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PubMed2000

Adenosine triphosphate-induced oxygen radical production and CD11b up-regulation: Ca(++) mobilization and actin reorganization in human eosinophils.

Eosinophils are major effector cells in cellular inflammatory conditions such as parasitic infections, atopic diseases, bullous dermatoses, and vasculitis. Biological activities of adenosine triphosphate (ATP) were characterized in human eosinophils and compared with those of other eosinophil activators such as complement fragment product C5a, platelet-activating factor (PAF), and eotaxin. ATP initiated production of reactive oxygen metabolites, as demonstrated by lucigenin-dependent chemiluminescence. Furthermore, ATP caused up-regulation of the integrin CD11b. In addition, fluorescence microscope measurements labeled with fura-2 (1-[2-(5-carboxy-oxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2' -amino-5' -methyl-phenoxy)-ethane-N, N, N, N'-tetraacetic acid, pentaacetoxymethyl ester) eosinophils in the presence or absence of ethyleneglycotetraacetic acid (EGTA) indicated that there was Ca(++) mobilization from intracellular stores by ATP. Flow cytometric studies showed transient actin polymerization upon stimulation with ATP and its stable analogues adenosine 5'-0-(3-thiotriphosphate) and 2-methylthioadenosine triphosphate tetrasodium (met-ATP). The reactions induced by ATP were comparable to those obtained by C5a, PAF, and eotaxin. Production of reactive oxygen metabolites and actin polymerization after stimulation with ATP was inhibited by pertussis toxin, which indicated involvement of receptor-coupled guanine nucleotide-binding proteins (G(i) proteins). In addition, experiments with oxidized ATP also suggest involvement of P2X receptors in this activation process. The results show that ATP is a strong activator of eosinophils and has biological activity comparable to those of the eosinophil chemotaxins C5a, PAF, and eotaxin. The findings strongly suggest a role of ATP in the pathogenesis of eosinophilic inflammation as an activator of proinflammatory effector functions.

Actin Cytoskeleton↗
PubMed2004

C5a-induced gene expression in human umbilical vein endothelial cells.

The endothelium plays a critical role in the inflammatory process. The complement activation product, C5a, is known to have proinflammatory effects on the endothelium, but the molecular mechanisms remain unclear. We have used cDNA microarray analysis to assess gene expression in human umbilical vein endothelial cells (HUVECs) that were stimulated with human C5a in vitro. Chip analyses were confirmed by reverse transcriptase-polymerase chain reaction and by Western blot analysis. Gene activation responses were remarkably similar to gene expression patterns of HUVECs stimulated with human tumor necrosis factor-alpha or bacterial lipopolysaccharide. HUVECs stimulated with C5a showed progressive increases in gene expression for cell adhesion molecules (eg, E-selectin, ICAM-1, VCAM-1), cytokines/chemokines, and related receptors (eg, VEGFC, IL-6, IL-18R). Surprisingly, HUVECs showed little evidence for up-regulation of complement-related genes. There were transient increases in gene expression associated with broad functional activities. The three agonists used also caused down-regulation of genes that regulate angiogenesis and drug metabolism. With a single exception, C5a caused little evidence of activation of complement-related genes. These studies indicate that endothelial cells respond robustly to C5a by activation of genes related to progressive expression of cell adherence molecules, and cytokines and chemokines in a manner similar to responses induced by tumor necrosis factor-alpha and lipopolysaccharide.

Blotting, Western↗
PubMed2006

Generation of C5a in the absence of C3: a new complement activation pathway.

Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3-/- mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc-/- mice (Hc encodes C5). Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice. Plasma from C3-/- mice contained threefold higher levels of thrombin activity compared to plasma from C3+/+ mice. There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3-/- mice compared to C3+/+ mice. A potent solid-phase C5 convertase was generated using plasma from either C3+/+ or C3-/- mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.

Animals↗
PubMed1996

Priming of circulating human eosinophils following late response to allergen challenge.

