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PubMed1990

Evidence that a receptor-operated event on the neutrophil mediates neutrophil accumulation in vivo. Pretreatment of 111In-neutrophils with pertussis toxin in vitro inhibits their accumulation in vivo.

The role of neutrophil chemoattractant receptors in neutrophil stimulation in vitro is well established, however, the precise mechanisms underlying local neutrophil accumulation at inflammatory sites in vivo have not been defined. A fundamental question that remains open is whether chemoattractants act on the endothelial cell or the neutrophil to initiate the process of neutrophil migration in vivo. To address this question we have investigated whether neutrophil accumulation in vivo can occur if chemoattractant receptor occupancy is uncoupled from neutrophil stimulation. For this purpose we have used pertussis toxin (PT) as the pharmacologic tool. We have investigated the effect of in vitro pretreatment of rabbit neutrophils with PT on their responses in vitro and on their accumulation in vivo. Pretreatment of rabbit neutrophils with PT inhibited FMLP- and C5a-, but not PMA- induced increases in CD18 expression, neutrophil adherence, and degranulation in vitro. This pretreatment procedure with PT inhibited the accumulation of radiolabeled neutrophils in vivo in response to intradermally injected FMLP, C5a, C5a des Arg, leukotriene B4, IL-8, and zymosan in rabbit skin. Further, in contrast to the in vitro results, PT inhibited the PMA-induced 111In-neutrophil accumulation in vivo. Interestingly, pretreatment of neutrophils with PT also inhibited accumulation in response to intradermally injected IL-1, despite the reports that IL-1 lacks neutrophil chemoattractant activity in vitro. Although the experimental techniques used cannot distinguish the different stages of neutrophil migration involved, these results suggest that the accumulation of neutrophils induced by local extravascular chemoattractants in vivo depends on a pertussis toxin-sensitive receptor operated event on the neutrophil itself. Further, PMA and IL-1 may release secondary chemoattractants in vivo.

Animals↗

PubMed1997

Characterization of elevated neutrophil-associated IgG in various autoimmune disorders: not anti-neutrophil autoantibodies, but possibly immune complexes, bind to neutrophils.

Neutropenia is frequently observed in a variety of autoimmune disorders. As the mechanism of neutropenia in these disorders, the destruction of neutrophils by anti-neutrophil autoantibodies has been believed since elevated levels of neutrophil-associated IgG (NAIgG) have been described. However, no data exists to characterize the nature of NAIgG and show NAIgG is an anti-neutrophil autoantibodies. We investigated whether the elevated NAIgG in these patients consists of anti-neutrophil autoantibodies. The NAIgGs of 91 patients with autoimmune disorders including 50 patients with idiopathic thrombocytopenic purpura, 13 patients with systemic lupus erythematosus, 11 patients with Hashimoto's thyroiditis and 10 patients with Graves' disease were analyzed. The level of NAIgG was high in 36 of 91 patients. Elution studies were performed to determine whether NAIgG has a nature of autoantibodies. In model experiments, the ether eluate from neutrophils sensitized with neutrophil-specific alloantibody (anti-NA2) reacted with donor neutrophils, whereas the eluates from those with model immune complexes (ICs) failed. These data indicated that the ether elution technique is useful to determine whether NAIgG consists of anti-neutrophil autoantibodies. The NAIgG on patient's neutrophils was eluted with ether and the reactivity of the eluate with normal neutrophils was investigated. The eluates from 34 of 36 patients with various autoimmune disorders with elevated NAIgG level failed to react with donor neutrophils. These data indicated that the elevated NAIgG in the majority of these patients did not consist of anti-neutrophil autoantibodies, but possibly of ICs.

Antigen-Antibody Complex↗

PubMed1987

Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysaccharide and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung.

