Effect of in vivo desensitization to leukotriene B4 on eosinophil infiltration in response to C5a in guinea-pig skin.
1. The effect of in vivo desensitization to leukotriene B4 (LTB4) on eosinophil infiltration in response to recombinant C5a was examined in guinea-pig skin. 2. LTB4 (10-300 ng) and C5a (1-10 micrograms) caused a dose-dependent increase in the levels of eosinophil peroxidase activity (a measure of eosinophil infiltration) 4 h after injection into guinea-pig skin. Leukotriene B4 and C5a were approximately equipotent on a molar basis. Platelet activating factor (0.01-10 micrograms) also caused eosinophil accumulation but was much less active than LTB4 or C5a. 3. 20-Hydroxy-LTB4 caused a dose-dependent desensitization of eosinophil responses to LTB4 (ED50 = 1.6 micrograms kg-1, s.c.) and partially reduced responses to C5a. At a dose of 20-hydroxy-LTB4 (10 micrograms) which inhibited responses to LTB4 completely, responses to C5a were reduced by 56.5 +/- 1.8% (n = 5). The structurally related metabolite of 20-hydroxy-LTB4, 20-carboxy-LTB4, which does not cause desensitization to the effects of LTB4, did not inhibit eosinophil infiltration in response to C5a. 4. The LTB4 receptor antagonist, SC-41,930 (10 mg kg-1, p.o.), also inhibited eosinophil accumulation in response to C5a by 63.0 +/- 3.9% (n = 5) at a dose which inhibited responses to LTB4 by 86.5 +/- 1.9% (n = 5). 5. These data indicate that eosinophil infiltration in response to C5a may, in part, be mediated by the generation of secondary chemotactic factors such as LTB4.
Pettipher
E R
ER
Department of Immunology and Infectious Diseases, Pfizer Inc., Groton, CT 06340.
Salter
E D
ED
Showell
H J
HJ
D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D015936:Complement C5a / Q000276:immunology*; D004804:Eosinophils / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000276:immunology; D007975:Leukotriene B4 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010544:Peroxidases / Q000378:metabolism; D010972:Platelet Activating Factor / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin / Q000276:immunology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D018836:Inflammation Mediators; D010972:Platelet Activating Factor; D011994:Recombinant Proteins; C059950:SC 41930; D007975:Leukotriene B4; C031571:5,12,20-trihydroxy-6,8,10,14-eicosatetraenoic acid; D015936:Complement C5a; D010544:Peroxidases; D000640:Amitrole