Therapeutic intervention in a rat model of adult respiratory distress syndrome: II. Lipoxygenase pathway inhibition.
The present study was designed to investigate the role of 5-lipoxygenase (5LO) metabolites in an endotoxin (LPS)-induced model of the adult respiratory distress syndrome (ARDS) in the rat. The therapeutic value of two 5LO inhibitors and a specific LTB4 and a LTD4 receptor antagonist were examined. Rats were treated 1 hr prior to administration of aerosolized LPS. Rats were either unexposed (n = 11), or pretreated with vehicle sham (n = 63), 50 mg/kg phenidone t.i.d. (n = 7, n = 10 for assessment of mortality), 30 mg/kg SK&F 103842 b.i.d. (n = 6), 50 mg/kg SK&F 106203 t.i.d. (n = 11), or 5 mg/kg SK&F 107324 b.i.d. (n = 6) 1 hr prior to the administration of aerosolized endotoxin (LPS, 7 mg/kg) or phosphate-buffered saline (PBS, n = 22). Twenty-four hours later, blood samples were collected for hematologic evaluation and after wet lung weight was determined, broncho-alveolar lavage (BAL) was performed to measure cells counts and total protein (TP). 5LO inhibition and LTD4 receptor antagonism reduced LPS-induced mortality to zero compared to 35% in rats pretreated with vehicle sham. Pretreatment with the LTD4 receptor antagonist attenuated the LPS-induced increased in wet/dry lung weight (W/D) whereas 5LO inhibition reduced TP increases. Both 5LO inhibition and LTD4 receptor antagonism attenuated the LPS-induced BAL erythrocyte increase. The LPS-induced thrombocytopenia was attenuated by phenidone, the 5LO receptor antagonist. We conclude that the increased microvascular permeability was associated with the formation of 5LO products since 5LO inhibition lessened the severity of the LPS-induced increase in W/D and TP.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Experimental Pathology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
C R
CR
Turner
M N
MN
Lackey
M F
MF
Quinlan
D E
DE
Griswold
L W
LW
Schwartz
E B
EB
Wheeldon
D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004487:Edema / Q000209:etiology; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D008954:Models, Biological; D010666:Phenylpropionates; D051381:Rats; D011919:Rats, Inbred Strains; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy*
D001577:Benzophenones; D003998:Dicarboxylic Acids; D016859:Lipoxygenase Inhibitors; D010666:Phenylpropionates; C065916:LY 223982; C065234:SK&F S-106203