leukotriene-b4 and Polycythemia-Vera

A series of studies have demonstrated a stimulus-specific defect in PMN oxidative metabolism after stimulation with surface receptor dependent stimuli such as fMLP, leukotriene B4 and platelet activating factor (PAF), whereas the response to phorbol myristate acetate was normal. Having discovered this defect, studies of the stimulus response coupling for oxidative responses were performed showing a normal interaction of fMLP with it's receptor, as well as an intact activation of phospholipase C, as measured by the generation of 1,4,5-inositoltrisphosphate, and the subsequent rise of intracellular calcium. In contrast, the formation of diacylglycerol and phosphatidylethanol was decreased in PV PMN, denoting an impaired activation of phospholipase D (PLD). It was shown by flow cytometry analyses that the hampered oxidative response was present both in single PMN and monocytes. Moreover, platelets from PV patients, whose PMN exhibit a lower oxidative response to PAF, also have a diminished aggregatory response to PAF. Thus three different cell lineages in PV have been revealed to respond abnormally to surface receptor dependent stimuli, indicating that the proposed impairment of PLD might be relevant for changes in the malignant stem cell clone. Since phosphatidic acid, produced as a result of PLD activation, may be implicated in the regulation of several oncogenes, perturbations of the PLD system could theoretically be important for the development of PV.

Topics: Enzyme Activation; Humans; Inositol 1,4,5-Trisphosphate; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxidative Stress; Phospholipase D; Platelet Activating Factor; Polycythemia Vera; Tetradecanoylphorbol Acetate

Topics: Humans; Leukotriene B4; Luminescent Measurements; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Polycythemia Vera; Superoxides; Tetradecanoylphorbol Acetate

We investigated polymorphonuclear granulocyte (PMN) function in polycythemia vera (PV) in relation to healthy controls. PMN oxidative metabolism, assessed by chemiluminescence (CL), was significantly lower in PV patients after stimulation with leukotriene B4 (LTB4) and f-Met-Leu Phe (fMLP) (60% of control), whereas no difference in CL was seen after stimulation with phorbol myristate acetate (PMA) (120% of controls). Spontaneous and fMLP-induced PMN adherence to an albumin-coated plastic surface, as well as spontaneous migration and LTB4 - and fMLP-induced chemotaxis, were similar to controls. This suggests the presence of a stimulus-specific defect in PMN oxidative metabolism in PV.

Topics: Cell Adhesion; Cell Movement; Chemotaxis, Leukocyte; Humans; Leukotriene B4; Luminescent Measurements; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxidation-Reduction; Oxygen; Polycythemia Vera

The arachidonate metabolism by leukocytes and platelets was studied in 14 patients with myeloproliferative disorders including 7 patients with chronic myeloid leukemia (CML), 5 with polycythemia vera (PV) and 2 with essential thrombocythemia (ET). When the leukocytes were incubated with arachidonate and A23187, leukotriene B4 and hydroxyeicosatetraenoic acids (HETEs) were constantly detected using reversed-phase high-performance liquid chromatography in normal subjects, while selective deficiency of 5-lipoxygenase products (leukotriene B4 and 5-HETE) was found in 4 patients with CML. this novel abnormality of the leukocytes seemed to be derived from the possible deficiency of 5-lipoxygenase in these patients' polymorphonuclear neutrophils (PMNNs). The formation of 15-HETE appeared to be almost normal in all the patients. Platelet 12-lipoxygenase deficiency was detected in 2 patients with PV and 2 with CML in whom one was associated with the deficiency of 5-lipoxygenase products. These bicellular abnormalities of the arachidonate metabolism might contribute to understand dysfunctions of PMNNs and platelets in some patients with myeloproliferative disorders.

Topics: Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Calcimycin; Humans; In Vitro Techniques; Leukemia, Myeloid; Leukocytes; Leukotriene B4; Lipoxygenase; Myeloproliferative Disorders; Polycythemia Vera; Prostaglandin-Endoperoxide Synthases; Thrombocytosis