Arachidonic acid lipoxygenase pathways and increased vascular permeability in isolated rabbit lungs.
Products of arachidonic acid (AA) pathways have repeatedly been implicated in acute lung vascular injury with respiratory distress. In blood-free perfused isolated rabbit lungs, AA endogenously released or exogenously applied causes an acute pressor response, mediated by metabolites of the cyclooxygenase pathway including thromboxane A2. Moreover, bolus application of AA (final concentration, 100 microM in the recirculating buffer) during an acute hydrostatic challenge was recently noted to cause a rapid, severalfold increase in the capillary filtration coefficient (Kf,c), though any significant rise in pulmonary vascular pressure was inhibited by indomethacin. In the present study, we showed that during this mode of AA bolus application in cell-free perfused rabbit lungs, microgram amounts of peptidoleukotrienes (LTE4 greater than LTC4 greater than LTD4) and LTB4 were released into the recirculating buffer within 5 min and continued to be released even after 2 exchanges of the perfusion fluid. In the presence of 2 structurally unrelated lipoxygenase inhibitors (nordihydroguaiaretic acid and AA-861), the leukotriene release was nearly completely inhibited and the AA-induced severe increase in vascular permeability was significantly reduced (2.5- to 3-fold rise in Kf,c, compared to a greater than 10-fold increase in Kf,c in the absence of lipoxygenase inhibition). Exogenous LTC4 caused a dose-dependent, sustained pressure rise in protein-free perfused lungs, apparently mediated via the pulmonary generation of AA cyclooxygenase products. Bolus application of 10 micrograms LTC4 or LTD4 or 7.5 micrograms LTB4 in protein-free perfused lungs during an acute hydrostatic challenge did not, however, mimic the AA bolus-induced severalfold increase in vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)
Seeger
W
W
Department of Internal Medicine, Justus-Liebig University, Giessen, Free Republic of Germany.
Menger
M
M
Walmrath
D
D
Becker
G
G
Grimminger
F
F
Neuhof
H
H
D000818:Animals; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001095:Arachidonic Acids / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000378:metabolism / Q000494:pharmacology; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D009929:Organ Size; D010477:Perfusion / Q000379:methods; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D013189:SRS-A / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
D001095:Arachidonic Acids; D013189:SRS-A; D007975:Leukotriene B4; D017999:Leukotriene E4; D001091:Arachidonate Lipoxygenases