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PubMed1985

A monoclonal antibody-defined membrane antigen complex is required for neutrophil-neutrophil aggregation.

We examined the aggregation responses of normal neutrophils treated with the murine monoclonal antibody (MoAb) 60.3. Addition of MoAb 60.3 to normal neutrophils produced dose-dependent inhibition of neutrophil aggregation in response to phorbol myristate acetate, zymosan-activated plasma, and N-formyl-methionylleucylphenylalanine. We conclude that the membrane glycoprotein complex recognized by MoAb 60.3--designated CDw18--is required for neutrophil-neutrophil aggregation in vitro.

Antibodies, Monoclonal↗

PubMed1981

A novel protein of rat neutrophils (NDP): its use in estimating the neutrophil content of solid tissues.

A protein has been isolated from rat neutrophils which does not appear to be present in other rat cells. This protein, which we have called neutrophil-derived protein or NDP, is confined to the cytosol of the cell and we estimate that it constitutes at least 6% of the total protein of the neutrophil. The native molecule is a cationic protein (pI approximately 9) of mol. wt 34-36,000 daltons that on SDS-PAGE yields two subunits of 10,000 and 13,000 daltons. The NDP does not bind lectins, is protease-resistant and strongly antigenic in the rabbit. Its behaviour on electrophoresis in agar and agarose show unusual features which may be relevant to other cationic proteins. NDP does not appear to correspond to any of the hitherto characterized neutrophil proteins and the only activity so far detected is a reaction of the protein with rat plasma (but not serum). Using simple immunological methods we have determined the concentration of NDP in various tissues of the rat to obtain an estimate of their neutrophil content. In addition, the NDP content in various body fluids has been determined. A similar protein to the rat NDP has been detected in the mouse.

Animals↗

PubMed1995

Results of a phase I/II trial of recombinant human granulocyte-macrophage colony-stimulating factor in very low birthweight neonates: significant induction of circulatory neutrophils, monocytes, platelets, and bone marrow neutrophils.

Neonates, especially those of very low birthweight (VLBW), have an increased risk of nosocomial infections secondary to deficiencies in development. We previously demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) production and mRNA expression from stimulated neonatal mononuclear cells are significantly less than that from adult cells. Recombinant murine GM-CSF administration to neonatal rats has resulted in neutrophilia, increased neutrophil production, and increased survival of pups during experimental Staphylococcus aureus sepsis. In the present study, we sought to determine the safety and biologic response of recombinant human (rhu) GM-CSF in VLBW neonates. Twenty VLBW neonates (500 to 1,500 g), aged < 72 hours, were randomized to receive either placebo (n = 5) or rhuGM-CSF at 5.0 micrograms/kg once per day (n = 5), 5.0 micrograms/kg twice per day (n = 5), or 10 micrograms/kg once per day (n = 5) given via 2-hour intravenous infusion for 7 days. Complete blood counts, differential, and platelet counts were obtained, and tibial bone marrow aspirate was performed on day 8. Neutrophil C3bi receptor expression was measured at 0 and 24 hours. GM-CSF levels were measured by a sandwich enzyme-linked immunosorbent assay at 2, 4, 6, 12, and 24 hours after the first dose of rhuGM-CSF. At all doses, rhuGM-CSF was well tolerated, and there was no evidence of grade III or IV toxicity. Within 48 hours of administration, there was a significant increase in the circulating absolute neutrophil count (ANC) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day, which continued for at least 24 hours after discontinuation of rhuGM-CSF. When the ANC was normalized for each patient's first ANC, there was a significant increase in the ANC on days 6 and 7 at each dose level. By day 7, all tested doses of rhuGM-CSF resulted in an increase in the absolute monocyte count (AMC) compared with placebo-treated neonates. In those receiving rhuGM-CSF 5.0 micrograms/kg twice per day, there was additionally a significant increase in the day 7 and 8 platelet count. Tibial bone marrow aspirates demonstrated a significant increase in the bone marrow neutrophil storage pool (BM NSP) at 5.0 micrograms/kg twice per day and 10.0 micrograms/kg once per day. Neutrophil C3bi receptor expression was significantly increased 24 hours after the first dose of rhuGM-CSF at 5.0 micrograms/kg once per day. The elimination half-life (T1/2) of rhuGM-CSF was 1.4 +/- 0.8 to 3.9 +/- 2.8 hours.(ABSTRACT TRUNCATED AT 400 WORDS)

Birth Weight↗

PubMed1994

Identification of neutrophil gelatinase-associated lipocalin as a novel matrix protein of specific granules in human neutrophils.

