Enhanced microvascular permeability of PMA-induced acute lung injury is not mediated by cyclooxygenase products.
Products of cyclooxygenase activity have been proposed to mediate the pulmonary hypertension and increased microvascular permeability associated with phorbol myristate acetate- (PMA) induced acute lung injury. Previously, we reported that thromboxane (Tx) does not mediate PMA-induced pulmonary hypertension in intact anesthetized dogs. In the present study, PMA was administered to isolated canine lungs perfused with autologous blood at constant flow to investigate a possible role for Tx in the PMA-induced increase in microvascular permeability. Changes in permeability were assessed by determining changes in the capillary filtration coefficient (Kfc). In lobes pretreated with papaverine to prevent PMA-induced increases in pulmonary vascular resistance, Kfc increased from a baseline value of 0.2 +/- 0.03 to 1.5 +/- 0.29 ml.min-1.cmH2O-1.100 g wet lobe wt-1 (P < 0.01) 30 min after PMA (5.8 x 10(-8) M, n = 10). Concomitantly, TxB2, the stable metabolite of TxA2, increased from 138 +/- 44 to 1,498 +/- 505 pg/ml (P < 0.05) in the blood. Both the selective Tx synthase inhibitor, OKY-046 (7 x 10(-4) M, n = 6), and the cyclooxygenase inhibitor, indomethacin (10(-4) M, n = 7), prevented the PMA-induced increase in TxB2, but neither compound attenuated the PMA-induced increase in Kfc. ONO-3708 (10(-6) M), a selective prostaglandin (PG) H2/TxA2 receptor antagonist, prevented the vasoconstriction resulting from administration of U-46619, a stable PGH2/TxA2 receptor agonist, but it did not prevent the PMA-induced increases in Kfc (n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)
Wurtz
M M
MM
Department of Internal Medicine, St. Louis University School of Medicine, Missouri 63104.
Stephenson
A H
AH
Sprague
R S
RS
Lonigro
A J
AJ
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D004285:Dogs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007958:Leukocyte Count; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D010208:Papaverine / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D008689:Methacrylates; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C049855:ONO 3708; D010208:Papaverine; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; C034364:ozagrel; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin