Evidence for pulmonary release of 5-hydroxyeicosatetraenoic acid (5-hete) during endotoxemia in unanesthetized sheep.
Leukocyte trapping in the pulmonary circulation may be an important component of the lung vascular injury response to endotoxin, but mediators of the pulmonary leukostasis and increased lung vascular permeability are unknown. The leukocyte 5-lipoxygenation pathway of arachidonic acid metabolism yields highly biologically active products including leukotrienes C4 and D4 (formerly slow reacting substance of anaphylaxis) and the potent chemotaxin, leukotriene B4. A major product of 5-lipoxygenation is 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE), for which a sensitive, stable isotope dilution assay employing combined gas chromatography-mass spectrometry is available. This assay was used to test the hypothesis that 5-lipoxygenation products might participate in pulmonary vascular responses to endotoxin. We measured 5-HETE concentrations in lung lymph at three intervals during endotoxemia in unanesthetized sheep. Concentrations of 5-HETE in lung lymph exceeded those in aortic blood plasma. Lymph 5-HETE concentrations increased from 1.7 +/- 0.3 (mean +/- SEM, N = 7) ng/ml during baseline to peak values of 6.1 +/- 1.8 ng/ml (p less than 0.05) during the 2 1/2 hours after endotoxemia and preceeding the steady state increased lung vascular permeability response. During the increased permeability steady state from 240 to 270 minutes after endotoxin, lymph 5-HETE concentrations (1.4 +/- 0.3 ng/ml) and lymph 5-HETE flow (i.e., 5-HETE concentration x lung lymph flow rate) returned to baseline values. Although these observations are consistent with the hypothesis that 5-lipoxygenation products participate in the pulmonary vascular injury response to endotoxin, lymph 5-HETE concentrations did not correlate with any of the other experimental measurements. It may be only coincidence that the increase in lymph 5-HETE concentrations appeared contemporaneous with the onset of lung vascular injury.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D004731:Endotoxins; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids; D008168:Lung / Q000378:metabolism*; D008196:Lymph / Q000032:analysis; D012756:Sheep; D013997:Time Factors; D014115:Toxemia / Q000378:metabolism*
D001095:Arachidonic Acids; D004731:Endotoxins; D006893:Hydroxyeicosatetraenoic Acids; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid