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Toxicologic Pathology
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Early Alterations of Lung Injury Following Acute Smoke Exposure and 21-Aminosteroid Treatment

Shengjun Wang

Department of Pediatrics, University of Arizona, Tucson, Arizona 85724

R. Clark Lantz

Department of Cell Biology and Anatomy, University of Arizona, Tucson, Arizona, 85724, Center for Toxicology, University of Arizona, Tucson, Arizona 85724

Raymond F. Robledo

Department of Pediatrics, University of Arizona, Tucson, Arizona 85724, Center for Toxicology, University of Arizona, Tucson, Arizona 85724

Veronica Breceda

Department of Pediatrics, University of Arizona, Tucson, Arizona 85724

Allison M. Hays

Department of Pediatrics, University of Arizona, Tucson, Arizona 85724

Mark L. Witten

Department of Pediatrics, University of Arizona, Tucson, Arizona 85724, Center for Toxicology, University of Arizona, Tucson, Arizona 85724, mwitten{at}peds.arizona.edu.

In a simulated fire-related smoke exposure protocol, New Zealand white rabbits were utilized to investigate the potential effects of the 21-aminosteroid (lazaroid) analog U75412E on the early events of acute lung injury. Inhalation of a total of 1.6 mg/kg U75412E aerosolized at a rate of 1.53 mg/min at 0.5 hr after smoke exposure significantly attenuated the extent of lung injury at 1 hr, as evidenced by decreased bronchoalveolar lavage (BAL) concentration of total protein, 6-keto-prostaglandin F1-{alpha}, and blood gas defect. Histopathologic examination demonstrated that the lazaroid significantly attenuated smoke-induced lung injury as evidenced by a decrease in wet lung/body weight ratio, necrosis, and sloughing of airway epithelial cells. Electron microscopy showed that the lazaroid decreased smoke-induced interstitial edema and the vacuolization of alveolar type II epithelium (21.6 ± 9.7 vs 8.5 ± 3.6 vacuoled blebs/cell, smoke only vs smoke + lazaroid). However, U75412E did not attenuate smoke-induced changes in BAL concentration of tumor necrosis factor-{alpha}, total cell count, and granulocyte percentage. These observations suggest that U75412E may exert its action through cooperative mechanisms, such as the modulation of arachidonic acid metabolism, in addition to its characterized antioxidative effects.

Key Words: Lazaroids • tumor necrosis factor-{alpha} • prostaglandin • gas exchange • respiratory epithelium

Toxicologic Pathology, Vol. 27, No. 3, 334-341 (1999)
DOI: 10.1177/019262339902700309
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