Evidence for an Acceleration of Programmed Cell Death in Bronchiolar Epithelium after Exposure to O,O,S‐Trimethyl Phosphorothioate

Abstract

Evidence for an Acceleration of Programmed Cell Death in Bronchiolar Epithelium after Exposure to O, O, S‐Trimethyl Phosphorothioate: Akio Koizumi, et al. Akita University School of Medicine—Exfoliation of Clara cells is a prelude to pathological alterations after exposure to a variety of toxicants. The reported morphological features of exfoliating Clara cells share similarity with some types of programmed cell death (PCD). The purpose of the present study is to characterize morphological changes in Clara cells in the process of PCD in physiological and pathological conditions. We used 0,0,S‐trimethyl phosphorothioate (OOS‐TMP) as a lung toxicant. Morphological changes in the lungs of control rats and rats killed at 2 to 48 hr after treatment with OOS‐TMP (po. 60 mg/kg) were investigated by electron microscopy. In situ DNA‐ fragmentation was determined by 3’‐OH end labeling in these rats. Immunoelectron microscopy was conducted to examine the morphological changes in Clara cells in PCD. Exfoliation of Clara cells started at 2 hr after dosing. At 6 hr, many Clara cells were sloughed. In situ DNA‐fragmentation positive cells were detected in the bronchiolar epithelium of both control and treated rats. Their relative incidences increased 13 fold by 6 hr and returned to basal levels by 48 hr. In contrast, no positive cells were detected in the alveolar cells of either group. Positive cells in the bronchiolar epithelium were identified exclusively as Clara cells. The ultrastructure of the DNA‐ fragmentation positive cells revealed similar changes in control and treated rats. DNA‐fragmentation, a hallmark of PCD, was detected in Clara cells of both control and treated rats, but not in alveolar cells. The relative increases in the DNA‐fragmentationpositive cells suggest an acceleration in PCD after treatment with OOS‐TMP. The results of this study indicate that different mechanisms of cellular death occur in Clara and alveolar cells in response to toxic insults. This difference most likely reflects the cell‐ specific mode of the action of lung toxicants.