The pathogenesis of acute lung injury in humans is obscure, but lipopolysaccharide (LPS), complement activation, and neutrophils have been implicated. We investigated in rabbits the interaction of small amounts of intravascularly administered LPS (100 ng) with neutrophil chemotactic factors, the synthetic chemotactic peptide formyl-norleucyl-leucyl-phenylalanine (FNLP), and the biologically relevant chemotactic fragments of C5 (C5f). These neutrophil stimuli produce neutropenia when injected intravascularly in rabbits, reflecting neutrophil adherence to vascular endothelium. When LPS was injected with FNLP, the duration of neutropenia was enhanced. Studies with radiolabeled neutrophils infused in vivo demonstrated prolonged neutrophil sequestration within the lung in rabbits that were given FNLP plus LPS, an effect that was visible for 4 h after injection. Morphometric analysis of tissue sections 4 h after infusion confirmed the presence of greater numbers of neutrophils in the lungs of animals receiving LPS and FNLP. When a combination of LPS and chemotactic factors was infused at both zero and 6 h, we found a marked enhancement of lung vascular permeability at 24 h (as assessed by radiolabeled albumin accumulation), an effect not seen with either LPS or chemotactic factor alone. Ultrastructural studies revealed neutrophil sequestration and alteration in endothelial cells in the animals that received the combination of LPS and chemotactic factors. Neutrophil depletion with nitrogen mustard completely abolished the increased vascular permeability seen in animals that received LPS and chemotactic factors. This study suggests that small amounts of intravascularly administered LPS enhance the sequestration of neutrophils within the lung and increase lung vascular permeability and endothelial injury caused by neutrophils stimulated by intravascularly administered chemotactic factors. This mechanism may be relevant to the production of acute lung injury in human beings.

Albumins↗

PubMed1992

An antibody that binds a neutrophil membrane protein, ERp72, primes human neutrophils for enhanced oxidative metabolism in response to formyl-methionyl-leucyl-phenylalanine. Implications for ERp72 in the signal transduction pathway for neutrophil priming.

Human neutrophils are primed by cytokines for enhanced oxidative metabolism in response to chemotactic factors, but the signal transduction pathways for cytokine activation and priming are unknown. Neutrophil priming may play an important role in mechanisms of host defense and inflammatory responses associated with autoimmune diseases. A rabbit antibody was produced that reacted with human neutrophils and induced priming in response to the chemoattractant, FMLP. The protein responsible for neutrophil priming in response to binding antibody was identified in a neutrophil cDNA library by expression cloning. The cloned protein absorbed the neutrophil-priming activity from rabbit serum. Furthermore, antibody priming activity was recovered by elution from the cloned protein. The gene for the protein associated with neutrophil priming was sequenced and identified as the endoplasmic reticulum protein, ERp72, which contains three copies of the active site sequences of protein disulfide isomerase. The antibody that primed neutrophils was shown to bind ERp72 in neutrophil membranes by immunoprecipitation of the same 72-kDa protein from neutrophils as a known antibody to ERp72. These studies implicate ERp72 in the signal transduction pathway for priming human neutrophils.

Amino Acid Sequence↗

PubMed1996

Biomaterial-neutrophil interactions: dysregulation of oxidative functions of fresh neutrophils induced by prior neutrophil-biomaterial interaction.

Biomaterial-associated infection results in increased morbidity and mortality, and may occur because of nonproductive premature activation of neutrophils resulting in impaired phagocyte function at the biomaterial surface in the event of bacterial challenge. To further explore the effects of this premature activation, we evaluated the supernatants of biomaterial associated neutrophils to determine whether soluble mediators were released, and the likely role of these mediators. We show that these supernatants contain a chemoattractant and thereby induce chemotaxis by fresh neutrophils. No evidence of enhanced oxidative free radical production by either unstimulated neutrophils or a primed response to other mediators occurs when neutrophils were incubated with these supernatants. We also examined the effect of adding fresh neutrophils to a biomaterial surface containing a previous inoculum of neutrophils, and observed that the fresh cells did not become stimulated to release reactive oxygen intermediates (ROI) and also exhibited impaired killing of staphylococci. These studies suggest that not only does the biomaterial surface activate the initial wave of neutrophils but that subsequent waves of neutrophils exhibit an impaired host-defense function. These results are consistent with the known impairment of host defense in the presence of biomaterials, and provide evidence for a long-term down-regulation of neutrophil function at biomaterial surfaces.

Biocompatible Materials↗

PubMed1998

Cytomegalovirus-infected endothelial cells recruit neutrophils by the secretion of C-X-C chemokines and transmit virus by direct neutrophil-endothelial cell contact and during neutrophil transendothelial migration.

