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Leukotrienes and lipoxins, arachidonate derived mediators from the lipoxygenase (LO) pathways, are associated with bronchial asthma.1-3 They have been detected in vivo in bronchoalveolar lavage (BAL) fluid4-6 and are biosynthesised in vitro by human alveolar macrophages (AM) and polymorphonuclear cells (PMN) after non-specific stimulation.7 Lipoxins were first isolated by Serhanet al 8 9 who incubated granulocytes with 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE). Lipoxin synthesis was also achieved by the addition of other exogenous substrates to cell cultures.8 10 11 In contrast, lipoxin synthesis by co-cultures of two different cell types does not require the addition of any exogenous substrates.11-13 The biosynthesis of lipoxins was shown to be the result of a cellular cooperation mechanism between two different cell types. The enzymatic mechanism of transcellular metabolism involves the action of at least two different lipoxygenases (fig 1). Thus, lipoxins may be generated following receptor mediated activation of either co-incubated PMN and platelets,13 or ionophore stimulation of PMN alone after exposure to exogenous 15(S)-HETE.14
As shown previously,15 AM from asthmatic patients display high levels of 5-LO activity. 15(S)-HETE is considered to be specific to human epithelium airways and endothelial cells.16-18Human epithelial and endothelial cells are unable to produce lipoxins from endogenous 15(S)-HETE16 19 but they are surrounded by several cell types which show 5-LO activity. Moreover, lipoxins have been identified in the BAL fluid of patients with lung disease20 and in stimulated whole blood.21Because of these observations, and assuming that peripheral blood cells were activated before trafficking to the airways, we have investigated whether AM and peripheral blood cells display sufficient LO activity to transform 15(S)-HETE and have determined whether the generation of lipoxins and their precursors is related to the severity of asthma and can be …
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