Therapeutic intervention in a rat model of ARDS: I. Dual inhibition of arachidonic acid metabolism.
The protective effects of altered arachidonic acid metabolism, using either methylprednisolone or a dual cyclooxygenase and 5-lipoxygenase inhibitor (SK&F 86002), were compared in a rat model of adult respiratory distress syndrome (ARDS). Rats were either unexposed (n = 9) or pretreated with vehicle (n = 25), 100 mg/kg SK&F 86002 (n = 8) or 30 mg/kg methylprednisolone (MP, n = 7) 1 h prior to the intratracheal administration of 7 mg/kg aerosolized endotoxin (LPS) or phosphate buffered saline (PBS). Twenty-four hours later, blood samples were collected and the rats were anesthetized and exsanguinated. The lungs were surgically removed, weighed and bronchoalveolar lavage (BAL) was performed. LPS caused 30-35% mortality and induced significant differences in body weight, BAL erythrocyte and neutrophil counts, lung wet/dry weight ratio (W/D), total BAL protein (TP), hemoglobin (Hb), hematocrit (HCT), and circulating leukocyte and platelet counts as compared with controls. Pretreatment with MP reduced mortality to zero and also attenuated the LPS-induced alterations in body weight, W/D, TP, BAL erythrocyte count, and circulating platelet count. However, MP exacerbated LPS-induced increases in Hb, HCT and circulating neutrophil counts while enhancing lymphopenia. Pretreatment with SK&F 86002 also reduced mortality to zero and attenuated LPS-induced alterations in W/D, TP, HCT and circulating platelet count. Like MP, SK&F 86002 exacerbated the LPS-induced lymphopenia, and increased circulating neutrophils above baseline values. We conclude that both MP and SK&F 86002 provided protection against LPS-induced responses in this model of ARDS. Mechanistically, this indicates the critical role of eicosanoid mediators in this model. Therapeutically, SK&F 86002, or a similar compound, may be beneficial in preventing the acute phase responses so harmful to ARDS patients.
Turner
C R
CR
SmithKline & Beecham Pharmaceuticals, Department of Experimental Pathology, King of Prussia, Pennsylvania.
Quinlan
M F
MF
Schwartz
L W
LW
Wheeldon
E B
EB
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000473:pathology; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004906:Erythrocyte Count; D004926:Escherichia coli; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D007093:Imidazoles / Q000627:therapeutic use*; D007958:Leukocyte Count; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use*; D009504:Neutrophils / Q000473:pathology; D010976:Platelet Count; D051381:Rats; D011919:Rats, Inbred Strains; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013844:Thiazoles / Q000627:therapeutic use*
D001095:Arachidonic Acids; D006454:Hemoglobins; D007093:Imidazoles; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D013844:Thiazoles; D016718:Arachidonic Acid; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D008775:Methylprednisolone