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PubMed1992

Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death.

In the absence of appropriate stimuli, polymorphonuclear neutrophils (PMN) undergo programmed cell death (PCD), also termed apoptosis. We show that granulocyte-macrophage colony-stimulating factor (GM-CSF), but not the chemotactic factors formyl-methionyl-leucyl-phenylalanine (FMLP), recombinant human (rh) C5a, transforming growth factor (TGF)-beta, and interleukin-8 (IL-8), or other cytokines including IL-3, IL-4, IL-6, and G-CSF, maintains viability of PMN in culture by preventing these cells from undergoing PCD. Prevention from PCD by GM-CSF was associated with induction of RNA and protein synthesis in PMN. Inhibition of RNA and protein synthesis by actinomycin-D and cycloheximide impeded the protection of apoptosis by GM-CSF. Similarly, neutralization of GM-CSF biologic activity by a specific antiserum abrogated GM-CSF-mediated inhibition of PCD.

Apoptosis↗
PubMed1988

Adherence of human basophils to cultured umbilical vein endothelial cells.

The mechanism by which circulating human basophils adhere to vascular endothelium and migrate to sites of allergic reactions is unknown. Agents have been identified which stimulate the adherence of purified basophils to cultured human umbilical vein vascular endothelial cells (HuVEC). Treatment of HuVEC with interleukin 1, tumor necrosis factor (TNF), bacterial endotoxin, and 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted in time and dose-dependent increases of adhesiveness for basophils. Coincubation of basophils and HuVEC for 10 min with C5a, formyl-methionyl-leucyl-phenylalanine, the calcium ionophore A23187, platelet-activating factor, TNF, and TPA also resulted in significant dose-dependent increases in basophil adherence; this effect resulted from activation of the basophil. Adherence of basophils to HuVEC was time and temperature dependent, required divalent cations, and was unaffected by glucocorticoids. Monoclonal antibody 60.3, directed against the beta-subunit of the leukocyte adherence complex CD18, inhibited the binding of basophils to HuVEC. Adherence of basophils to vascular endothelium may be important in initiating basophil infiltrates in vivo.

Basophils↗
PubMed1991

Neutrophil chemotactic factors in the tears of giant papillary conjunctivitis patients.

This study was designed to determine the presence of neutrophil chemotactic factors in the tears of patients with giant papillary conjunctivitis (BPC) secondary to contact lenses. Chemotactic activity was measured using modified Boyden chambers and the chemoattractant formylmethionyl-leucyl-phenylalanine (f-MLP) for 100 percent response. Elevated levels of chemotactic activity were found in the tears of symptomatic patients (80.8 +/- 6.4, % f-MLP) compared with control tears of asymptomatic contact lens wearers (15.7 +/- 3.3%) and non-contact lens wearers (5.6 +/- 1.2%). Using radioimmunoassay, C5a (serum-derived chemoattractant), leukotriene-B4, and interleukin-1 (immune cell-derived chemoattractants) were not detected in the tears of symptomatic patients. The authors determined whether injured conjunctival cells participate in this process by releasing neutrophil chemotactic factors. Isolated rabbit bulbar conjunctiva incubated with culture medium for 4 and 6 hr released high levels of neutrophil chemotactic factors. The release of these factors from injured conjunctiva support the premise that physical trauma of conjunctival cells induced by contact lenses may be an important component of the pathophysiology of giant papillary conjunctivitis.

Adolescent↗
PubMed1994

IgE-dependent IL-4 secretion by human basophils. The relationship between cytokine production and histamine release in mixed leukocyte cultures.

