We investigated the roles of
eicosanoid mediators in acute systemic
anaphylaxis in anesthetized sheep. Sheep were sensitized with dinitrophenylated Ascaris suum extract and were challenged with an
intravenous injection of dinitrophenylated
bovine serum albumin. During
anaphylaxis,
cyclooxygenase inhibitors eliminated the elevation of arterial plasma levels of
thromboxane B2 and 6-ketoprostaglandin F 1 alpha but markedly elevated the levels of
leukotriene E4 in lung lymph without significantly eliminating elevation of plasma levels of
histamine. Most of the measured physiological abnormalities accompanying
anaphylaxis were aggravated by
cyclooxygenase blockade. Enhancement of this anaphylactic mediator response was associated with an accentuated and prolonged increase of airway pressure (P less than 0.05, compared with sensitized,
antigen-challenged but otherwise untreated sheep), a more intense
hypoxemia (P less than 0.0001), and
leukopenia (P less than 0.001), changes that were largely eliminated by pretreating with the sulfidopeptide
leukotriene (SPLT) antagonist
FPL 55712, suggesting that the SPLTs were important mediators of these responses. In contrast, the prolonged, but less severe, systemic vascular collapse and the reduced
pulmonary hypertension induced by
cyclooxygenase inhibitors were not influenced by the SPLT antagonist. These results demonstrate that in sheep
cyclooxygenase metabolites are mainly involved in the acute, but transient, systemic and pulmonary vascular response of systemic
anaphylaxis, whereas SPLTs are primarily implicated in the airway and secondary cardiovascular response. SPLT may act either directly or by potentiating the release of and reactivity to
histamine and other mediators. Our data therefore suggest that a combination of
cyclooxygenase and
lipoxygenase inhibition will be necessary to more effectively protect against the consequences of an
anaphylactic reaction.