TOXIC EFFECTS OF MECHLORETHAMINE ON MAMMALIAN RESPIRATORY MUCOCILIARYEPITHELIUM IN PRIMARY CULTURE

Mechlorethamine (HN2) is an alkylating agent usually used in cancer ch emotherapy. Nevertheless, HN2 is extremely toxic and its use is accomp anied by severe side-effects that may cause lung complications. Many s tudies report the morphological and biochemical modifications induced by sulfur mustard (SM) but no report has been published concerning the toxic effects of HN2 on the ultrastructural and functional activity o f surface respiratory epithelial cells. This study was performed on ra bbit tracheal epithelium (RTE) cells in primary culture. The functiona l activity of the culture was evaluated by measuring the ciliary beati ng frequency (CBF) of the ciliated cells using a videomicroscopic meth od, and the culture growth was determined by an image analysis system. The morphological aspects of the cells were analyzed by light, scanni ng electron, and transmission electron microscopy. An important inhibi tion of cell growth was observed associated with a detachment of the o utgrowth cells. Morphological changes were expressed by vacuolization, increases in the intercellular spaces, and by disorganization of the cytoskeleton associated with a specific attack of the ciliated cells t hat show ciliary blebbing. The sudden CBF inhibition is more likely du e to the detachment and the death of the ciliated cells than to a spec ific ciliotoxic effect of HN2. All these observations demonstrated the high sensitivity of respiratory epithelial cells to HN2 and showed th at HN2-induced injuries were irreversible, and time- and dose-dependen t.