Infection of endothelial cells with an endothelial cell-tropic clinical isolate of cytomegalovirus (CMV), C1FE, induced enhanced production of the neutrophil chemoattractant C-X-C chemokines interleukin-8 and GROalpha. Infected endothelial cell supernatants induced neutrophil chemotaxis in a transendothelial migration assay. Neutrophils acquired the CMV structural protein pp65 following either coculture with infected endothelial cells or transmigration through infected endothelium. The lack of CMV p72 expression in the neutrophils indicated that viral replication had not occurred in these cells. Of importance, neutrophils acquired infectious CMV during transmigration across infected endothelium and were subsequently able to transmit infectious virus to fibroblasts. Thus, CMV-infected endothelial cells can recruit neutrophils by the secretion of C-X-C chemokines and can transmit the virus to them by direct cell-to-cell contact and during neutrophil transendothelial migration, suggesting that the neutrophil-endothelial cell interaction plays an important role in virus dissemination in vivo.

Cell Communication↗

PubMed1991

Neutrophil-activating peptide 2 and gro/melanoma growth-stimulatory activity interact with neutrophil-activating peptide 1/interleukin 8 receptors on human neutrophils.

Neutrophil-activating peptide 1/interleukin 8 (NAP-1/IL-8), neutrophil-activating peptide 2 (NAP-2), and gro/melanoma growth-stimulatory activity (gro/MGSA) are potent inflammatory cytokines with homologous structure and similar neutrophil-activating properties. Receptors on human neutrophils that interact with these peptides were studied. Analysis of 125I-NAP-1/IL-8 binding at 0-4 degrees C revealed 64,500 +/- 14,000 receptors/cell with an apparent Kd of 0.18 +/- 0.07 nM (mean +/- S.D. of six independent experiments). Unlabeled NAP-1/IL-8, NAP-2, and gro/MGSA competed with 125I-NAP-1/IL-8 for binding to human neutrophils. Competition with increasing concentrations of unlabeled NAP-2 and gro/MGSA resolved two classes of NAP-1/IL-8 binding sites: about 70% of them bound NAP-2 and gro/MGSA with high affinity (Kd: 0.34 +/- 0.2 and 0.14 +/- 0.02), while 30% were of low affinity (Kd: 100 +/- 20 and 130 +/- 10 nM). Different binding sites, however, were not apparent upon competition with unlabeled NAP-1/IL-8, suggesting that both classes of receptors have similar affinities for NAP-1/IL-8. The existence of two receptors was also suggested by ligand cross-linking and cross-desensitization experiments. Two neutrophil membrane proteins with apparent Mr of 66,000-74,000 and 42,000-46,000 became cross-linked to 125I-NAP-1/IL-8, and the labeling was decreased when excess NAP-1/IL-8, NAP-2, or gro/MGSA was present. Stimulation of neutrophils with NAP-1/IL-8 resulted in desensitization toward a subsequent challenge with NAP-2 or gro/MGSA as shown by the rise in cytosolic free calcium. By contrast, following primary stimulation with NAP-2 or gro/MGSA, responses to NAP-1/IL-8 were only moderately attenuated, supporting the existence of NAP-1/IL-8 receptors which bind NAP-2 or gro/MGSA with low affinity. In conclusion, our results demonstrate that NAP-2 and gro/MGSA act upon human neutrophils by directly interacting with two classes of receptors for NAP-1/IL-8.

Amino Acid Sequence↗

PubMed1986

Phospholipid metabolism in human neutrophils activated by N-formyl-methionyl-leucyl-phenylalanine. Degranulation is not required for release of arachidonic acid: studies with neutrophils and neutrophil-derived cytoplasts.

Neutrophils respond to chemoattractants by aggregating, degranulating, remodelling of phospholipids and releasing arachidonic acid. To determine whether ligand-induced remodelling of phospholipids depends on redistribution of intracellular organelles (degranulation), we compared phospholipid remodelling of human neutrophils with that of neutrophil-derived cytoplasts. Cytoplasts, organelle-depleted vesicles of cytosol surrounded by plasmalemma, cannot degranulate. Without a stimulus, [3H]arachidonate was incorporated preferentially into phosphatidylinositol (PI) and phosphatidylcholine (PC). Exposure of cytoplasts and neutrophils prelabelled with [3H]arachidonate or [14C]glycerol to fMet-Leu-Phe (10(-7) M) induced rapid changes in distribution of label and mass of individual phospholipids: [3H]arachidonate in phosphatidic acid (PA) increased 500% (120 s), [14C]glycerol incorporation and mass of PA approached 200% of unstimulated values, and [3H]arachidonate in PI decreased continuously; these data are compatible with activity of a PI/PA cycle. However, the mass of PI in both preparations and [14C]glycerol label in intact neutrophils increased initially (5 s), suggesting net synthesis and mobilization of more than one pool of PI. Heterogeneity of PC pools was also observed: [3H]arachidonate was lost from PC immediately upon addition of stimulus, whereas mass and [14C]glycerol values increased. Thus, net phospholipid synthesis, redistribution of arachidonate and activation of the PI/PA cycle are immediate responses of the neutrophil to receptor occupancy by chemoattractants. Furthermore, the similarity in response to fMet-Leu-Phe of neutrophils and granule-free cytoplasts indicates that these processes are independent of degranulation.

