Munehiro Yamazaki

Abnormal Membrane Fluidity as a Cause of Impaired Functional Dynamics of Chemoattractant Receptors on Neonatal Polymorphonuclear Leukocytes: Lack of Modulation of the Receptors by a Membrane Fluidizer

ABSTRACT: Membrane properties associated with chemoattractant-mediated cellular responsiveness of neonatal polymorphonuclear leukocytes (PMN) were analyzed using n-formylmethionyl-leucyl-phenylalanine. Inasmuch as aliphatic alcohols as a membrane fluidizer can enhance the chemoattractant binding and affect subsequent cellular responsiveness in adult PMN, neonatal PMN were studied for such properties by their treatment with iso-propyl alcohol, an aliphatic alcohol. The alcohol (<2.5%) treatment enhanced the N-formylmethionyl-leucyl-phenylalanine binding to adult PMN, but there were no changes in the N-formylmethionyl-leucyl-phenylalanine binding to neonatal PMN. Although the N-formylmethionyl-leucyl-phenylalanine-induced subsequent responsiveness including migration, lysosomal enzyme release and superoxide anion production were modulated by the alcohol treatment in adult PMN, there was no such modulation in neonatal PMN. Because membrane fluidity is largely involved in the regulation of the receptor functions, the membrane fluidity of neonatal PMN was next measured by an excimer-forming lipid technique in flow cytometry. The membrane fluidity value (0.45 ± 0.037) of neonatal PMN was lower than that (0.74 ± 0.072) of adult PMN (p < 0.01). Although the aliphatic alcohol enhanced the membrane fluidity of adult PMN, it did not affect the membrane fluidity of neonatal PMN. We conclude that there is abnormal membrane fluidity as a cause of impaired functional dynamics of the chemoattractant receptors, which appears to underlie the defective modulation of cell functions by the membrane fluidizer in neonatal PMN.

Dopamine inhibition of superoxide anion production by polymorphonuclear leukocytes

To examine the modulatory effects of catecholamines on the respiratory burst in polymorphonuclear leukocytes (PMNs), dopamine was tested for its capacity to modify the superoxide anion (O2-) production by PMNs under their stimulation with several stimuli. Dopamine inhibited the O2- production by PMNs when PMNs were stimulated with N-formylated chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), phorbol myristate acetate, or opsonized zymosan, whereas dopamine did not alter the PMN mobility. The values of percentage inhibition of the O2- production by FMLP-stimulated PMNs were 57% under treatment with 10(-5) mol/L and 83% with 10(-4) mol/L of dopamine. Isoproterenol also inhibited PMN O2- production in response to FMLP. Although a beta-adrenergic blockade, propranolol, diminished the isoproterenol-induced inhibition of the O2- production, it did not affect the inhibitory effect of dopamine. The increase in intracellular cyclic AMP levels in dopamine-treated PMNs was much smaller than the increase in isoproterenol-treated cells. Furthermore, dopamine inhibited the reduced nicotinamide-adenine dinucleotide phosphate-dependent O2- production by subcellular particles. These results indicate that dopamine inhibits PMN O2- production through its effect on PMN reduced nicotinamide-adenine dinucleotide phosphate-oxidase system rather than through its beta-adrenergic action.

Effects of high‐dose granulocyte colony‐stimulating factor on neutrophil functions

We evaluated the effects of high‐dose recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) therapy on N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP)‐induced chemotaxis and superoxide (O −2) production in neutrophils from four patients with aplastic anaemia. The FMLP‐induced chemotaxis and O −2 production in the neutrophils of all four patients were normal before the rhG‐CSF treatment. After the administration of high‐dose rhG‐CSF, chemotaxis in agarose was decreased, adherence and O −2 production were enhanced in all the patients. An excessive increase of neutrophils with augmented adhesiveness and oxygen radical production may be harmful. Care should be taken in regard to neutrophil toxicity when high‐dose G‐CSF is used clinically.

Monocyte Chemotaxis in Primary Immunodeficiency Syndrome

We studied monocyte chemotaxis in children with various types of primary immunodeficiency syndrome. The clinical and immunologic features of the patients with defective monocyte chemotaxis were then analyzed. Monocyte chemotaxis was defective in two patients with a monocyte disorder characterized by chronic candidiasis, absence of delayed‐type hypersensitivity, and normal T cell functions. Monocyte chemotaxis was also impaired in a patient with Chédiak‐Higashi syndrome, and in two of six patients with hyper‐IgE syndrome. Major infections in the patients with defective neutrophil chemotaxis but normal monocyte chemotaxis included recurrent pyogenic infections such as otitis media, superficial abscess, lymphadenitis and pneumonia. On the other hand, the clinical features of the patients with defective monocyte chemotaxis were characterized by chronic candidiasis. Delayed‐type hypersensitivity was negative in all of the patients in whom monocyte chemotaxis was defective, despite the absence of apparent T cell dysfunctions. These results demonstrated that there is defective monocyte chemotaxis in some types of primary immunodeficiency syndrome. The monocyte chemotaxis defect is probably responsible for candidiasis and related to the absence of delayed‐type hypersensitivity.