The eosinophil is recognized as an important effector cell in asthma. To investigate the role of eosinophils in the aetiology of asthma, we have examined whether peripheral blood eosinophils are primed following whole-lung allergen challenge. Nineteen mild asthmatics, who each demonstrated a late asthmatic response (LAR), were studied. The priming of eosinophils following allergen challenge was assessed by measuring: 1) platelet-activating factor (PAF) and complement factor 5a (C5a) stimulated H2O2 release upon fibrinogen-coated tissue culture plates (n = 8); and 2) ex-vivo cell survival (n = 11). Subjects were venepunctured before and 24 h after allergen challenge and eosinophils were prepared by immunomagnetic separation. Basal H2O2 release was increased from eosinophils following allergen challenge. The response to PAF stimulation was significantly increased in terms of cell sensitivity (negative log of concentration producing half the maximal effect (pD2)) and responsiveness (maximum effect Emax). With C5a, although there was no change in sensitivity there was a significant increase in the maximal response. Ex-vivo eosinophil survival (at 3 days and cell half-life) was significantly prolonged following allergen challenge. In conclusion, we have demonstrated the priming of circulating eosinophils following allergen challenge.

Adult↗
PubMed1986

Role of protein kinases in stimulation of human polymorphonuclear leukocyte oxidative metabolism by various agonists. Differential effects of a novel protein kinase inhibitor.

Isoquinoline sulfonamides have recently been shown to exert novel inhibitory effects on mammalian protein kinases by competitively binding to the ATP substrate site (Hidaka, H., M. Inagaki, S. Kawamoto, and Y. Sasaki, 1984, Biochemistry, 23: 5036-5041). We synthesized a unique analog of the previously reported compounds, 1-(5-isoquinolinesulfonyl) piperazine (C-I), in order to assess the role of protein kinases in modulating the agonist-stimulated oxidative burst of human polymorphonuclear leukocytes (PMN). Compound C-I, at micromolar concentration, markedly inhibited the release of superoxide anion from human PMN stimulated with phorbol myristate acetate or the synthetic diacylglycerol, 1-oleoyl-2-acetyl glycerol. These data are consonant with previously reported data which indicate that the calcium and phospholipid-dependent protein kinase, protein kinase C, serves as the intracellular receptor for these agonists. In contrast, superoxide anion production stimulated by the complement anaphylatoxin peptide C5a or the synthetic chemotaxin formyl-methionyl-leucyl-phenylalanine were not inhibited by C-I. These data suggest that parallel pathways exist for the agonist-stimulated respiratory burst of human neutrophils, only one of which utilizes the calcium and phospholipid-dependent protein kinase.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2004

Increase of Escherichia coli inoculum doses induces faster innate immune response in primiparous cows.

The objective of the current study was to evaluate the dynamics of infection and the immunological response to varying numbers of Escherichia coli injected into the mammary glands of primiparous cows during the periparturient period. Primiparous cows have been shown to be more resistant to intramammary E. coli challenge, and an increase of the inoculum dose by 2 log10 units induced a more rapid clinical response and clearance of the organisms. Recognition of lipopolysaccharide (LPS) is a key event in the innate immunity response to gram-negative infection and is mediated by the accessory molecules CD14 and LPS-binding protein (LBP). Primiparous cows were inoculated with 1 x 10(4) (Group A; n=8) or 1 x 10(6) (Group B; n=8) cfu E. coli P4:O32 in their 2 left quarters during the periparturient period. Clinical examination and analysis of blood and milk parameters, including IL-8, complement fragment 5a (C5a), LBP, and soluble CD14 (sCD14), were performed from d -4 to d +3 relative to infection. Primiparous cows in Group B initiated a more rapid clinical response following intramammary infection (IMI), resulting in typical clinical signs and changes in blood and milk parameters approximately 3 h earlier compared with primiparous cows in Group A. Based on average milk production in the noninfected quarters on d +2 postinoculation, all heifers reacted as moderate responders. Distinct differences in the kinetic patterns of rectal temperature, somatic cell count (SCC), IL-8, C5a, LBP, and sCD14 were observed between both groups during the early phase of inflammation. Both C5a and IL-8 increased before cellular influx into the infected glands, followed by increases in sCD14 and LBP. In conclusion, primiparous cows are able to clear an intramammary E. coli infection efficiently. Moreover, increasing the inoculum dose induces a more rapid inflammatory reaction, mainly because of early activation of the innate host immune response.

Animals↗
PubMed2005

Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease.

We have previously shown that complement factor 5a (C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(d-Cha)WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(d-Cha)WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(d-Cha)WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(d-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03-10 mg/kg/day p.o.) in the 8-day rat TNBS-colitis model, against the comparator drug AcF-[OP(d-Cha)WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(d-Cha)WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP(d-Cha)WR], equiactive in vitro to AcF-[OP(d-Cha)WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(d-Cha)WR]. However, in the rat TNBS-colitis model, HC-[OP(d-Cha)WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30-fold lower oral doses than AcF-[OP(d-Cha)WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(d-Cha)WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(d-Cha)WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.

