Thromboxane A₂ induces leukotriene B₄ synthesis that in turn mediates neutrophil diapedesis via CD 18 activation

Previous studies have indicated that thromboxane (Tx) and leukotriene (LT) B₄ act synergistically to induce neutrophil (PMN) adhesion in the microvasculature. This study explores the ability of Tx to induce LTB₄ synthesis, which then leads to activation of PMN and endothelial adhesion receptors. Tx-mimic (U46619, 1 μg/ml) was administered into abraded skin chambers placed on the backs of rabbits (n = 6). After 3 hr LTB₄ was synthesized in the blister fluid at 385 pg/ml, a value higher than levels in saline-treated blisters, 10 pg/ml (P < 0.05). The LTB₄ generation following Tx-mimic was correlated (P < 0.05, r = 0.70) with neutrophil diapedesis. These averaged 645 PMN/mm³, values higher than saline values of 20 PMN/mm³ (P < 0.05). Intravenous (iv) treatment of other rabbits (n = 4) with the lipoxygenase inhibitor diethylcarbamazine at 60 mg/kg, followed by 40 mg/kg/hr, prevented Tx-mimic-induced LTB₄ synthesis (10 pg/ml) and diapedesis (19 PMN/mm³) (both P < 0.05). Intravenous treatment of yet other rabbits (n = 4) with the anti-CD 18 monoclonal antibody R 15.7 at 1 mg/kg abolished Tx-induced diapedesis (3 PMN/mm³) (P < 0.05). In contrast, local administration of 3 ng of the protein synthesis inhibitor actinomycin D, to prevent expression of endothelial adhesion proteins, limited TNF- but not Tx-induced diapedesis. The data indicate that Tx-induced diapedesis is mediated by the generation of LTB₄ and the activation of neutrophil CD 18 but not endothelial adhesion proteins.