Eosinophil-eicosanoid interactions: inhibition of eosinophil chemotaxis in vivo by a LTD4-receptor antagonist.
Chemotaxis of guinea-pig eosinophils in vivo has been studied in the guinea-pig conjunctiva. Guinea-pig eosinophils were labelled with 111In oxine and injected i.v. into recipient animals. Circulating radioactivity remained constant over a period of 4 h but dropped transiently in response to a bolus injection (1 nmol) of platelet activating factor (PAF), suggesting that the 111In-labelled eosinophils had retained their responsiveness to PAF. Leukotriene D4 (LTD4, 1 nmol/eye) and PAF (10 nmol/eye), but not histamine (5 nmol/eye), induced a significant 2.5-fold increase in conjunctival radioactivity, a measure of eosinophil chemotaxis in vivo, after 17 h. Antigen challenge (250 micrograms/eye) in ovalbumin-sensitized animals produced larger responses (8-fold increases) at the same time point. A specific LTD4 receptor antagonist MK-571 (10 micrograms/eye) completely inhibited in vivo chemotactic responses to LTD4, and partially inhibited (54%) the responses to ovalbumin (observations subsequently confirmed by histological studies). As eosinophils may play an important role in allergic diseases, the results with MK-571 indicate that selective and potent LTD4 receptor antagonists may provide a novel therapy for allergic conjunctivitis, rhinitis and asthma.
Chan
C C
CC
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire/Dorval, Quebec, Canada.
McKee
K
K
Tagari
P
P
Chee
P
P
Ford-Hutchinson
A
A
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003228:Conjunctiva / Q000187:drug effects; D015777:Eicosanoids / Q000494:pharmacology*; D004804:Eosinophils / Q000187:drug effects*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006651:Histocytochemistry; D007205:Indium Radioisotopes; D008297:Male; D010047:Ovalbumin / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000187:drug effects*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D015777:Eicosanoids; D007205:Indium Radioisotopes; D010972:Platelet Activating Factor; D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C059141:verlukast; D006632:Histamine; D010047:Ovalbumin