Neutrophil gelatinase-associated lipocalin (NGAL) is a novel 25-kD protein of human neutrophils, that is in part covalently complexed with neutrophil gelatinase. However, both NGAL and gelatinase exist mainly in forms not associated with each other. An explanation for this phenomenon might be that the unassociated proteins reside in different subcellular compartments. The aim of the present study was to determine the subcellular localization of NGAL. An enzyme-linked immunosorbent assay (ELISA) for NGAL was developed using specific anti-NGAL antibodies. The assay was applied on subcellular fractions of neutrophils obtained after centrifugation of a postnuclear supernatant on a two-layer Percoll gradient. The distribution profile of NGAL was found to colocalize strictly with the distribution profile of lactoferrin. This was confirmed by immunogold double-labeling of frozen thin sections of neutrophils that showed a high degree of colocalization of NGAL and lactoferrin, and by exocytosis experiments, which showed lactoferrin, vitamin B12-binding protein, and NGAL to be similarly released upon stimulation. Therefore, NGAL is a novel matrix protein of specific granules and thus partly segregated from gelatinase, the major part of which is located in a separate compartment, the gelatinase granules. An ELISA specific for the NGAL/gelatinase complex was developed and the subcellular distribution and release of this complex was determined. The distribution and mobilization of the complex allowed us to confirm the existence of differentially mobilized granule subpopulations among peroxidase negative granules.

Acute-Phase Proteins↗

PubMed1993

Protein kinases potentially capable of catalyzing the phosphorylation of p47-phox in normal neutrophils and neutrophils of patients with chronic granulomatous disease.

A procedure for uncovering novel protein kinases was used to search for enzymes in neutrophils that may catalyze the phosphorylation of the 47-Kd subunit of the NADPH oxidase system (p47-phox). This component of the oxidase can undergo phosphorylation on multiple sites. The method is based on the ability of renatured kinases to recognize exogenous substrates fixed in gels. We report that neutrophils contain several uncharacterized protein kinases that catalyze the phosphorylation of a peptide substrate that corresponds to amino acid residues 297 through 331 of p47-phox. Some of these enzymes are strongly activated on stimulation of the cells with phorbol 12-myristate 13-acetate (PMA). The results indicate that the phosphorylation of p47-phox in neutrophils may be more complicated than previously appreciated and may involve multiple protein kinases. In addition, we have examined both the renaturable protein kinases and the properties of protein kinase C (PKC) in neutrophils from patients with chronic granulomatous disease (CGD) who are deficient in cytochrome b558. Previous studies have shown that these cells exhibit incomplete phosphorylation of p47-phox on stimulation. In this study, we were unable to detect any alterations in the renaturable protein kinases or PKC in CGD neutrophils that could explain these defects in the phosphorylation of p47-phox.

Amino Acid Sequence↗

PubMed1993

Cross-linking of human neutrophil surface proteins to iodinated interleukin 8 or neutrophil activating peptide-2 results in at least four separable proteins.

The human neutrophil activating peptides-1 and -2 (NAP-1/IL-8, NAP-2) are two structurally and functionally related members of the chemokine cytokine family. They are chemoattractants and activators of neutrophils and exert their effects by binding to specific receptors which are expressed on responsive cells. Two closely related IL-8 receptors of neutrophils have been characterized recently by molecular cloning. We show here that NAP-1/IL-8 and NAP-2 can be cross-linked to at least four protein bands from human neutrophil surfaces with apparent molecular masses of 55, 65, 71 and 81 kDa. The two cross-linked proteins with lower masses were associated with high, the two with the higher masses with low affinity binding of NAP-2, NAP-1/IL-8 was bound to all bands with high affinity. NAP-1/IL-8 and NAP-2 could also be cross-linked to form dimers when bound to cells and in solution. Our results show that more than two NAP-1/IL-8 receptors, or more than two forms of the known receptors exist. Alternatively, the four protein bands can be explained by cross-linking of ligand monomers and dimers, respectively, to the known receptors of neutrophils.

Cross-Linking Reagents↗

PubMed2002

Novel neutrophil elastase inhibitors as a treatment for neutrophil-predominant inflammatory lung diseases.

Acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are progressive and frequently fatal disorders, which have, at present, few effective therapeutic methods. The pathogenesis of these lung diseases is characterized by a neutrophil-predominant inflammation associated with excessive release of neutrophil proteases, including neutrophil elastase (NE), a terminal pulmonary tissue destroyer. Although precise pathogenic mechanisms have been under debate, the NE-mediated severe pulmonary tissue damage, based upon the protease-antiprotease imbalance hypothesis, may be a major pathogenic determinant of these diseases, in particular COPD. Novel aggressive therapeutic approaches to these lung disorders are required, and prevention of NE release may be considered as a promising strategy for disease outcome. This review mainly focuses upon the pathogenic contribution of NE to these neutrophil-predominant inflammatory lung diseases, and evaluates the experimental and clinical efficacies of the two-types of appropriate small molecular weight human neutrophil elastase (HNE) inhibitors: acyl-enzyme inhibitors and transition-state inhibitors. While much progress has been made in the investigation of these disorders and the contribution of HNE inhibitors, several fundamental questions remain to be answered, and so further studies are required.

Journal Article↗

PubMed1995

CD66-dependent neutrophil activation: a possible mechanism for vascular selectin-mediated regulation of neutrophil adhesion.

We have examined the role of CD66 in the modulation of neutrophil adhesion and effector function. Engagement of neutrophil CD66 with anti-carcinoembryonic antigen (anti-CEA) Ig results in activation-associated phenomena including shape change, activation of beta 2-integrins, and priming of the respiratory burst. Anti-CEA Ig-treated neutrophils underwent transient shape change distinct from that induced by formyl-Met-Leu-Phe (fMLP). fMLP stimulated beta 2-integrin up-regulation and 70% loss of L-selectin, whereas only low-level up-regulation of the beta 2-integrins, without loss of L-selectin, occurred with anti-CEA Ig. Anti-CEA F(ab')2 fragments and whole Ig augmented beta 2-integrin-dependent adhesion. Anti-CEA Ig-induced beta 2-integrin activation was transient, whereas fMLP-induced activation persisted longer. Although they did not cause a significant increase in respiratory burst activity, CEA Ig and F(ab')2 fragments of antibody primed neutrophils so that the subsequent fMLP-induced respiratory burst was significantly increased.

Amino Acid Sequence↗

PubMed1993

Neutrophilic dermatosis associated with chronic neutrophilic leukemia.

Chronic neutrophilic leukemia is an uncommon myeloproliferative disorder. We report a new case that fulfills the clinical and biologic criteria for such a diagnosis. The hematologic disease was revealed by a neutrophilic dermatosis that finally disappeared spontaneously after a duration of 1 year. Despite the lack of parallelism in the course of dermatologic and hematologic manifestations, we believe they were strongly linked. Occurrence of neutrophilic dermatoses in the course of other myeloproliferative disorders is well known. However, in our case, clinical and histologic features could not be used to distinguish between atypical Sweet's syndrome and specific cutaneous lesions because of the mature appearance of both skin and blood neutrophils.

Aged↗

PubMed2005

Albumin attenuates neutrophil activation induced by stimulators including antibodies against neutrophil-specific antigens.

As neutrophil activation is related to several adverse transfusion reactions, we studied about the activation induced by anti-neutrophil antibodies and the stabilizing effects of albumin pretreatment by means of flow cytometry. Anti-neutrophil monoclonal antibody (anti-HNA-1a, 1b, 2a) alone induced CD11b expression and shedding of L-selectin, and anti-HNA-1a reinforced reactive oxygen species (ROS) production. Albumin pretreatment significantly reduced CD11b expression and L-selectin shedding induced by fMLP and ROS production induced by PMA, G-CSF combined with PMA or LPS-fMLP, or anti-HNA-1a combined with PMA. These findings suggest that anti-HNA-1a is related to adverse reactions and albumin has a regulating effect on neutrophil activation.

Antibodies, Monoclonal↗

PubMed1998

Demonstration of clonality in neutrophils using FISH in a case of chronic neutrophilic leukemia.

A patient previously diagnosed with chronic neutrophilic leukemia (CNL) was studied using fluorescent in situ hybridization (FISH) to determine clonality of neutrophils. By cytogenetic studies the patient's blood and bone marrow had an 11q14 deletion and were negative for the Philadelphia (Ph) chromosome. FISH was performed on peripheral blood smears using probes for the bcr/abl translocation and a probe for 11q23 (MLL). The patient's white blood cells were negative for the bcr/abl translocation; neutrophils and eosinophils, but not lymphocytes, were monosomic for the 11q23 probe indicating a clonal population within the neutrophil population.

