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 PO2, leukocyte count (WBC), and plasma thromboxane B2 (TxB2), 6-keto-PgF1 alpha and PgF2 alpha were obtained, before and at predetermined intervals after a 10-min infusion of E. coli endotoxin (0.3 microgram/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 hr), 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-PgF1 alpha and PgF2 alpha. The FPL-57231 completely blocked the endotoxin-induced changes in PVR, RL, and PaO2 during both phases without preventing the increases in TxB2; however, it partly attenuated the increases in 6-keto-PgF1 alpha and enhanced the generation of PgF2 alpha. Indomethacin, which blocked the endotoxin-induced increases in TxB2, 6-keto-PgF1 alpha, PgF2 alpha, and RL, only partly blocked the increase in PVR during the early phase, followed by an exaggerated increase of PVR during the late phase.(ABSTRACT TRUNCATED AT 250 WORDS)
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D015237:Dinoprost; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D008084:Lipoxygenase / Q000502:physiology*; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011460:Prostaglandins F / Q000097:blood; D012119:Respiration / Q000187:drug effects*; D013189:SRS-A / Q000037:antagonists & inhibitors; D012756:Sheep; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors
D002867:Chromones; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D011460:Prostaglandins F; D013189:SRS-A; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C034338:FPL 57231; D015237:Dinoprost; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin