Profile and quantity of
leukotriene (LT) and hydroxyeicosatetraenoic
acid (
HETE) generation upon selective stimulation of isolated polymorphonuclear neutrophils (PMN) compared with neutrophils in a model of pulmonary
leukostasis were investigated. Freshly prepared human PMN (2 x 10(8) were injected into the pulmonary artery of isolated, ventilated, and bloodfree perfused rabbit lungs, resulting in nearly quantitative sticking in the microvasculature. The sequestered neutrophils and, in parallel, aliquots of isolated PMN were stimulated with mAb in the presence of C, known to activate PMN arachidonate metabolism via formation of membrane attack complexes. In the isolated cells, a typical LT profile including
LTB4 and its omega-oxidation products, 5-
HETE and nonenzymatic hydrolysis products of
LTA4 was evoked. The latter indicate secretion of
LTA4 in considerable amounts. In the model of pulmonary
leukostasis, no nonenzymatic
LTA4-derivatives were detected, coincident with a predominance of cysteinyl-LT. This finding gives indirect evidence for an efficient
LTA4-transfer between PMN feeder cells and vascular acceptor cells with
glutathione-S-transferase activity. Moreover, a threefold increase in the total amount of
LTA4-derived products was noted in the model of
leukostasis, paralleled by a marked decrease in 5-
HETE liberation. This effect was further enhanced by inhibition of lung
cyclooxygenase. These findings were corroborated in a homologous system, in which rabbit PMN, sticking in the rabbit lung microvasculature, were stimulated with
calcium-ionophore A23187. Collectively, these data suggest a complex interaction between microvascular tissue and adhering neutrophils in LT synthesis, involving transcellular
LTA4-shift, modulation of the PMN
5-lipoxygenase pathway, and amplification of LT generation. These findings may be relevant for inflammatory events with neutrophils involved.