IL-4 protein and mRNA have recently been detected in pure basophil cultures after stimulation. It has also been established in mixed leukocyte cultures obtained by elutriation and challenged with anti-IgE that the basophil is the only cell that makes detectable IL-4. We have used cells prepared using Percoll gradients (5 to 30% basophils) to study the relationship between histamine release and IL-4 synthesis. In cultures challenged with anti-IgE after a 15-min pretreatment with IL-3, detectable IL-4 secretion ranged from 40 to 630 pg/10(6) basophils in 18 of 22 donors, with no significant correlation (r = 0.21, p = 0.34) with basophil purity. IL-4 synthesis was dissociated from histamine release, with optimal production consistently occurring at 10 ng/ml anti-IgE, whereas histamine levels peaked at 50 to 100 ng/ml of stimulus. Stimulation with anti-IgE alone was sufficient for IL-4 secretion but protein levels were enhanced two- to threefold in low responders by increasing the calcium concentration to 5 mM with no significant changes in histamine release. The IgE-independent secretagogues, F-met peptide (1 microM) and C5a (25 ng/ml), demonstrated limited ability to generate detectable IL-4, despite promoting vigorous histamine release. Additional studies showed no significant difference between IL-4 secretion in atopic and nonatopic donors. Finally, IL-4 levels generated with specific Ags were comparable to those levels produced in response to anti-IgE. We predict that basophil IL-4 generation will have a proinflammatory effect, but it appears that the signal transduction mechanisms for its synthesis and release differ from those for histamine release and thus may require different methods of pharmacologic control.

Basophils↗
PubMed1992

ONO-4057, a novel, orally active leukotriene B4 antagonist: effects on LTB4-induced neutrophil functions.

ONO-4057(5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E- hexenyl]oxyphenoxy]valeric acid), an orally active leukotriene B4(LTB4) antagonist, displaced the binding of [3H] LTB4 to the LTB4 receptor in human neutrophil (Ki = 3.7 +/- 0.9 nM). ONO-4057 inhibited the LTB4-induced rise in cytosolic free calcium (the concentration causing 50% inhibition (IC50) = 0.7 +/- 0.3 microM) and inhibited human neutrophil aggregation, chemotaxis or degranulation induced by LTB4 (IC50 = 3.0 +/- 0.1, 0.9 +/- 0.1 and 1.6 +/- 0.1 microM) without showing any agonist activity at concentration up to 30 microM. ONO-4057 did not inhibit fMLP or C5a-induced neutrophil activation at concentrations up to 30 microM. In the in vivo study, ONO-4057 given orally, prevented LTB4-induced transient neutropenia or intradermal neutrophil migration in guinea pig (the dose causing 50% efficacy (ED50) = 25.6mg/kg or 5.3mg/kg). Furthermore, ONO-4057 given topically, suppressed phorbol-12-myristate-13-acetate (PMA)-induced neutrophil infiltration in guinea pig ear (the effective dose = 1 mg/ear). These results indicate that ONO-4057 is a selective and orally active LTB4 antagonist and may be a potential candidate for the treatment of various inflammatory diseases.

Animals↗
PubMed1983

Anaphylatoxins inhibit C2 production.

Anaphylatoxins C5a and C3a and their des Arg derivatives inhibited C2 production by mononuclear phagocytes. C5a and C5adesArg which were approximately equipotent (IC50 = 10(-10) mol/l) were more effective than C3a (IC50 = 5 X 10(-8) mol/l) which was approximately 10-20-fold more potent than C3adesArg IC50 = 5 X 10(-6) mol/l). Inhibition of C2 production was only reversed slightly by the addition of either indomethacin or ETYA to the cultures. Intracellular levels of cAMP, were increased by anaphylatoxins. The level of cAMP showed a good inverse correlation with C2 levels in the culture supernatants. The data suggest that the reduction in C2 production produced by anaphylatoxins may be mediated by an increase in intracellular cAMP.

Anaphylatoxins↗
PubMed1994

Neutrophil polarisation in plasma differs to that induced by endogenous chemoattractants with regard to frequency of uropod formation and requirement for divalent cations.

Human neutrophils suspended in Hanks' balanced salt solution (37 degrees C, 20 mM Hepes, pH 7.2) produced extensions, elongated and developed a polarised morphology with both a pseudopod and uropod when exposed to C5a (10 nM), leukotriene B4 (10 nM), platelet activating factor (40 nM) or interleukin-8 (12.5 nM). Responses to each mediator were generally enhanced or unaffected by chelators of extracellular Ca2+ and Mg2+. Neutrophils suspended in heparinised plasma (90-10% v/v in Hanks' balanced salt solution) produced extensions, elongated and developed a pseudopod, but rarely developed a uropod unless additional Mg2+ ions (0.5-5 mM) were added. These findings demonstrate that the polarisation of neutrophils in plasma is significantly different to that induced by endogenous chemoattractants with regard to the frequency of uropod formation and requirement for extracellular divalent cations.

