title: Potentiation of alpha-naphthyl thiourea-induced lung injury by prostaglandin E1 and platelet depletion.
abstract: alpha-Naphthyl thiourea ( ANTU ) produces pulmonary endothelial injury, pulmonary edema, and pleural effusions in rats in a dose-dependent manner. Since prostaglandins of the E series have been shown to modulate inflammatory responses in vivo and neutrophil and platelet function in vitro we investigated the effects of prostaglandin E1 (PGE1) on ANTU -induced lung injury. Systemic administration of 15-(S)-15-methyl-PGE1 (15-M-PGE1), a stable analog of PGE1, potentiated lung injury induced by ANTU in a dose- and time-dependent manner. 15-M-PGE1 (1 mg/kg, subcutaneously) administered 1 hour prior to ANTU treatment (1 mg/kg, intraperitoneally) resulted in a 164% increase (p less than 0.001) in pleural effusion formation and a 42% increase (p less than 0.02) in wet lung weight at 4 hours after ANTU administration. This was associated with increased pulmonary endothelial cell blebbing and gap formation with a decrease in the number of platelet thrombi in 15-M-PGE1-treated animals compared with controls. 15-(S)-15-methyl-prostaglandin F2 alpha, was less effective than 15-M-PGE1 in potentiating ANTU -induced lung injury. Platelet depletion, but not neutrophil depletion, also potentiated ANTU -induced lung injury, suggesting a protective role for platelets. Platelets isolated from 15-M-PGE1-treated animals demonstrated an approximately 50% decreased aggregation response to adenosine diphosphate. 15-M-PGE1 (1 mg/kg) treatment combined with platelet depletion resulted in a 1.7-fold increase (p less than 0.01) in pleural effusions in ANTU -treated (1 mg/kg) animals compared with platelet depletion alone. These studies indicate that systemic treatment of rats with 15-M-PGE1 will potentiate ANTU -induced lung injury. This injury may be in part secondary to the ability of 15-M-PGE1 to inhibit platelet function. However, platelet depletion studies suggest that 15-M-PGE1 has additional effects, possibly on endothelial cells and/or vascular smooth muscle cells that contribute to the potentiation of ANTU -induced lung injury.
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives*; D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D010996:Pleural Effusion; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000139:chemically induced; D051381:Rats; D011919:Rats, Inbred Strains; D012378:Rodenticides; D013047:Specific Pathogen-Free Organisms; D013890:Thiourea / Q000031:analogs & derivatives* / Q000506:poisoning; D013997:Time Factors
chemical_list: D011459:Prostaglandins E, Synthetic; D012378:Rodenticides; C025170:15(S)-15-methylprostaglandin E1; D000527:Alprostadil; D013890:Thiourea; C005277:alpha-naphthyl thiourea