Whole body plethysmography as a noninvasive assay of toxic lung injury in mice: Studies with the pulmonary alkylating agent and cytotoxin, 4-ipomeanol

Abstract

The effect of 4-ipomeanol on the lungs of experimental animals often is measured by destructive assays, such as death, histology, or pulmonary alkylation. Breathing rate is a noninvasive assay routinely used to quantify the effects of radiation on the lungs of mice, which may be useful in assessing injury from other lung toxins. The effects of graded single doses of 4-ipomeanol on the breathing rate of mice were studied up to 3 weeks after treatment. Changes in breathing rate were observed up to 4 days after 4-ipomeanol treatment with nonlethal doses of the compound giving a clear, dose-dependent increase in breathing rate at 8 hr and 4 days after treatment. Time course and dose-response studies showed good agreement between changes in breathing rate and pulmonary alkylation after 4-ipomeanol treatment. Pretreatment of the mice with diethylmaleate (DEM) increased the pulmonary alkylation and toxicity of 4-ipomeanol. However, breathing rate was severely depressed by all doses of DEM that were examined. This decrease was not dose dependent within the range of doses studied. These studies indicate that breathing rate can be used to quantify the effects of nonlethal doses of 4-ipomeanol on the lungs of mice and does not require killing the animal. The technique may be similarly applicable to studies of other pulmonary toxins, but careful attention must be given to time and dose relationships and the possible effects of other drugs or pretreatments.