Synergistic effects of LTB4 and LTD4 on leukocyte emigration into the guinea pig conjunctiva.
Leukotrienes (LT) B4 and D4, alone and in combination, were topically applied to the eyes of guinea pigs, and their effects on conjunctival leukocyte infiltration studied. LTD4 potentiated the neutrophil response to LTB4, even though no neutrophil emigration was evoked by LTD4 itself over a dose range of 10-1000 ng. LTB4 alone at the 1-ng and 10-ng doses failed to evoke any leukocyte emigration, but significant numbers of neutrophils were observed at these concentrations when LTD4 (1-1000 ng) was present. Although a dose-dependent increase in neutrophil infiltration was observed for the 100-ng and 1000-ng doses of LTB4, cell counts were substantially higher with these doses in the presence of LTD4. Eosinophil numbers increased in a dose-related manner in response to LTB4 and LTD4 alone, with a greater response to LTD4. The addition of either 10 ng or 100 ng of LTB4 to graded doses of LTD4 (10-1000 ng) caused increased eosinophil numbers, the lower dose of LTB4 potentiating the response to LTD4 and the higher LTB4 dose showing no significant effect. The effects on leukocyte infiltration that were evoked by the LT combinations could not be explained simply on the basis of an increase in vascular permeability. Bradykinin (BK), a potent conjunctival microvascular permeability factor that does not elicit any leukocyte infiltration, did not significantly potentiate LTB4-induced eosinophil or neutrophil emigration. The synergistic effects of LTs on leukocyte emigration are also difficult to ascribe to hyperemia (ie, increased blood volume in the conjunctiva), because both LTB4 and LTD4 caused only very modest increases in conjunctival blood content, and BK, which did not potentiate the leukocytic responses to LTB4, caused marked increases in tissue blood content. High-dose LT combinations caused eosinophils, but not neutrophils, to migrate into the conjunctival epithelium and fragment, resulting in overt tissue damage. These results further suggest a synergistic interaction between LTB4 and LTD4 that directly alters leukocyte function. The relevance of these observations to a number of disease and trauma states is discussed.
Spada
C S
CS
Pharmacology Department, Allergan Eye and Skin Care Group, Irvine, CA 92715.
Woodward
D F
DF
Hawley
S B
SB
Nieves
A L
AL
Williams
L S
LS
Feldmann
B J
BJ
D000818:Animals; D001810:Blood Volume; D001920:Bradykinin / Q000494:pharmacology; D002199:Capillary Permeability; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D003228:Conjunctiva / Q000098:blood supply / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007975:Leukotriene B4 / Q000008:administration & dosage / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D013189:SRS-A / Q000008:administration & dosage / Q000494:pharmacology*
D013189:SRS-A; D007975:Leukotriene B4; D001920:Bradykinin