Animals↗
PubMed2002

Cellular adhesion is required for effector functions of human eosinophils via G-protein coupled receptors.

BACKGROUND: Eosinophils play an important role in the pathogenesis of allergic diseases. Chemoattractants, including platelet-activating factor (PAF) and complement component 5a (C5a), induce eosinophil infiltration and promote eosinophil effector functions. OBJECTIVE: To compare eosinophil degranulation and superoxide anion (O2-) generation induced by various chemoattractants, and to elucidate the role of cellular adhesion on these effector functions. METHODS: Human eosinophils were stimulated with PAF, C5a, eotaxin, or leukotriene B4 (LTB4). O2- generation was assayed by a chemiluminescence method using a Cypridina luciferin analog as the amplifier. Degranulation and adhesion were measured by quantitating eosinophil protein X by radioimmunoassay. Expression of CD11b on eosinophils was measured by flow cytometry. RESULTS: PAF and C5a induced significant degranulation and O2- generation from eosinophils. In contrast, the potency of eotaxin or LTB4 for these functions was much less. PAF and C5a also significantly enhanced eosinophil adhesion, whereas eotaxin and LTB4 did not. CD11b expression on eosinophils was enhanced by all four stimulants, and the order of potency to induce CD11b expression was C5a > PAF > eotaxin > LTB4. CONCLUSIONS: The potency of PAF and C5a for inducing effector function in eosinophils was greater than that of eotaxin or LTB4. The magnitude of the effector function was consistent with the degree of eosinophil adherence induced by each stimulant. These results suggest that effector functions of eosinophils which are mediated through G-protein coupled receptors are dependent on cellular adhesion.

Cell Adhesion↗
PubMed1988

15-Hydroxyeicosatetraenoic acid (15-HETE) specifically inhibits LTB4-induced chemotaxis of human neutrophils.

15-Hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase (15-LO) product of arachidonic acid has the potential to inhibit leukotriene formation. In the present study the effect of 15-HETE on leukotriene B4 (LTB4)-induced polymorphonuclear leukocytes (PMN) and monocyte chemotaxis was investigated. LTB4-induced chemotaxis of PMNs was inhibited in a dose-dependent manner by 15-HETE. Maximum inhibition (68%) occurred at a 15-HETE concentration of 10(-4) M. The 15-LO product of eicosapentaenoic acid (15-HEPE) was approximately 10 times less potent in inhibiting LTB4-induced PMN chemotaxis. LTB4-induced chemotaxis of monocytes was unaffected by both 15-HETE and 15-HEPE. Using N-formyl-methionyl-leucyl-phenylalanine (FMLP) and complement split product C5a as chemoattractants, 15-HETE did not decrease PMN chemotaxis. Furthermore, 15-HETE itself did not affect random migration of leukocytes. The present results demonstrate that 15-HETE inhibits LTB4-induced chemotaxis of PMNs in vitro in a specific and selective way. Because 15-HETE not only inhibits formation, but also the effect of LTB4, it may be important in regulating LTB4-induced inflammation.

Adult↗
PubMed2001

Activation and priming of neutrophil nicotinamide adenine dinucleotide phosphate oxidase and phospholipase A(2) are dissociated by inhibitors of the kinases p42(ERK2) and p38(SAPK) and by methyl arachidonyl fluorophosphonate, the dual inhibitor of cytosolic and calcium-independent phospholipase A(2).

Arachidonic acid (AA) generated by phospholipase A(2) (PLA(2)) is thought to be an essential cofactor for phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Both enzymes are simultaneously primed by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha). The possibility that either unprimed or cytokine-primed responses of PLA(2) or NADPH oxidase to the chemotactic agents formyl-methionyl-leucyl-phenylalanine (FMLP) and complement factor 5a (C5a) could be differentially inhibited by inhibitors of the mitogen-activated protein (MAP) kinase family members p42(ERK2) (PD98059) and p38(SAPK) (SB203580) was investigated. PD98059 inhibited the activation of p42(ERK2) by GM-CSF, TNF-alpha, and FMLP, but it did not inhibit FMLP-stimulated superoxide production in either unprimed or primed neutrophils. There was no significant arachidonate release from unprimed neutrophils stimulated by FMLP, and arachidonate release stimulated by calcium ionophore A23187 was not inhibited by PD98059. In contrast, PD98059 inhibited both TNF-alpha- and GM-CSF-primed PLA(2) responses stimulated by FMLP. On the other hand, SB203580 inhibited FMLP-superoxide responses in unprimed as well as TNF-alpha- and GM-CSF-primed neutrophils, but failed to inhibit TNF-alpha- and GM-CSF-primed PLA(2) responses stimulated by FMLP, and additionally enhanced A23187-stimulated arachidonate release, showing that priming and activation of PLA(2) and NADPH oxidase are differentially dependent on both the p38(SAPK) and p42(ERK2) pathways. Studies using C5a as an agonist gave similar results and confirmed the findings with FMLP. In addition, methyl arachidonyl fluorophosphonate (MAFP), the dual inhibitor of c and iPLA(2) enzymes, failed to inhibit superoxide production in primed cells at concentrations that inhibited arachidonate release. These data demonstrate that NADPH oxidase activity can be dissociated from AA generation and indicate a more complex role for arachidonate in neutrophil superoxide production.

