Perspectives on additional areas for research in leukotrienes.
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Animals↗
Biomedical subjects
F Austen
Publications and source records attributed to F Austen.
Intracellular retention of the 5-lipoxygenase pathway product, leukotriene B4, by human neutrophils activated with unopsonized zymosan.
The cellular and extracellular distribution of leukotriene B4 (LTB4) generated in human neutrophilic polymorphonuclear leukocytes (PMN) stimulated with unopsonized zymosan has been compared with that generated in PMN activated by the calcium ionophore. The amounts of extracellular and intracellular LTB4 were quantitated by radioimmunoassay. The authenticity of the immunoreactive LTB4 was confirmed by the elution of a single immunoreactive peak after reverse phase-high performance liquid chromatography (RP-HPLC) at the retention time of synthetic LTB4, by the identical elution time of a peak of radiolabeled product derived from [3H]arachidonic acid-labeled PMN with the immunoreactive product, and by the comparable chemotactic activity on a weight basis of immunoreactive LTB4 and synthetic LTB4 standard. Under optimal conditions of stimulation by unopsonized zymosan, more than 78% of the generated immunoreactive LTB4 remained intracellular, whereas with optimal activation by the ionophore, less than 8.6% of immunoreactive LTB4 was retained. Resolution by RP-HPLC of the products from the supernatants and cell extracts of [3H]arachidonic acid-labeled PMN stimulated with unopsonized zymosan and those stimulated with calcium ionophore allowed identification and measurement of 5-hydroxyeicosatetraenoic acid (5-HETE), 6-trans-LTB4, LTB4, and omega oxidation products of LTB4 by radioactivity. With zymosan stimulation of PMN, 5-HETE and the 6-trans-LTB4 diastereoisomers were not released, LTB4 was partially released, and the omega oxidation products of LTB4 were preferentially extracellular in distribution. In contrast, with ionophore stimulation, only 5-HETE had any duration of intracellular residence being equally distributed intra- and extracellularly throughout the 30-min period of observation; 6-trans-LTB4, LTB4, and the omega oxidation products of LTB4 were retained at less than 19%. The respective distributions of 5-HETE after zymosan and ionophore stimulation were not altered by the introduction of albumin to the reaction mixtures to prevent reacylation, or by hydrolysis of the cell extract to uncover any product that had been reacylated. The finding that stimulation of PMN with unopsonized zymosan results in the cellular retention of 5-lipoxygenase products suggests that release of these metabolites may be an event that is regulated separately from their generation.
Arachidonate Lipoxygenases↗
Urticaria, angioedema, and mediator release in humans in response to physical environmental stimuli.
The activation of mast cells by immunologic or physical stimuli leads to the generation of unstored intermediates (mediators) such as slow reacting substance of anaphylaxis (SRS-A) and platelet activating factor (PAF), and to their release along with performed mediators, histamine, eosinophil chemotactic factor of anaphylaxis (ECF-A), and neutrophil chemotactic factor (NCE), and macromolecular heparin. The internal regulation of mast cell-dependent phenomenons occurs at at least four levels: 1) the intensity and nature of the activating stimulus, 2) the regulation of mediator generation and release of cellular levels of the cyclic nucleotides, 3) the capacity of target cells to bind and respond to primary mediators, and 4) the rate at which mediators undergo biodegradation. Inasmuch as the mast cell is present at cutaneous and mucosal surfaces about venules, it seems likely that the initial or humoral phase of its response achieves an influx of plasms proteins, such as immunoglobulins and complement components, whereas the subsequent cellular phase augments local host defense through the entrance of neutrophils and eosinophils that terminate the humoral phase. The activation of mast cells is considered herein in terms of defined physical stimuli that are characterized by urticaria and angioedema.
Angioedema↗
Eosinophil polymorphonuclear leukocyte function in immediate hypersensitivity.
An eosinophil chemotactic factor of anaphylaxis (ECF-A), released along with other chemical mediators of immediate hypersensitivity from sensitized mast cells that have been challenged with specific antigen, is capable of selectively attracting eosinophils. The rate and magnitude of tissue eosinophil influx may be enhanced by ascorbate and inhibited by the neutrophil immobilizing factor (NIF). Eosinophils may then exercise a local regulatory function. Phagocytosis or the action of ECF-A at high concentrations causes eosinophils to release arylsulfatase, which inactivates slow reacting substance of anaphylaxis (SRS-A). Additional possible functions of eosinophils may follow from their content of factors that inhibit histamine release or its mediator function, and the high levels of intracellular plasminogen and phospholipase B. Thus, the unique enzymes and factors released from eosinophils may form the basis of their role in immediate and subacute hypersensitivity reactions.
Anaphylaxis↗