Arachidonic Acids↗

PubMed1990

Mutual influence between eosinophil peroxidase (EPO) and neutrophils: neutrophils reversibly inhibit EPO enzymatic activity and EPO increases neutrophil adhesiveness.

The effects of the interactions between eosinophil peroxidase (EPO) and neutrophils were studied. It is shown that binding of EPO to neutrophils results on the one hand in reversible inhibition of EPO peroxidase activity and, on the other, in an increased neutrophil aggregation and neutrophil adhesion to endothelial cell monolayers. After prolonged periods of exposure to EPO, neutrophils also show a decreased ability to exclude the vital dye erythrosin B. The reversible inhibition of EPO activity may represent a means of keeping under control the oxidative potential of EPO, while the increased neutrophil aggregation and adherence to endothelial cells suggest that EPO may influence at least two key events of inflammation, that is, the margination of neutrophils and/or their accumulation in the inflammatory site.

Cell Adhesion↗

PubMed1993

Effect of NPC 15669, an inhibitor of neutrophil recruitment and neutrophil-mediated inflammation, on neutrophil function in vitro.

The new anti-inflammatory agent N-[9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine (NPC 15669) inhibits inflammation in several animal models dependent upon neutrophil activation and recruitment into the inflammatory lesion. NPC 15669 appears to elicit its pharmacological action by inhibiting the cell surface expression of CD11b/CD18 (Mac-1) on the neutrophil and subsequent adhesion of the neutrophil to the vascular endothelium. The current study sought to further characterize the action of NPC 15669 on neutrophil function. In the range of 1-100 microM, this fluorene enhanced superoxide production in a concentration-dependent fashion. Using spin trapping/ESR spectroscopy, NPC 15669 was found to inhibit myeloperoxidase (MPO)-dependent hydroxyl radical primarily by scavenging hypochlorous acid, and secondarily by inhibiting agonist-stimulated degranulation as assessed by MPO and elastase release. These studies demonstrated that NPC 15669, in addition to inhibiting adhesion, alters other neutrophil functions. Whether the pharmacological activities described for NPC 15669 resulted directly from changes in Mac-1 expression or through some other mechanism is currently under investigation.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1994

Acute lung inflammation: neutrophil elastase versus neutrophils in the bronchoalveolar lavage--neutrophil elastase reflects better inflammatory intensity.

OBJECTIVE: To test the hypothesis whether PMN-Elastase in bronchoalveolar lavage fluid (BALF) could reflect neutrophil activity in the lower respiratory tract. DESIGN: Prospectively, morphologic findings of acute and chronic inflammation in the transbronchial lung biopsy specimens were compared with the numbers of neutrophils in the BALF and the concentration of PMN-Elastase in the same. SETTING: Ambulatory outpatient service of bronchology and respiratory physiopathology and intensive care unit of a communal hospital. PATIENTS: 50 ambulatory outpatients and 10 critically ill patients of the ICU, presenting infiltrative lung diseases. INTERVENTIONS: Transbronchial lung biopsies and bronchoalveolar lavage were performed through a fiberoptic bronchoscope. Venous blood samples were obtained after bronchoscopy. MEASUREMENTS AND RESULTS: Biopsy specimens and cell count in the BALF were examined by light microscopy. PMN-Elastase and albumin were measured in the BALF-supernatant and in the plasma. C-reactive protein (CRP) and a1 proteinase inhibitor (a1-PI) were measured in the plasma. Intrapulmonary originating PMN-Elastase was calculated with reference to albumin. The results concerning acute inflammation obtained by transbronchial lung biopsy (TBLB) (n = 16) correlated better with the levels of PMN-Elastase in the BALF (n = 21) than with the neutrophil count (n = 28) (p < 0.5 versus p < 0.025 for chi 2). The sensitivities and specificities of the above methods were respectively 76.9%, 100%, 100% and 100%, 95.2%, 63.1%. The intrapulmonary originating PMN-Elastase was about 99.7% of the measured BALF-Elastase. CONCLUSION: The PMN-Elastase concentration in the BALF is a more accurate indicator of the inflammatory intensity in the alveolar structures than in the number of neutrophils. It may therefore be useful to the clinician in his attempt to detect acute inflammation in the lower respiratory tract.