Arachidonic Acid↗
PubMed2000

Ex vivo biocompatibility of avidin-agarose: a new device for direct adsorption of biotinylated antibodies from human whole blood.

Radioimmunotherapy using radiolabeled antitumor antibodies (RAA) is limited by the toxicity of unbound antibodies in the circulation. Removal of excessive antibodies by affinity-adsorption could therefore allow the administration of increased dosages of RAA while decreasing their adverse effects. Recently, avidin-agarose (AA) minicolumns were used in animal experiments for the removal of biotinylated antibodies from whole blood exploiting the high affinity binding of biotin to avidin (pK 1015 M-1). This study was performed to evaluate the ex vivo biocompatibility of AA minicolumns with human blood. Ten ml AA minicolumns were perfused online ex vivo in the single pass mode with fresh blood from 8 healthy donors at a flow rate of 6.25 ml/min. The anticoagulation consisted of 0.5 IU heparin plus 0.0-2.1 mg citrate per ml of blood. In Part 1 of the study (40 min perfusion, n = 4), the optimal anticoagulation was found to be 0.5 IU heparin plus about 1 mg citrate per ml of blood. In Part 2 of the study, four 80 min test-runs were performed. No signs of hemolysis were found, and the thrombogenicity of the AA gel was negligible. Cell counts and column inlet pressures remained constant; toward the end of the 80 min test-runs, some activation of blood cells (elastase, beta-thromboglobulin), the complement system (C3a, C5a) and the plasmatic coagulation (thrombin-antithrombin complex) was detectable. A moderate initial bradykinin release rapidly subsided to very low levels. In summary, AA minicolumns showed good biocompatibility upon contact with human whole blood and merit further investigation in a closed-loop system for a potential application of direct tumor antibody removal by hemoperfusion.

Adsorption↗
PubMed2005

Novel C5a regulators in inflammatory disease.

Complement is part of the innate immune system, acting to protect the host from microorganisms such as bacteria, and other foreign and abnormal cells. Although primarily protective, complement activation can also cause damage to the host. In a number of inflammatory diseases, including rheumatoid arthritis and dermatitis, there is excessive and inappropriate complement activation. Many of the toxic effects seen in these conditions are attributable to the excessive production of the anaphylatoxin C5a, which may contribute to both the initiation and progression of the disease. Therefore, the regulation of C5a production and modulation of its function are good pharmacological targets in these disorders. As yet, there are no effective agents for the therapeutic regulation of C5a in routine clinical practice. This review describes the role of C5a in inflammatory disease, animal models used to study C5a-related effects, and current strategies aimed at regulating C5a. There is also a discussion of the strengths and weaknesses of these approaches, and an outline of the likely progress of this class of drugs in the future.

Animals↗
PubMed1983

Role of cell surface contact in the kinetics of superoxide production by granulocytes.

