent the loss of glutathione. The se results suggested that allopurinol was not blocking metabolic activ ation of NFT by xanthine oxidase but scavenging metal cations which ca n initiate and/or propagate the oxidative stress cascade. 4 We conclud ed that, in the isolated perfused rat lung, the classic pathway of oxi dative stress induced by NFT is interrupted at the stage of GSH loss. These experiments demonstrated that organ function was compromised mor e than the individual cells. They also suggested that allopurinol may prove beneficial in modulating NFT pulmonary toxicity.