Acute Disease↗

PubMed1990

Temporal adaptation of human neutrophil metabolic responsiveness to the peptide formylmethionyl-leucyl phenylalanine: a comparison between human neutrophils and granule-depleted neutrophil cytoplasts.

When polymorphonuclear leukocytes (neutrophils) and soluble or particulate matter interact, the cells produce superoxide anions (O2-) and hydrogen peroxide (H2O2). The chemotactic peptide formylmethionyl-leucyl-phenylalanine (FMLP) induced a very weak response in normal neutrophils. The cellular response was changed, however, as a result of in vitro aging of the cells, i.e. the magnitude of the response was increased following storage of the cells at 22 degrees C for up to 120 min, in the absence of any stimulus, and before the addition of the peptide. When phorbol myristate acetate was used as a stimulus, there was a pronounced production of O2- and H2O2, but no change in magnitude as a result of in vitro aging. When neutrophil cytoplasts (granule-free vesicles of cytoplasm enclosed by plasmalemma) were exposed to the peptide FMLP of PMA, the vesicles produced both O2- and H2O2. There was, however, no increase in oxidative metabolite production in cytoplasts as a result of in vitro aging when either FMLP or PMA was used as a stimulus. The results thus indicate that mere incubation at room temperature primed the cells to increase their production of oxidative metabolites as a result of spontaneous exposure of hidden receptors. The fact that no such effects were observed with cytoplasts indicates that spontaneous receptor recruitment is a granule-dependent process.

Cell Degranulation↗

PubMed1985

The role of neutrophil membrane glycoprotein GP-150 in neutrophil adherence to endothelium in vitro.

We have previously described two patients with a congenital defect in neutrophil function characterized by an inability to form pus. The patients' neutrophils lack a membrane glycoprotein of mol wt 150,000 daltons (GP-150) on analysis by SDS-PAGE. This glycoprotein is part of a membrane antigen complex recognized by the murine monoclonal antibody (MoAb) 60.3. Addition of MoAb 60.3 to normal neutrophils produces defects in chemotaxis and phagocytosis in vitro similar to those observed in the patients. Since neutrophil adherence to vascular endothelium is prerequisite to neutrophil emigration in vivo, we examined the interaction of the patients' neutrophils and normal neutrophils treated with MoAb 60.3 with cultured endothelium. Adherence was determined as the percentage of 51Cr-labeled purified peripheral blood neutrophils which remained adherent to plastic wells or endothelial monolayers after a 45-minute incubation at 37 degrees C. The percentage of neutrophils from patient 1 remaining adherent to uncoated, fibronectin-coated, or laminin-coated plastic was similar to that observed in normal neutrophils (55% to 84% adherence with normal neutrophils v 73% to 78% adherence with the patient's neutrophils and 63% to 82% adherence with MoAb 60.3-treated normal neutrophils). The adherence of the neutrophils from patient 1 and MoAb 60.3-treated normal neutrophils to human or bovine endothelium in serum-free medium was also not significantly different from that observed in normal neutrophils (less than 10% adherence with normal, MoAb 60.3-treated, and patient neutrophils). In medium containing 10% autologous or heterologous human plasma, however, the adherence of neutrophils from patient 1 or MoAb 60.3-treated normal neutrophils to endothelial monolayers was significantly reduced (35% +/- 7% of normal neutrophils in seven experiments). Although phorbol myristate acetate (PMA) (10 ng/mL) and calcium ionophore A23187 (10(-5) mol/L) markedly increased the adherence of normal neutrophils to endothelial monolayers in serum-free medium (40% to 85% adherence), neither agent increased the adherence of the neutrophils from patient 1 or normal neutrophils treated with MoAb 60.3 (less than 5% adherence). The adherence of PMA-activated neutrophils from patient 2 to endothelial monolayers was also markedly decreased when compared with that of normal neutrophils. Postsecretory cell-free supernatants from PMA-activated normal neutrophils failed to augment adherence of neutrophils from patient 1 (less than 5% adherence).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Difference in hydrogen peroxide release between human neutrophils and neutrophil cytoplasts following calcium ionophore activation. A role of the subcellular granule in activation of the NADPH-oxidase in human neutrophils?

