Endotoxin-induced changes in pulmonary hemodynamics and respiratory mechanics: Role of lipoxygenase and cyclooxygenase products

We investigated the role of leukotrienes and cyclooxygenase products in endotoxin-induced pulmonary vascular and airway changes. In 11 conscious sheep, measurements of pulmonary vascular resistance (PVR), lung resistance (RL), arterial P(O₂), leukocyte count (WBC), and plasma thromboxane B₂ (TxB₂), 6-keto-PgF(1α) and PgF(2α) were obtained, before and at predetermined intervals after a 10-min infusion of E. coli endotoxin (0.3 μg/kg). On a separate occasion, 5 sheep received an infusion of the leukotriene end-organ receptor antagonist FPL-57231 (0.7 to 1 mg/kg/min), before and for as long as 4 h after endotoxin infusion; and 6 sheep received a single injection of the cyclooxygenase inhibitor indomethacin (2 mg/kg) 1 h before endotoxin infusion. Endotoxin caused a biphasic response with an increase in mean PVR and RL to 441 and 353% of baseline, respectively, during the early phase (0 to 1 h), and lesser increases to 168 and 195% of baseline during the late phase (1.5 to 4 h). These changes were associated with mild hypoxemia, marked leukopenia, and marked increases in plasma TxB₂, 6-keto-PgF(1α) and PgF(2α). The FPL-57231 completely blocked the endotoxin-induced changed in PVR, RL, and Pa(O₂) during both phases without preventing the increases in TxB₂; however, it partly attenuated the increases in 6-keto-PgF(1α) and enhanced the generation of PgF(2α). Indomethacin, which blocked the endotoxin-induced increases in TxB₂, 6-keto-PgF(1α) PgF(2α), and RL, only partly blocked the increase in PVR during the early phase, followed by an exaggerated increase in PVR during the late phase. Both FPL-57231 and indomethacin failed to prevent the endotoxin-induced decrease in WBC count. In another group of 5 sheep, a 10-min infusion of FPL-57231, 4 h after endotoxin, reversed the Phase II increase in PVR. These data indicate that leukotrienes may play an important role in endotoxin-induced changes in pulmonary hemodynamics and airway mechanics. The increase in RL and initial changes in PVR may be mediated by leukotrienes and cyclooxygenase products, whereas the subsequent changes in PVR appear to be predominantly mediated by leukotrienes.