Calcium↗
PubMed1994

Multiple signalling pathways in the C5a-induced expression of adhesion receptor Mac-1.

The CD11/CD18 family of leukocyte glycoproteins is essential in the process of adherence to endothelial and other cells that occurs during the acute inflammatory response. The cell surface expression of one member of this family, CD11b/CD18, or Mac-1, is increased on monocytes, neutrophils and other cell types by a number of agents, including chemotactic peptides and lipid mediators. The intracellular signalling mechanisms which control Mac-1 expression are not fully understood. In this report we have investigated the role of G proteins and extracellular Ca2+ in the stimulation of Mac-1 upregulation by the chemoattractant C5a in the human monocyte-like cell line, U937. Two signal transduction pathways are apparently involved and can be distinguished by their sensitivity to pertussis toxin, which inhibits activation of the Gi class of G proteins. The results indicate that a pertussis toxin-insensitive influx of extracellular Ca2+ may be one part of a network of signals leading to Mac-1 upregulation on U937 cells. This is in contrast to the stimulation of this process in neutrophils by chemotactic peptide, which is reported to be entirely dependent on pertussis toxin sensitive G proteins and independent of extracellular Ca2+.

Actins↗
PubMed1992

Inflammatory mechanisms in the passive cutaneous anaphylactic reaction in the rabbit: evidence that novel mediators are involved.

1. We have examined the mechanisms of local oedema formation in the passive cutaneous anaphylactic (PCA) reaction in the rabbit. 2. IgE-containing antiserum was injected i.d. and allowed to sensitize skin sites for periods up to 240 h. Antigen (bovine gamma globulin) was injected i.d. or i.v. and local oedema formation assessed by the accumulation of i.v. injected 125I-labelled rabbit serum albumin. Potential inhibitors were mixed with antigen prior to i.d. injection or were administered i.v. 3. Maximum oedema formation was observed when a sensitization period of 48-72 h was used. Oedema formation in the PCA reaction was of short duration with a t 1/2 of approximately 15 min. No evidence of late oedema formation (up to 6 h) was found. 4. Local oedema formation in the PCA was reduced by indomethacin suggesting that vasodilator, oedema-potentiating prostaglandins were released. However, it was likely that other vasodilators were also generated. 5. Antihistamines were poor inhibitors of oedema formation as were PAF antagonists, a 5-lipoxygenase inhibitor, a kallikrein inhibitor, a bradykinin antagonist and anti-C5a antibody. 6. Local oedema formation in the PCA was partially reduced by neutrophil depletion and colchicine suggesting that neutrophil-dependent mediators were involved. 7. Exudate fluid from anaphylactic reactions in the rabbit peritoneal cavity contained permeability-increasing activity when injected into rabbit skin. This activity is now being characterized. 8. A vasodilator prostaglandin appears to be released in the rabbit PCA reaction but none of the established permeability-increasing mediators appears to be involved. Thus, there may be novel inflammatory mediators generated in this reaction which may have relevance for human allergic skin diseases.

Animals↗
PubMed1989

Proteins of the respiratory tract after heart-lung transplantation.

Heart-lung transplant recipients represent a unique population who experience episodic lung injury caused by infection or rejection. We hypothesized that the proteins in the respiratory lining fluids of these patients might reflect and provide insights into the in vivo immunologic and inflammatory events that occur in the transplanted lung. Structural, inflammatory, and immune proteins were quantitated in 57 samples of BAL fluid recovered from 17 heart-lung recipients when infections, rejection, or neither was present. Protein levels were compared with those of normal subjects and between the clinical transplant groups. When neither infection nor rejection was present, levels of albumin, fibronectin, and immunoglobulins G, M, and A were all higher in the transplanted lungs as compared with the normal lungs. These findings suggest that a new steady state of these proteins is established in the transplanted lungs. When infection or rejection was present, there was a further significant increase in albumin, fibronectin, IgG, and especially C5a in the transplanted lungs. These findings suggest that at least some elements of host defense remain intact in the posttransplantation period despite the use of immunosuppressive drugs and a HLA-incompatible microenvironment. The profiles of recovered alveolar proteins did not, however, help to differentiate infection from rejection. This is disappointing because distinguishing between infection and rejection without examination of lung tissue remains an unresolved and important clinical problem. Nevertheless these data provide new insights into organ tolerance and defense of the newly transplanted lung from infection or rejection.

