Abstract
The reactive intermediate formed by 5-lipoxygenase metabolism of arachidonic acid, leukotriene A4, is known to be released from cells and subsequently taken up by other cells for biochemical processing. The objective of this study was to determine the relative amount of leukotriene A4 synthesized by human polymorphonuclear leukocytes (PMNL) that is available for transcellular biosynthetic processes. This was accomplished by diluting cell suspensions and measuring the relative amounts of enzymatic versus nonenzymatic leukotriene A4-derived metabolites after challenge with the Ca2+ ionophore A23187. Nonenzymatic leukotriene A4-derived metabolites were used as a quantitative index of the amount of leukotriene A4 released into the extracellular milieu. The results obtained demonstrated that in human PMNL, the relative amounts of nonenzymatic versus enzymatic leukotriene A4-derived metabolites increased with decreasing cell concentrations. After a 20-fold dilution of PMNL in cell preparations, a doubling in the amount of nonenzymatic leukotriene A4-derived metabolites was observed following challenge (from 53.9 +/- 1.3 to 110.4 +/- 8.9 pmol/10(6) PMNL, p < 0.01). Reduction of possible cell-cell interactions by dilution suggested that over 50% of leukotriene A4 synthesized is released from the PMNL. These data provide evidence that, in human PMNL preparations, transfer of leukotriene A4 to neighboring PMNL is taking place, resulting in additional formation of leukotriene B4 and its omega-oxidized metabolites 20-hydroxy- and 20-carboxy-leukotriene B4. Neutrophil reuptake of extracellular leukotriene A4 leads to an underestimation of the fraction of leukotriene A4 that is in fact available for transcellular metabolism when tight cell-cell interactions occur, such as during PMNL adhesion to the microvascular endothelium and diapedesis.
Highlights
Arachidonic acid oxidation, catalyzed by cyclo-oxygenase or 5-lipoxygenase, leads to potent biologically active molecules such as thromboxane, prostacyclin, and leukotrienes [1, 2]
The objective of this study was to determine the relative amount of leukotriene A4 synthesized by human polymorphonuclear leukocytes (PMNL) that is available for transcellular biosynthetic processes
Polymorphonuclear leukocytes (PMNL) are able to take up exogenously added LTA4 [21] and metabolize it into LTB4, reducing the fraction of released LTA4 that is available for transcellular metabolism
Summary
Arachidonic acid oxidation, catalyzed by cyclo-oxygenase or 5-lipoxygenase, leads to potent biologically active molecules such as thromboxane, prostacyclin, and leukotrienes [1, 2]. Significant amounts of LTB4 and its -oxidized metabolites 20-hydroxy- and 20-carboxy-LTB4 are released into the extracellular milieu together with nonenzymatic breakdown products of LTA4, namely ⌬6-trans-LTB4 isomers and 5,6-dihydroxyeicosatetraenoic acids (5,6-diHETEs) (10 –12). Recent studies in complex organ systems [13,14,15,16,17,18] showed that perfusion of PMNL in the isolated lung or heart of the rabbit only caused a significant increase in the production of cysteinyl leukotrienes when PMNL were activated during the perfusion process These data suggest that transcellular biosynthesis of cysteinyl leukotrienes might be of physiopathological relevance when tight cell-cell interactions occur, such as during adhesion and diapedesis of PMNL through the microvascular endothelium of a functioning organ system. PMNL are able to take up exogenously added LTA4 [21] and metabolize it into LTB4, reducing the fraction of released LTA4 that is available for transcellular metabolism (or nonenzymatic hydrolysis)
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