title: Enhanced microvascular permeability of PMA-induced acute lung injury is not mediated by cyclooxygenase products.
abstract: 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)
authors: Department of Internal Medicine, St. Louis University School of Medicine, Missouri 63104.
authors: M M
authors: MM
authors: Wurtz
authors: A H
authors: AH
authors: Stephenson
authors: R S
authors: RS
authors: Sprague
authors: A J
authors: AJ
authors: Lonigro
mesh_terms: 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
chemical_list: 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