Administration of
monocrotaline pyrrole (
MCTP), a putative toxic metabolite of the
pyrrolizidine alkaloid,
monocrotaline (MCT), results in delayed and progressive pneumotoxicity in the rat. It has been suggested that the
lung injury caused by this compound may be initiated by an interaction between
MCTP and cells of the pulmonary vasculature. A likely site for initial binding of this reactive electrophile is the pulmonary endothelium.
MCTP causes direct toxicity to cultured bovine and porcine pulmonary artery endothelial cells (BECs and PECs, respectively), but there exist species differences both in whole-animal response to the parent
alkaloid and in cellular response to direct application of
MCTP. In this study, the changes in cultured rat pulmonary vascular endothelial cells (RECs) after a single administration of
MCTP were characterized in order to compare these with changes previously identified in this species in vivo. Studies with RECs have also provided an additional model for examination of species-related differences in response to this toxicant.
MCTP caused a delayed and progressive release of
lactate dehydrogenase from REC monolayers. Progressive cell detachment was evident and remaining cells became enlarged, with morphologic changes comparable to those reported previously in BECs, including cytoplasmic vacuolization and nuclear enlargement.
MCTP inhibited cell proliferation at concentrations of 0.05 micrograms
MCTP/ml or greater, and
DNA crosslinking was evident at 24 and 48 hr post-treatment. These results suggest that
MCTP is directly toxic to cultured RECs, and the development of changes is reminiscent of that seen in the rat in vivo. The
cytostatic nature of the compound, in combination with its cytolytic effect on RECs, could contribute to the development of
pulmonary edema and other lung vascular changes seen in rats treated with MCT or
MCTP.