Adolescent↗
PubMed2004

Inflammatory response in an immunosuppressed patient with Wegener's granulomatosis.

BACKGROUND: The use of cardiopulmonary bypass (CPB) triggers a systemic inflammatory response (IR), but it is not known if a similar response occurs in an immunosuppressed patient with autoimmune disease. METHODS AND RESULTS: Observational study in a 56-year-old man receiving immunosuppressive therapy for Wegener's granulomatosis (WG) who underwent aortic valve replacement on CPB. The following markers for IR were studied in the perioperative period: C3a, C5a, neutrophil elastase (NE), interleukin eight (IL-8), white cell count (WCC) and C-reactive protein (CRP). Results were compared with published literature on the IR in patients undergoing coronary revascularisation with and without the use of CPB. All inflammatory markers increased in the perioperative period. The intensity of IR was markedly reduced compared to published literature for patients undergoing coronary revascularisation on CPB and the temporal patients and extend resembled that for off-pump. CONCLUSION: In a patient with WG on immunosuppressive therapy the CPB-related IR is reduced.

Aortic Valve Insufficiency↗
PubMed1996

Actin polymerization in human eosinophils, unlike human neutrophils, depends on intracellular calcium mobilization.

Eosinophils represent major effector cells in the allergic inflammation. In contrast to neutrophils, the mechanism of eosinophil activation during the inflammatory response is poorly understood. In this study, the relation between calcium fluxes, chemotaxis, and actin polymerization in eosinophils from healthy non-atopic donors was investigated. Pre-incubation of eosinophils with the intracellular calcium chelator BAPTA dose-dependently prevented an increase in the intracellular calcium concentration ([Ca2+]i), whereas the depletion of extracellular calcium in the test medium had no effect. The chemotactic response of eosinophils, which was measured by the modified boyden chamber technique upon stimulation with RANTES, C5a and PAF, was dose-dependently inhibited by the chelation of intracellular calcium as well as inactivation of the cells in Ca2+ -depleted medium. To evaluate whether other cell functions which are involved in the migratory response of eosinophils might be dependent on intracellular and extracellular calcium, actin polymerization was investigated. Flow-cytometric measurement of F-actin with NBD-phallacidin revealed that actin polymerization in human eosinophils in response to RANTES, C5a, and PAF was dose-dependently inhibited by the intracellular calcium chelator BAPTA. Since it is well known that actin polymerization in neutrophils is not affected by chelation of intracellular calcium, actin polymerization in these cells was investigated under the same conditions as for eosinophils. In contrast to eosinophils, BAPTA did not inhibit actin polymerization in neutrophils. In summary, these data demonstrate that intracellular calcium fluxes represent a prerequisite for eosinophil chemotaxis and actin polymerization in human eosinophils. Furthermore, regulation of actin polymerization in eosinophils differed from that of neutrophils on the level of intracellular calcium fluxes.

Actins↗
PubMed1990

Neutrophil disorders in burn injury: complement, cytokines, and organ injury.

Because of the association of burn injury with subsequent bacterial infection, numerous studies have been performed characterizing neutrophil function in burn injury. These studies provide a picture of intravascular complement activation, neutrophil-C5a interactions, and consequent disordered cellular function. Neutrophil dysfunction includes suppressed random and C5a-directed migration and hyperresponsiveness to oxidative stimuli. These observations do not explain the histologic and functional involvement of neutrophils in ARDS and perhaps other organ failure states. Circumstantial and extrapolated information suggests that macrophage-lineage cells function as regulators of neutrophil function within matrix environments in burn injury. Elevated endotoxin levels have been found in burned patients, which would support the notion of endotoxin-stimulated monocytes/macrophages as inducing neutrophil migration into connective tissue matrices (LTB4 and IL-8), inducing prolonged oxidant production (TNF-alpha, GM-CSF), and inducing neutrophil release of regulatory substances from neutrophils (G-CSF). This information suggests a variety of experimental approaches to testing this hypothesis.

