Influence of steroidal and nonsteroidal anti-inflammatory agents on the accumulation of arachidonic acid metabolites in plasma and lung lymph after endotoxemia in awake sheep. Measurements of prostacyclin and thromboxane metabolites and 12-HETE.

The influence of methylprednisolone and meclofenamate on endotoxin-induced release of 3 arachidonic acid metabolites was studied in unanesthetized sheep. Concentrations in plasma and lung lymph of prostacyclin and thromboxane (Tx) A2 metabolites (6-keto-PGF1 alpha and TxB2, respectively) were measured by radioimmunoassay. Concentrations of 12-HETE in lung lymph were measured by stable isotope dilution assay employing gas chromatography-mass spectroscopy. Thromboxane B2 concentrations increased quickly to peak values during the first hour after endotoxin infusion, then decreased to baseline by 1.5 hr. 6-keto-PGF1 alpha concentrations increased more gradually to peak values between 1 and 2 h after endotoxin infusion and remained elevated at 2.5 h. Lymph concentrations of both cyclooxygenase metabolites exceeded those in blood plasma. Methylprednisolone significantly inhibited accumulation of 6-keto-PGF1 alpha in lymph and plasma, but did not significantly inhibit accumulation of TxB2 in lymph or plasma. The combination of meclofenamate and methylprednisolone completely inhibited accumulation of TxB2 and 6-keto-PGF1 alpha in lymph and plasma. The concentration of 12-HETE in lung lymph increased significantly to peak values by 2.5 h after endotoxemia, and methylprednisolone, with or without meclofenamate, inhibited accumulation of 12-HETE in lung lymph. These data support participation of TxA2 in acute pulmonary hypertension after endotoxemia. That methylprednisolone treatment inhibited accumulation of 6-keto-PGF1 alpha and prevented the increase in lung vascular permeability suggests that prostacyclin production is a consequence of lung vascular injury. Increased lung lymph concentrations of the lipoxygenation product, 12-HETE, were coincident with physiologic evidence of increased lung vascular permeability, but whether release of lipoxygenase products after endotoxemia contributes to or results from lung vascular injury remains to be established.