Chromosomes, Human, Pair 11↗

PubMed2004

Granule localization of glutaminase in human neutrophils and the consequence of glutamine utilization for neutrophil activity.

The provision of glutamine in vivo has been observed to reduce to normal levels the neutrophilia observed after exhaustive exercise and to decrease the neutrophil chemoattractant, interleukin-8. Thus, the role for glutamine in the regulation of inflammatory mediators of human neutrophil activation was investigated. The study sought to establish whether glutamine supplementation in vitro affects neutrophil function at rest and whether glutaminase, the major enzyme that metabolizes glutamine, is present in human polymorphonuclear neutrophils (PMN). During in vitro studies, the addition of 2 mm glutamine increased the respiratory burst of human PMN stimulated with both phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine. These observations were made using a highly sensitive, real time chemiluminescent probe, Pholasin. Glutamine alone did not stimulate the release of reactive oxygen species. In a novel finding using glutaminase-specific antibodies in combination with flow cytometry and confocal microscopy, glutaminase was shown to be present on the surface of human PMN. Subcellular fractionation revealed that the enzyme was enriched in the secondary granules and could be released into cell culture medium upon stimulation with PMA. In conclusion, human PMN appeared to utilize glutamine and possess the appropriate glutaminase enzyme for metabolizing glutamine. This may depress some pro-inflammatory factors that occur during prolonged, exhaustive exercise.

Cytoplasmic Granules↗

PubMed1992

Neutrophil function in chronic neutrophilic leukemia: defective respiratory burst in response to phorbol esters.

Functional analyses were performed on neutrophils isolated from 6 patients from two institutions who displayed features of chronic neutrophilic leukemia (CNL). These neutrophils demonstrated a consistent deficiency (44 +/- 8% of control values) in superoxide anion (O2-) production in response to the phorbol ester, phorbol myristate acetate (PMA). O2- production in response to chemotactic peptides was near normal (82.3 +/- 10.7% of control values). Bacterial killing was normal in the two patients studied, and chemotaxis was diminished in response to zymosan-activated plasma and to high concentrations of chemotactic peptides in the patients studied. Cytosolic C kinase activity was decreased in one of the two patients studied. These results suggest that a deficient O2- release in response to PMA is a hallmark of neutrophils in CNL and may provide a diagnostic indicator of this condition.

Aged↗

PubMed2003

TNF-alpha induces phosphorylation of p47(phox) in human neutrophils: partial phosphorylation of p47phox is a common event of priming of human neutrophils by TNF-alpha and granulocyte-macrophage colony-stimulating factor.

Phosphorylation of p47(phox) is a key event in NADPH oxidase activation. We examined the ability of proinflammatory cytokines such as TNFalpha, IL-1, and G-CSF to induce this process compared with GM-CSF. Only TNF-alpha and GM-CSF induced a clear p47(phox) phosphorylation. This phosphorylation was time dependent and reached its maximum at 20 min. Two-dimensional phosphopeptide mapping of p47(phox) phosphorylated in neutrophils primed with TNF-alpha revealed partial phosphorylation of p47(phox) on the same peptide as for GM-CSF. Neutrophil incubation with TNF-alpha and subsequent addition of the chemotactic peptide fMLP resulted in more intense phosphorylation of p47(phox) sites than with each reagent alone. A neutralizing Ab against the p55 TNF receptor, contrary to a neutralizing Ab against the p75 TNF receptor, inhibited TNF-alpha-induced p47(phox) phosphorylation. Neutrophil treatment with both TNF-alpha and GM-CSF resulted in more intense phosphorylation of the same p47(phox) peptide observed with each cytokine alone, suggesting that they engaged pathways converging on common serines. This additive effect was also obtained on the priming of NADPH oxidase activity. The use of protein kinase inhibitors pointed to the involvement of a protein tyrosine kinase, but not protein kinase C. These findings show that TNF-alpha, via its p55 receptor, induces a protein tyrosine kinase-dependent selective phosphorylation of p47(phox) on specific serines. The ability of TNF-alpha and GM-CSF, two different cytokines with two different receptors to induce this specific p47(phox) phosphorylation, suggests that this event could be a common element of the priming of neutrophils by TNF-alpha and GM-CSF.

