Leukotrienes, thromboxane A2, and prostaglandins during systemic anaphylaxis in sheep.
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.
Morel
D R
DR
Department of Anesthesia, Harvard Medical School, Massachusetts General Hospital, Boston 02114.
Skoskiewicz
M
M
Robinson
D R
DR
Bloch
K J
KJ
Hoaglin
D C
DC
Zapol
W M
WM
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000707:Anaphylaxis / Q000503:physiopathology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors; D004140:Dinitrophenols; D005260:Female; D006636:Histamine Release; D007093:Imidazoles / Q000494:pharmacology; D017999:Leukotriene E4; D015289:Leukotrienes / Q000378:metabolism*; D008168:Lung / Q000502:physiology / Q000503:physiopathology*; D008196:Lymph / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D011453:Prostaglandins / Q000097:blood*; D011652:Pulmonary Circulation / Q000187:drug effects; D013189:SRS-A / Q000031:analogs & derivatives / Q000378:metabolism; D012710:Serum Albumin, Bovine; D012756:Sheep; D013318:Stroke Volume / Q000187:drug effects; D013929:Thromboxane B2 / Q000097:blood*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects
D002867:Chromones; D016861:Cyclooxygenase Inhibitors; D004140:Dinitrophenols; D007093:Imidazoles; D015289:Leukotrienes; D011453:Prostaglandins; D013189:SRS-A; C034638:dinitrophenyl-bovine serum albumin; D012710:Serum Albumin, Bovine; C039242:dazmegrel; D008469:Meclofenamic Acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D017999:Leukotriene E4; C006312:FPL 55712; D013930:Thromboxane-A Synthase