The role of subcellular granule in the capacity to generate reactive oxygen metabolites in human granulocytes was studied using normal cells and organell-free neutrophil cytoplasts. The cytoplasts are devoid of granules but have an intact ligand-receptor coupling mechanism. Both the chemotactic peptide formylmethionylleucylphenylalanine (FMLP) and the ionophore ionomycin induced a chemiluminescence response in normal cells, but only FMLP stimulation was associated with any notable hydrogen peroxide production. However, in the presence of azide, a potent inhibitor of the hydrogen peroxide-consuming enzymes, catalase and myeloperoxidase, a pronounced release of hydrogen peroxide was also induced by ionomycin. The response of cytoplasts to FMLP proceeded with a rate and time-course similar to those seen in intact cells, whereas in response to ionomycin they produced very low quantities of hydrogen peroxide, even in the presence of azide. Analysis of the data presented in this study leads to the following conclusion: (i) FMLP, which acts through cell surface receptors, causes the cells to produce oxygen metabolites, which, to a large extent, are released from the cells, a process that is not dependent on subcellular granule; and (ii) ionomycin, which bypasses cell surface receptors, is also capable of stimulating hydrogen peroxide formation that is granule-dependent and that is retained inside the cells.

Azides↗

PubMed1986

Abnormal neutrophil-pulmonary interaction in the adult respiratory distress syndrome. Qualitative and quantitative assessment of pulmonary neutrophil kinetics in humans with in vivo 111indium neutrophil scintigraphy.

In the absence of direct toxins, the majority of evidence from animal models suggests that neutrophils (PMN) are necessary for the full expression of the abnormal pulmonary permeability accompanying acute microvascular lung injury. We therefore studied the role of the PMN in the human correlate of this disease, the adult respiratory distress syndrome (ARDS), by assessing the pulmonary retention of infused autologous 111Indium-labeled PMN (PMN-In). We evaluated 79 patients, prospectively categorized as: "active" ARDS (Aa; n = 30), "active" ARDS and concurrent corticosteroid therapy (As; n = 11), "resolving" ARDS (Ar; n = 13), sepsis without pulmonary edema (S; n = 7), and cardiac pulmonary edema (C; n = 18). This clinical separation was confirmed by retrospective analysis of associated measures of hemodynamic and respiratory dysfunction. We found that both analog scintigrams (positive/negative for diffuse pulmonary PMN-In sequestration) and computer-assisted quantitative analysis in 46 patients (T 1/2 of first hour demargination and percentage of peak activity/pixel/second remaining at 17 to 20 h) showed a significant rank order decrease in the pulmonary retention of labeled PMN-In through the Groups Aa----As----S----Ar----C. Our findings recognized aspects of in vivo PMN-In behavior that implied pathophysiologic differences between groups of critically ill patients in either the PMN themselves or in PMN-pulmonary endothelial interaction. This demonstrates the possibility of abnormal in vivo PMN-endothelial interaction in ARDS by virtue of the greater pulmonary localization of PMN in active ARDS versus resolving disease, septic non-ARDS states, and cardiac pulmonary edema.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1981

Modulation of human lymphocyte responses by neutrophil-derived factors: effects of neutrophils and neutrophil-derived factos.

Lymphocytes and polymorphonuclear neutrophils (PMNs) occur together in inflammatory sites. We have examined the possibility that PMNs, or PMN-derived factors, might influence human peripheral blood lymphocyte (PBL) functions. PBL were cultured with or without antigen or phytomitogen, and with or without purified PMNs, PMN lysates or supernatants (SPTs) from PMNs that had phagocytized zymosan-complement complexes. PMN-derived enhancing and inhibitory activities were identified. Studies indicated: (1) PMNs exhibited concentration-dependent enhancement or inhibition of PVL methyl-3H-thymidine uptake; (2) lysates of PMNs similarly inhibited PBLs at high concentrations, enhanced with dilution, and inhibited with further dilution; (3) SPTs from PMN that had phagocytized zymosan-complement also exhibited concentration-dependent enhancement and inhibition; (4) inhibition did not result from (a) mitogen binding or inactivation, (b) exhaustion of in vitro nutrients, (c) change of expected kinetics of responses, (d) alterations of cell numbers or viability; (5) enhancement and inhibition of PBL persisted after exposure to PMN SPT and washing before stimulation; and (6) PMN SPTs increased PBL ability to rosette with sheep erythrocytes. These observations identified two or more PMN-derived factors that may be important in modulating lymphocyte responses in acute and chronic inflammation.

