Morphologic and morphometric evaluation of the effect of ICRF-187 on bleomycin-induced pulmonary toxicity.
Morphologic and morphometric studies were made of the protective effects of ICRF-187 against the pulmonary damage induced by bleomycin in male and female C57/BL6 mice. Sixty minutes prior to the subcutaneous administration of 15 mg/kg of bleomycin, animals received either saline or ICRF-187 (300 or 150 mg/kg) intraperitoneally, twice a week for 4 weeks. The lungs of animals treated with bleomycin alone showed inflammation, hyperplasia of type II epithelial cells, squamous cell metaplasia and fibrosis. The extent of fibrosis was quantified by means of a color videometric system and histologic sections of lung stained according to a modified Masson trichrome method. The severity of these alterations, particularly of fibrosis, was reduced in all groups of animals pretreated with ICRF-187. The fibrosis was reduced to a similar extent in female mice treated with the 300 mg/kg and the 150 mg/kg doses of ICRF-187, from 39.3% to 17.6% and 13.3%, respectively. ICRF-187 induced significantly different degrees of reduction in fibrosis in the 2 groups of male mice treated with the 150 mg/kg and the 300 mg/kg doses, from 30% to 19.7% and 12.2%, respectively. In vitro studies indicated that both ICRF-187 and its open-ring hydrolysis product (ADR-925) remove iron slowly from the bleomycin-iron complex. This observation provides a basis for the concept that ICRF-187 protects by chelating iron involved in the formation of the bleomycin-Fe3+ complex that generates reactive oxygen radicals capable of causing pulmonary damage.
Herman
E H
EH
Division of Research & Testing, Food and Drug Administration, Laurel, MD 20708, USA.
Hasinoff
B B
BB
Zhang
J
J
Raley
L G
LG
Zhang
T M
TM
Fukuda
Y
Y
Ferrans
V J
VJ
D000818:Animals; D001761:Bleomycin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D011929:Razoxane / Q000494:pharmacology*; D013053:Spectrophotometry
D005029:Ethylenediamines; D001761:Bleomycin; D011929:Razoxane; C059866:ICRF 198; D007501:Iron; D005998:Glycine