Reduction of polymorphonuclear leukocyte accumulations by inhibition of cyclooxygenase and thromboxane syntase in the rabbit.
Thromboxane (Tx) inhibition prevents pulmonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (1) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 +/- 874 PMN/mm3 (mean +/- SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p less than 0.05) accumulations to 205 +/- 139 PMN/mm3, 485 +/- 387 PMN/mm3, and 504 +/- 260 PMN/mm3, respectively. In ZAS sites, placebo pretreatment led to 2006 +/- 866 PMN/mm3, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p less than 0.05) responses of 295 +/- 218 PMN/mm3, 444 +/- 477 PMN/mm3, and 386 +/- 151 PMN/mm3, respectively. Pretreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 +/- 164 pg/ml, 460 +/- 144 pg/ml, and 440 +/- 260 pg/ml, respectively, as compared with 1168 +/- 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by 133Xe washout. The in vitro chemotactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole, OKY 1555, or OKY 046. These data show that cyclooxygenase and Tx syntase are integrally associated with PMN accumulations.
Palder
S B
SB
Huval
W
W
Lelcuk
S
S
Alexander
F
F
Shepro
D
D
Mannick
J A
JA
Hechtman
H B
HB
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors; D007052:Ibuprofen / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology*; D011292:Premedication; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011817:Rabbits; D012867:Skin / Q000276:immunology; D012882:Skin Tests; D013928:Thromboxane A2 / Q000502:physiology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology
D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D008689:Methacrylates; D013928:Thromboxane A2; C031517:2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic acid; C029899:imidazole; D011451:Prostaglandin-Endoperoxide Synthases; D013930:Thromboxane-A Synthase; C034364:ozagrel; D007052:Ibuprofen