B-Lymphocytes↗

PubMed1985

The role of neutrophil membrane glycoprotein 150 (Gp-150) in neutrophil-mediated endothelial cell injury in vitro.

In this study we examined the importance of neutrophil adherence in neutrophil-mediated endothelial cell injury. Phorbol myristate acetate (PMA)-activated neutrophils from a patient with a congenital defect in neutrophil adherence (Gp-150 deficiency) and PMA-activated normal neutrophils pretreated with monoclonal antibody (MoAb) 60.3 were used. Both Gp-150-deficient and MoAb 60.3-treated normal neutrophils failed to adhere to cultured human umbilical vein endothelial cell (HEC) monolayers when activated by PMA (adherence less than 10% with patient and MoAb 60.3-treated cells compared with 53 +/- 3% with normal cells). The addition of PMA-activated normal neutrophils to 51Cr-labeled HEC monolayers failed to induce significant 51Cr release but did produce marked HEC detachment (percentage of detachment 50 +/- 3 at 6 hr). In marked contrast, PMA-activated Gp-150-deficient neutrophils failed to induce significant HEC detachment (percentage of detachment zero (0) at 6 hr). Moreover, the addition of MoAb 60.3 to normal neutrophils inhibited neutrophil-mediated HEC detachment in a time- and dose-dependent fashion. Non-lytic HEC detachment was determined to be largely oxygen radical independent, because PMA-activated chronic granulomatous disease neutrophils and PMA-activated normal neutrophils produced similar disruption of HEC monolayers. Soybean trypsin inhibitor, a chloromethylketone elastase inhibitor, and autologous serum all failed to inhibit neutrophil-mediated HEC detachment. From these studies there is no evidence that nonlytic HEC detachment by PMA-activated neutrophils is mediated by the neutrophil-derived proteases, elastase and cathepsin G. Neutrophil-mediated HEC detachment also required intact neutrophils, because postsecretory medium from PMA-activated normal neutrophils and a suspension of frozen-thawed PMA-activated normal neutrophils were without effect. These in vitro studies indicate that the neutrophil cell surface glycoprotein Gp-150 is required for nonlytic HEC detachment by intact PMA-activated neutrophils.

Animals↗

PubMed1996

Neutral endopeptidase 24.11 in neutrophils modulates protective effects of natriuretic peptides against neutrophils-induced endothelial cytotoxity.

This study was performed to determine effects of atrial and brain natriuretic peptides (ANP, BNP) on neutrophils-induced endothelial injury which is known to play a role in the pathophysiology of ischemia/reperfusion myocardial injury and to examine whether the effects of ANP and BNP on neutrophils are modulated by neutral endopeptidase 24.11 (NEP) in neutrophils themselves. The incubation of human neutrophils with ANP and BNP inhibited the neutrophils-induced detachment of cultured human endothelial cells (HEC). The inhibitory effect of ANP and BNP was associated with the suppressions of the neutrophils adhesiveness to HEC, CD18 expression on the neutrophils and elastase release from the neutrophils. Coincubation with UK73967 or phosphoramidon, inhibitors of NEP, potentiated all of the effects of ANP and BNP on the neutrophil functions, and the NEP inhibitors protected degradation of ANP and BNP by the neutrophils. NEP enzymatic activity in the particulate fractions and immunoreactive NEP expression were found to increase in the neutrophils from patients with early phase of acute myocardial infarction (AMI) by 5.2- and by 4.2-fold of the neutrophils from patients with late phase of AMI, respectively. In an in vivo canine model of myocardial ischemia/reperfusion, the intravenous administration of UK73967 suppressed the neutrophil adherence to endothelium and the neutrophil accumulation in the ischemic/reperfused myocardium. The results indicate that ANP and BNP, which are known to increase in AMI, modulate the neutrophil functions and exert protective effects against the neutrophils-induced endothelial cytotoxity. But the effects are suppressed due to their degradation by the neutrophil own NEP. Thus, neutrophil NEP, which also increases in AMI, may play a role in the pathophysiology of neutrophils-mediated ischemia/reperfusion endothelial and myocardial injury.

Animals↗