The complement-derived anaphylatoxin C5a and a putative analogue of bacterial chemotactic factor (N-formyl-methionyl-leucyl-phenylalanyl [fMLP]), as well as bacterial lipid A, all stimulate human granulocyte (PMN) adhesiveness and superoxide (O-2) production in a concentration-dependent manner. Since attachment of particulate matter to the PMN membrane is an early event in the triggering of respiratory burst of these cells, we further examined how adherence might modulate the release of O-2 induced by soluble mediators of inflammation. We found that both the quantity and kinetics of O-2 production depend on prior attachment of the cells to a surface. In stirred suspensions of PMN, fMLP induces only a short burst (2.5 min) of O-2 release associated with reversible PMN aggregation. The magnitude, but not the time course, of both these responses depend on the fMLP concentration. Unlike the short respiratory response of cells in suspension, PMN allowed to settle onto stationary petri dishes, then overlaid with fMLP, rapidly spread and attach to the surface where they remain and release O-2 throughout the 60-min test period. Prolonged O-2 release also follows fMLP stimulation in suspensions of PMN pretreated with cytochalasin B, in which case aggregation becomes irreversible during the 20-min burst. If fMLP is slowly infused into a suspension of cells at 37 degrees C or if PMN are challenged at 0 degrees C, and then warmed to 37 degrees C, O-2 release greatly decreases or becomes undetectable. Suspended PMN do not respond to a second challenge by the same stimulus regardless of the rate or temperature at which the first stimulus was added, a phenomenon formerly described as desensitization. However, if PMN challenged with fMLP in suspension undergo the short respiratory response and then are later placed in petri dishes, they adhere and resume production of O-2 without further stimulation. Chemotactic factor-induced adherence and O-2 release of PMN on a surface is entirely independent of either the mode of activation or prior O-2 release during preincubation in suspension. Human C5a also promotes PMN adherence and prolonged O-2 release in petri dishes. Furthermore, lipid A increases O-2 release and adherence of settled PMN, but fails to elicit either response from suspended PMN. These results indicate that cell surface contact plays an essential role in triggering the respiratory burst of PMN activated by soluble stimuli. This long-lasting O-2 release by chemotactic factor-stimulated PMN may play a significant role in inflammatory reactions when PMN become adherent in vivo.

Adult↗
PubMed1985

Increased expression of an adhesion-promoting surface glycoprotein in the granulocytopenia of hemodialysis.

To identify the mechanisms accounting for hemodialysis-induced granulocytopenia, we undertook quantitative kinetic studies of a granulocyte-adhesion-promoting surface glycoprotein (Mo1). In eight patients undergoing maintenance hemodialysis, there was a fivefold increase in the mean cell-surface expression of Mo1 within 15 minutes after the start of dialysis with a new cuprophane membrane. The peak increase in surface Mo1 coincided with the maximal drop in neutrophil count and with the peak rise in the plasma levels of the complement-activation products C5a desArg and C3a desArg. During dialysis on a membrane being reused for the fifth time, no significant complement activation, no increase in Mo1 expression, and no change in neutrophil count were seen. C5a desArg (but not C3a desArg) induced a comparable increase in Mo1 expression on normal granulocytes in vitro at concentrations similar to those measured in vivo. Chemotactic peptide-induced granulocyte aggregation (a reflection of increased cell-to-cell adhesiveness) was specifically blocked by mouse monoclonal antibodies to Mo1 in vitro. These data suggest that the increased expression of Mo1 on granulocytes in vivo is in part mediated by C5a (and C5a desArg). The quantitative increase in granulocyte-surface Mo1 may provide a mechanism for initiating leukoaggregation, sequestration of granulocytes, and neutropenia during hemodialysis.

Adult↗
PubMed1991

Modulation and induction of eosinophil chemotaxis by granulocyte-macrophage colony-stimulating factor and interleukin-3.

Eosinophilia and eosinophil function are regulated by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5. We have investigated the modulatory role of GM-CSF and IL-3 on the platelet-activating factor (PAF)-, neutrophil-activating factor (NAF/IL-8)-, leukotriene B4 (LTB4)-, N-formyl-methionyl-leucyl-phenylalanine (FMLP)-, and human complement factor C5a-induced chemotaxis of eosinophils from normal individuals. These eosinophils show a chemotactic response toward PAF, LTB4, and C5a, but not to NAF/IL-8 and FMLP. Preincubation of the eosinophils with picomolar concentrations of GM-CSF caused a significant increase in the response toward LTB4 and induced a significant chemotactic response toward NAF/IL-8 and FMLP. Preincubation of the eosinophils with picomolar concentrations of IL-3 also induced a chemotactic response toward NAF/IL-8 and FMLP, and enhanced the PAF-induced chemotaxis response toward C5a was not influenced by both cytokines. Nanomolar concentrations of GM-CSF or IL-3 caused a significant inhibition of the C5a-induced chemotaxis. The LTB4-induced chemotaxis was also significantly inhibited in case of GM-CSF. At these concentrations both GM-CSF and IL-3 acted as chemotaxins for eosinophils were washed after pretreatment with GM-CSF and IL-3 the potentiation of the chemotactic response remained, whereas the inhibitory mode of action disappeared. Our data indicate that at picomolar concentrations the cytokines GM-CSF and IL-3 can modulate eosinophil chemotaxis and at nanomolar concentrations these cytokines can act as chemotaxins for eosinophils.

