Arachidonic Acid Lipoxygenase Pathways and Increased Vascular Permeability in Isolated Rabbit Lungs

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Abstract
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 .mu.M 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 ppetidoleukotrienes (LTE4 > LTC4 > LTD4) and LTB4 were released into the recirculating butter within 5 min and continued to be released even after 2 exchanges of the perfusion fluid. In the presence of 2 structurally unrelated lipoxygenase inhibitions (nondihydroguaiaretic acid and AA-7861), 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 > 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 .mu.g LTC4 or LTD4 or 7.5 .mu.g LTB4 in protein-free perfused lungs during an acute hydrostatic challenge did not, however, mimic the AA bolus-induced severalfold increase in vascular permeability. We conclude that metabolites of pulmonary AA lipoxygenase pathways appear to be involved in the dramatic increase in vascular permeability after AA bolus application. A conclusive cause and effect relationship can, however, not be established for the larger quantities of endogenously formed peptidoleukotrienes and LTB4.

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