Burns↗
PubMed1983

[The role of eosinophils in inflammatory reactions].

Recent findings have contributed substantially to a better understanding of the ontogeny and function of eosinophil leukocytes. Together with other granulocytes, the cells originate in the bone marrow from a common stem cell. Their development is regulated by genetic factors and by products of T-lymphocytes. Chemotactic factors of the complement cascade (C5a), lymphokines and eosinophil chemotactic leukotrienes (ECL) stimulate their migration to tissue sites. Generation and biological effectiveness of eosinophil chemotactic factors can be modulated in numerous ways, thus changing the outcome of the inflammatory event. The probably most important effector function of eosinophils is their cytotoxicity which plays a role in the killing of parasites. Markedly elevated numbers of eosinophils can, however, cause auto-aggression against the body's own cells, such as the Purkinje cells of the brain, cardiac muscle cells or epithelial cells of the skin and the bronchial tree. Eosinophils are therefore cells capable of both serving and damaging the human host.

Anaphylaxis↗
PubMed1983

Abnormalities of lymphocyte locomotion in immunodeficiency disease.

Lymphocyte and neutrophil locomotion were studied in 23 patients with well defined, primary immunodeficiencies. These included eight patients with common variable immune deficiency, three patients with X-linked agammaglobulinaemia, two patients with the Wiskott-Aldrich syndrome, three patients with ataxia telangiectasia, three patients with immunodeficiency and normal serum immunoglobulin concentrations, one patient with immune deficiency and hyper-IgM syndrome, two patients with Job syndrome and one patient with a granulocyte adherence defect. Random and stimulated lymphocyte and neutrophil migration were evaluated. C5a and casein were used to stimulate lymphocyte migration and C5a and formyl-methionyl-leucyl-phenylalanine (f-MLP) were used to stimulate neutrophil migration. Significantly depressed lymphocyte migration in response to casein and C5a was observed in patients with common variable immune deficiency, patients with immune deficiency and normal immunoglobulin concentration, and patients with Job syndrome. No consistent defect in lymphocyte locomotion was observed in the other patients studied. Neutrophil migration in response to C5a and f-MLP was depressed in Job syndrome, the patient with a granulocyte adherence defect, one of the six patients with common variable immune deficiency and none of the remaining patients. No significant correlation of skin test reactivity and lymphocyte migration was noted, but a correlation between the degree of lymphocyte proliferation in response to phytohaemagglutinin and lymphocyte migration in response to casein was observed. The results presented indicate that aberrations in lymphocyte migration occur in several types of immunodeficiency diseases and that defects in lymphocyte and neutrophil migration can occur simultaneously or totally independent of each other.

Adolescent↗
PubMedDate not supplied

The releasability of lysosomal enzymes from neutrophil leukocytes in patients with rheumatoid arthritis.