Adjuvants, Immunologic↗

PubMed1989

[Neutrophil dysfunction in chronic neutrophilic leukemia without rearrangements of bcr and immunoglobulin heavy chain genes].

A 67-year-old man was admitted to our hospital with abdominal distension due to hepatosplenomegaly. The peripheral blood revealed Hb content 6.5 g/dl, platelet count 4.7 x 10(4)/microliter, and WBC count 105.8 x 10(3)/microliter with 88% of mature neutrophils. The neutrophil alkaline phosphatase score was 421. Bone marrow aspiration revealed hypercellularity with increased megakaryocytes and myeloid hyperplasia. 46, XY, del 20(q 11) without Philadelphia chromosome was identified by cytogenetic study. The patient was diagnosed as having chronic neutrophilic leukemia and was successfully treated with busulfan, but he died of atypical mycobacteriosis about 20 months later. Analysis of neutrophil function demonstrated diminution of deformability, random mobility, and chemotaxis, but almost normal phagocytosis and bactericidal capacity. Southern analysis showed no rearrangements of breakpoint cluster region (bcr) gene and immunoglobulin heavy chain gene.

Aged↗

PubMed1997

Erythromycin A-derived macrolides modify the functional activities of human neutrophils by altering the phospholipase D-phosphatidate phosphohydrolase transduction pathway: L-cladinose is involved both in alterations of neutrophil functions and modulation of this transductional pathway.

All erythromycin A derivatives, irrespective of the size of the lactone ring and the nature of the substituent, inhibit oxidant production by neutrophils and promote their degranulation. We demonstrate in this study that the L-cladinose at position 3 of the lactone ring is a key structure in the modulation of these two neutrophil functions, suggesting that this sugar (alone or combined with a lactone structure) interferes with cell target(s) involved in both oxidant production and exocytosis. Taking roxithromycin as an example of erythromycin A derivatives, we also found that these molecules interfered with the phospholipase D (PLD)-phosphatidate phosphohydrolase pathway in two ways. In nonstimulated neutrophils, roxithromycin and all L-cladinose-bearing molecules activated PLD, as reflected by 1-O-[3H]alkyl-2-acyl-phosphatidyl-ethanol production. In addition, these drugs induced an accumulation of 1-O-[3H]alkyl-2-acyl-phosphatidic acid (PA), but not 1-O-[3H]alkyl-2-acylglycerol. PA accumulation seems to be involved in the induction of exocytosis by macrolides, as the roxithromycin-induced release of granular enzymes was impaired strongly in the presence of ethanol. By contrast, in stimulated neutrophils, roxithromycin inhibited PLD activity and totally impaired 1-O-[3H]alkyl-2-acylglycerol production. The inhibition of diglyceride production by roxithromycin (not its descladinosyl derivative) could explain its inhibitory effect on oxidant production. The relevance of our data to the clinical situation, particularly the anti-inflammatory activity of these drugs, requires further investigation.

Diglycerides↗

PubMed1980

Intrinsic neutrophil defects in a child with impaired neutrophil chemotaxis and immunodeficiency.

A boy with recurrent pyogenic infection was found to have occasional neutropenia, defective neutrophil chemotaxis, hypogammaglobulinemia with increased IgM, and impaired cellular immunity. The T and B lymphocytes were defective in IgG production in vitro. Ultrastructure of the neutrophils was normal. The marrow cells formed normal numbers of granulocytic colonies in culture, but the colonies were apparently small in size. The levels of colony-stimulating activity were normal. The lymphocytes did not impair granulopoiesis of control marrow cells. These data indicate that the neutropenia and defective neutrophil chemotaxis are due to the intrinsic neutrophil defects and are not secondary to T and/or B lymphocyte dysfunctions in the patient.

Agammaglobulinemia↗

PubMed1989

Both recombinant interleukin-1 (beta) and purified human monocyte interleukin-1 prime human neutrophils for increased oxidative activity and promote neutrophil spreading.

Both purified human monocyte interleukin-1 and recombinant interleukin-1 (beta) primed neutrophils for increased superoxide production and chemiluminescence in response to f-met-leu-phe. In addition, purified human monocyte interleukin-1 and recombinant interleukin-1 (beta) altered neutrophil shape. Recombinant interleukin-1 (alpha) used at the same concentration of interleukin-1 (beta) did not prime neutrophils for increased superoxide production after stimulation with f-met-leu-phe. Interleukin-1 expressed by monocytes in response to endotoxin stimulation could act as a modulator of neutrophil function.

Humans↗