Monocrotaline pyrrole (
MCTP), a reactive electrophile, induces delayed and progressive
pulmonary edema,
vascular remodeling, and
pulmonary hypertension after a single
intravenous administration to rats. The effects of a single exposure of cultured bovine pulmonary artery endothelial cells (BEC) and bovine pulmonary artery smooth muscle cells (BSMC) to
MCTP were examined.
Monocrotaline pyrrole caused a dose-dependent, delayed, and progressive cell detachment and release of
lactate dehydrogenase activity from monolayers of BECs but not BSMCs. Monolayers of BECs also released increased concentrations of 6-keto-prostaglandin F1 degrees, the stable metabolite of
prostacyclin, as the post-treatment interval increased. Progressive and marked endothelial cell
hypertrophy occurred after exposure to a nominal concentration of 5 or 50 micrograms/ml of
MCTP but not after 0.5 micrograms/ml. Morphologic changes in monolayers of BSMCs were minimal, even up to 2 weeks after exposure. Ultrastructurally the hypertrophic,
MCTP-treated BECs had enlarged cell profiles with enlarged nuclei. The nucleoli were prominent, occasionally multiple, and had separation of granular and fibrillar components. Cytoplasmic microtubules and perinuclear intermediate filaments were prominent in some cells, as were the golgi apparatus and endoplasmic reticulum. Degenerative changes were not prominent in cells that remained in the monolayer.
Monocrotaline pyrrole inhibited proliferation of both cell types at concentrations (0.5 micrograms/ml) that were not cytotoxic. These findings indicate that
MCTP induces direct, dose-dependent injury to cells in culture that is delayed and progressive, and the expression of this injury depends, in part, on the cell type.