Cyclooxygenase inhibition prevents PMA-induced increases in lung vascular permeability.
The effect of cyclooxygenase inhibition in phorbol myristate acetate (PMA)-induced acute lung injury was studied in isolated constant-flow blood-perfused rabbit lungs. PMA caused a 51% increase in pulmonary arterial pressure (localized in the arterial and middle segments as measured by vascular occlusion pressures), a 71% increase in microvascular permeability (measured by the microvascular fluid filtration coefficient, Kf), and a nearly threefold increase in perfusate thromboxane (Tx) B2 levels. Cyclooxygenase inhibition with three chemically dissimilar inhibitors, indomethacin (10(-7) and 10(-6) M), meclofenamate (10(-6) M), and ibuprofen (10(-5) M), prevented the Kf increase without affecting the pulmonary arterial pressure increase or resistance distribution changes after PMA administration. The specific role of TxA2 was investigated by pretreatment with OKY-046, a specific Tx synthase inhibitor, or infusion of SQ 29548, a TxA2 receptor antagonist; both compounds failed to protect against either the PMA-induced permeability or the vascular resistance increase. These results indicate that cyclooxygenase-mediated products of arachidonic acid other than TxA2 mediate the PMA-induced permeability increase but not the hypertension.
Zanaboni
P B
PB
Department of Pharmacology, St. Louis University School of Medicine, Missouri 63104.
Bradley
J D
JD
Baudendistel
L J
LJ
Webster
R O
RO
Dahms
T E
TE
D015121:6-Ketoprostaglandin F1 alpha / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001826:Body Fluids / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002199:Capillary Permeability / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D011453:Prostaglandins / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects; D011817:Rabbits; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014655:Vascular Resistance / Q000187:drug effects
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008689:Methacrylates; D011453:Prostaglandins; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C045749:SQ 29548; D013930:Thromboxane-A Synthase; C034364:ozagrel; D013755:Tetradecanoylphorbol Acetate