OBJECTIVE: To study the enzyme content and the "releasability" of lysosomal enzymes (lysozyme and beta-glucuronidase) in neutrophils purified from peripheral blood of patients with rheumatoid arthritis (RA) or normal subjects. METHODS: Neutrophils were obtained from 13 patients (10 women and 3 men) with rheumatoid arthritis and from 11 healthy subjects (8 women and 3 men). We measured: (1) lysosomal enzyme (lysozyme and beta-glucuronidase) content; (2) spontaneous enzyme release; (3) lysosomal enzyme release after cell challenge with different segretagogues (FMLP, C5a, aggregated IgG, zymosan and Ca2+ ionophore A23187). RESULTS: The lysosomal enzyme content was not statistically different in control subjects and in patients with RA (7.4 +/- 1.9 vs 6.3 +/- 0.8 micrograms/10(6) neutrophils for lysozyme; 102.9 +/- 16.4 vs 78.9 +/- 11.2 micrograms/10(6) neutrophils for beta-glucuronidase in control and RA subjects, respectively, p = NS). Unstimulated release of lysozyme was significantly lower in RA patients (3.8 +/- 1.1%) when compared to control subjects (9.5 +/- 2.1%) (p < 0.05). In contrast, spontaneous release of beta-glucuronidase did not differ in the two groups (5.5 +/- 0.9% and 3.8 +/- 1.1% in control and RA subjects, respectively). Enzyme release induced by FMLP (3 x 10(-9)-3 x 10(-7) M), C5a (10(-8)-10(-7) M), aggregated IgG (0.1-0.6 mg/ml), or Ca2+ ionophore A23187 (0.1-1 microgram/ml) did not differ statistically in the two groups of subjects. Neutrophil stimulation by serum-treated zymosan, at the concentration of 0.3 mg/ml, induced a release of lysozyme that was significantly higher in patients with RA when compared to control subjects (p < 0.05), whereas zymosan-activated beta-glucuronidase secretion was similar in the two donor populations. CONCLUSIONS: This study suggests that the contribution of leukocytes to the inflammatory processes typical of RA does not depend on an altered "releasability" of preformed mediators from peripheral blood neutrophils.

Adult↗
PubMed1991

Interleukin-3, interleukin-8, FMLP and C5a enhance the release of leukotrienes from neutrophils of patients with atopic dermatitis.

The influence of the receptor-specific stimuli interleukin-3 (IL-3), interleukin-8 (IL-8), C5a and formyl-methionyl-leucyl-phenylalanine (FMLP) on the generation of arachidonic acid-derived inflammatory mediators from neutrophils (PMN) has been studied in patients with atopic dermatitis (AD) as well as in healthy, non-atopic volunteers. The release of leukotriene (LT)B4, the omega-oxidation products 20-COOH- and 20-OH-LTB4 and the cysteinyleukotriene LTC4 were measured by reverse-phase HPLC and radioimmunoassay. The incubation of neutrophils with these stimuli led to a significantly higher release of LTB4 and LTC4 in the AD group. The spontaneous leukotriene generation of PMN from patients with AD was on average threefold higher compared to the control group. C5a stimulated the release of LTB4 and its metabolites from atopic cells up to 9 ng in contrast to low amounts from non-atopic cells. Furthermore, FMLP distinctly enhanced the leukotriene release of neutrophils from patients with AD compared to unstimulated cells and to cells of normal donors. IL-3 and IL-8 also significantly stimulated the generation of LTB4 and LTC4 of PMN from atopic patients. Our data emphasize that neutrophils may play an important role in the pathogenesis of AD by an increased responsiveness to receptor-specific stimuli and further suggest that IL-3 and IL-8 influence the acute and chronic inflammatory reactions in patients with AD.

Cells, Cultured↗
PubMed1982

Basophil releasability in the newborn: factors limiting immunoglobulin E-mediated histamine release.

Cord basophil preparations from 53 term neonates were studied for various factors affecting immediate hypersensitivity reactions including: basophil IgE receptor density and histamine releasability following incubation with calcium ionophore A23187, zymosan-activated serum (C5a), and anti-IgE. Basophil histamine content (geometric mean, 0.4 pg/basophil, with content in 14/28 cord blood samples below 0.2 pg/cell) is considerably below that of atopic and nonatopic individuals (geometric mean, 2.3 pg/basophil). Histamine release is normal with both A23187 (range 33% to 88%) and C5a (range 11% to 58%). Normal release with anti-IgE was shown in five of nine cord blood samples (range 13% of 52%), but four of five cell preparations required IgE preincubation. Indirect evidence indicates that basophils from newborns contain less than 30,000 total IgE receptors/cell. IgE-mediated histamine release in basophils from newborns is minimized by suboptimal IgE binding. Optimal IgE binding is not favored in basophils from neonates because of low serum IgE and low IgE receptor density. Serum IgE and IgE receptors increase to a variable degree as the child grows older and may determine the clinical onset of allergic disease.

Adult↗