Effects of cyclooxygenase inhibitors on the alterations in lung mechanics caused by endotoxemia in the unanesthetized sheep.
The effects of Escherichia coli endotoxin on lung mechanics, hemodynamics, gas exchange, and lung fluid and solute exchange were studied in 12 chronically instrumented unanesthetized sheep. A possible role for cyclooxygenase products of arachidonate metabolism as mediators of the endotoxin-induced alterations in lung mechanics was investigated by studying sheep before and after cyclooxygenase inhibition with sodium meclofenamate and ibuprofen. Sheep were studied three times in random order: (a) sodium meclofenamate (or ibuprofen) infusion alone; (b) E. coli endotoxin alone; and (c) meclofenamate (or ibuprofen) and endotoxin. Meclofenamate alone had no effect on any of the variables measured. Endotoxin alone caused early marked changes in lung mechanics: resistance to airflow across the lungs (RL) increased 10-fold, dynamic lung compliance (Cdyn) decreased 80% and functional residual capacity (FRC) decreased by greater than 30%. The alveolar-to-arterial oxygen difference (delta AaPO2) increased markedly following endotoxemia. In the presence of sufficient meclofenamate to inhibit accumulation of thromboxane-B2 and 6-keto-prostaglandin F1 alpha in lung lymph, endotoxin caused no increase in RL, Cdyn decreased by less than 40%, and FRC decreased by only 6%. Meclofenamate significantly attenuated the hypoxemia and early pulmonary hypertension caused by endotoxemia but had no effect on the late increases in lung fluid and solute exchange. Ibuprofen had similar effects to those observed with meclofenamate. We conclude that both the pulmonary hypertension and changes in lung mechanics observed after endotoxemia may be mediated, at least in part, by constrictor prostaglandins or thromboxanes and that gas exchange may be improved by preventing endogenous synthesis of these mediators.
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects; D007052:Ibuprofen / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000502:physiology*; D008170:Lung Compliance / Q000187:drug effects; D008196:Lymph / Q000378:metabolism; D008469:Meclofenamic Acid / Q000494:pharmacology; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D013929:Thromboxane B2 / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D008469:Meclofenamic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D007052:Ibuprofen