Evidence that peptidoleukotriene is a prerequisite for antigen-dependent thromboxane synthesis in IgG1-passively sensitized guinea pig lungs.
Lungs from guinea pigs passively sensitized with an affinity-purified IgG1 antibody produce both leukotriene (LT)D4 and thromboxane (Tx)B2 upon ex vivo antigen challenge. This study was undertaken to determine the possibility of endogenously generated peptido-LTs being a prerequisite for Tx synthesis. In immunoglobulin G1-sensitized lungs, exogenous LTD4 induced TxB2 production with a median effective dose of 4.1 nM, whereas the response to LTE4, LTB4 or platelet-activating factor was relatively weak. Although LTC4 was as potent as LTD4 in stimulating TxB2 generation, LTC4's dose-response curve was shifted significantly to the right by AT-125, an irreversible gamma-glutamyl transpeptidase inhibitor, suggesting that at least a part of LTC4 sensitized lungs with antigen (0.01-30 micrograms/ml ovalbumin) for 20 min precipitated a significant amount of LTD4 production. The levels of LTD4 range from 8 to 26 nM (without taking LTD4 recovery into consideration). This level is 2- to 7-fold greater than the median effective dose value observed with exogenous LTD4. Moreover, pretreatment of sensitized lungs with ICI-198,615 a specific LTD4 antagonist, blocked equally both antigen (IC50 = 0.01 microM)- and LTD4 (IC50 = 0.017 microM)-induced TxB2 production. When sensitized lung fragments were treated with 5 mM AT-125, ICI-198,615 was effective in preventing not only antigen-but also LTC4-dependent production of TxB2 (IC50 = 0.018 and 0.021 microM, respectively). In contrast, neither WEB-2086, a platelet-activating factor antagonist, nor pyrilamine, a histamine antagonist, inhibited antigen and LTD4 responses (IC50 greater than 30 microM). Unlike its effect on antigen response, ICI-198,615 was unable to block Ca2+ ionophore-induced TxB2 production.2
Cheng
J B
JB
Department of Immunology and Infectious Diseases, Central Research Division, Pfizer Inc., Groton, Connecticut.
Pillar
J S
JS
Conklyn
M J
MJ
Breslow
R
R
Shirley
J T
JT
Showell
H J
HJ
D000818:Animals; D000941:Antigens / Q000276:immunology*; D006168:Guinea Pigs; D007074:Immunoglobulin G / Q000276:immunology*; D007191:Indazoles / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism; D008297:Male; D010972:Platelet Activating Factor / Q000502:physiology; D013189:SRS-A / Q000378:metabolism / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis*
D000941:Antigens; D007074:Immunoglobulin G; D007191:Indazoles; D007555:Isoxazoles; D010972:Platelet Activating Factor; D013189:SRS-A; C054217:ICI 198615; D013929:Thromboxane B2; C006303:acivicin