Effects of monocrotaline pyrrole on cultured rat pulmonary endothelium.
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.
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
C M
CM
Hoorn
J G
JG
Wagner
R A
RA
Roth
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
C014114:monocrotaline pyrrole; D016686:Monocrotaline; D007770:L-Lactate Dehydrogenase