Bleomycin-induced lung injury in the rat: effects of the platelet-activating factor (PAF) receptor antagonist BN 52021 and platelet depletion.
Bleomycin is a highly effective antitumor agent, but pulmonary toxicity, characterized by an acute inflammatory reaction and associated pulmonary edema, limits clinical use of the drug. Platelets and platelet-activating factor (PAF), a membrane-derived phospholipid, have been implicated in the mechanisms that can mediate pulmonary microvascular injury. We sought to investigate the role of PAF in bleomycin-induced lung injury in the rat, using the PAF receptor antagonist BN 52021; and the role of platelets though the use of an anti-platelet antibody. Lung injury was induced by intratracheal bleomycin (1.5 mg) and assessed by measurements of lung wet weight and total pulmonary extravascular albumin space (TPEAS). Bleomycin caused a significant increase in both indices after 48 hr, compared with control animals (p less than 0.05). A single dose of BN 52021 (20 mg/kg orally) significantly reduced the bleomycin-induced increase in lung weight, but not the rise in TPEAS (p greater than 0.05). Increasing the dose of BN 52021 (20 mg/kg/12 hr, orally) had no additional effect. Reducing circulating platelet numbers by approximately 75% had no effect on either the increase in lung weight or TPEAS, observed 48 hr after bleomycin (p greater than 0.05). PAF may partially contribute to the acute inflammatory reaction seen after intratracheal bleomycin in rats.
Department of Thoracic Medicine, Brompton Hospital, London, UK.
T W
TW
Evans
R J
RJ
McAnulty
D F
DF
Rogers
K F
KF
Chung
P J
PJ
Barnes
G J
GJ
Laurent
D000280:Administration, Inhalation; D000284:Administration, Oral; D000418:Albumins / Q000032:analysis; D000818:Animals; D001761:Bleomycin / Q000008:administration & dosage / Q000633:toxicity*; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects; D046934:Ginkgolides; D007783:Lactones; D008171:Lung Diseases / Q000097:blood* / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010976:Platelet Count / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew
D000418:Albumins; D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010972:Platelet Activating Factor; D001761:Bleomycin; C045856:ginkgolide B