Therapeutic intervention in a rat model of adult respiratory distress syndrome: III. Cyclooxygenase pathway inhibition.
Current strategies for the treatment of ARDS have been unsuccessful in reducing mortality. In the present study, we have evaluated the role of cyclooxygenase (CO) products in a rat model of ARDS by testing naproxen, indomethacin, ibuprofen, and a thromboxane A2 (TXA2) receptor antagonist (SK&F 96148). Rats were treated 1 hr prior to endotoxin (LPS) exposure and 24 hr later, survival, body weight changes, wet/dry lung weight (W/D), total protein content (TP) of the bronchoalveolar lavage (BAL) fluid, and total erythrocyte and differential leukocyte counts of the BAL fluid were measured. In addition, the following hematologic measurements were taken: hemoglobin (Hb), hematocrit (Hct), circulating erythrocyte, differential leukocyte, and platelet counts. Treatment with the TXA2 receptor antagonist reduced mortality to zero after 24 hr after LPS administration. Other compounds had no significant effect on LPS-induced mortality. Pretreatment with CO inhibitors or the TXA2 receptor antagonist attenuated the LPS-induced increase in TP and W/D. Although all compounds tended to reduce the LPS-induced increase in BAL erythrocytes, only the TXA2 receptor antagonist did so significantly. The LPS-induced increase in BAL neutrophil counts was significantly reduced by 30 mg/kg ibuprofen, but not by the other compounds. In fact, the TXA2 receptor antagonist actually exacerbated BAL neutrophil counts, but diminished the peripheral neutrophilia and lymphopenia induced by LPS. None of the CO inhibitors tested significantly affected LPS-induced hematologic responses. We conclude that by virtue of its protection against LPS-induced mortality, the TXA2 receptor antagonist was the most effective compound in this model. However, it did cause certain negative side effects such as increased pulmonary inflammation.(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
L W
LW
Schwartz
E B
EB
Wheeldon
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004487:Edema / Q000209:etiology; D008297:Male; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy*
D016861:Cyclooxygenase Inhibitors