Chemotaxis, Leukocyte↗
PubMed1988

Epidermal lymphocyte chemotactic factor specifically attracts OKT4-positive lymphocytes.

Epidermal lymphocyte chemotactic factor (ELCF) from skin overlying a positive tuberculin reaction was compared with the chemoattractants leukotriene B4 (LTB4), N-formyl-methionyl-leukyl-phenylalanine (FMLP), and complement split product C5a (C5a). The chemotactic assay used is a modified Boyden chamber technique. The lymphocytes were subsets of T lymphocytes from healthy young individuals first separated by flotation of E rosettes on Isopaque Ficoll followed by incubation of T cells with anti-CD4 and anti-CD8 monoclonal antibodies and further separation using fluorescence-activated cell sorting. ELCF specifically attracted OKT4+ lymphocytes, while LTB4, FMLP, and C5a induced significant migration in both OKT4+ and OKT8+ lymphocytes without any clear difference between the various chemoattractants or cell populations. We found no blocking of the chemotactic capacity of ELCF when we added antibodies towards IL-1 alpha and IL-1 beta to the chemotactic assay. Further recombinant IL-1 alpha and Il-1 beta did not induce any chemotactic response. Our observation may be of significance in explaining the predominance of OKT4+ cells in allergic contact dermatitis and certain other skin diseases.

CD4-Positive T-Lymphocytes↗
PubMed1992

[Use of cardiopulmonary bypass decreases leukocyte count and activation of the complement system].

Platelet damage, complement activation and neutropenia during extracorporeal circulation are the result of blood contact with artificial surfaces, mainly in the oxygenator. To evaluate the biocompatibility of the ++auto-oxygenation technique of cardiopulmonary bypass (CPB) 2 techniques of extracorporeal circulation were compared in 40 patients undergoing elective coronary bypass surgery. Patients were studied in 2 groups, 20 patients in each: I (++auto-oxygenation --patients lungs used in CPB) and II (conventional technique of CPB with bubble oxygenator). Several blood samples were taken before, during and after perfusion to estimate pulmonary leukocytes sequestration in all patients and additionally complement C3a and C5a anaphylatoxins + were measured (radioimmunoassays) in 6 patients of each group. During cardiopulmonary bypass the decline in leukocyte number was observed in both groups, but leukocyte count was higher in group I then II, due to the transpulmonary leukocyte sequestration which was higher in group II. The difference between leukocytes count in group II was 1.46 +/- 0.5 x 10(3)/mm3 vs only 0.34 +/- 0.2 x 10(3)/mm3 in group I, p less than 0.001. In postoperative period an increase in circulating white blood cells was observed in both groups when compared to pre-bypass time, but the difference between groups was non significant. The level of C3a increased in group I from 244 +/- 46 ng/ml to 418 +/- 34 ng/ml, in group II from 268 +/- 46 ng/ml to 521 +/- 65 ng/ml, p less than 0.001, but in group I the levels were significantly lower, p less than 0.001. The current study confirms that cardiopulmonary bypass results in significant leukocyte and complement activation and supports the theoreticaly better biocompatibility of CPB with lung over oxygenator.

Adult↗
PubMed1989

15-hydroxyeicosatetraenoic acid (15-HETE) specifically inhibits the LTB4-induced skin response.

15-Hydroxyeicosatetraenoic acid (15-HETE), a 15-lipoxygenase product of arachidonic acid, inhibits leukotriene B4 (LTB4)-induced chemotaxis of polymorphonuclear leukocytes (PMNs) in vitro. In this study the effects of intradermal injections of LTB4 were determined in the absence or presence of 15-HETE. For comparison intradermal injections of purified human complement split product C5a were performed in the absence or presence of 15-HETE. The skin response was evaluated by measuring the diameter of the wheal, the area of the flare and by intensity of the erythema (erythema index). LTB4 and C5a were injected at the concentration of 200 ng/ml. At this concentration the maximal skin response of LTB4 and C5a were equivalent. In contrast to C5a reaction, which resolved within 1 h, LTB4-induced skin response lasted up to 18 h. In all subjects the skin response was significantly decreased when LTB4 was injected together with 300 ng of 15-HETE. The decrease of wheal, flare, and erythema index averaged 81.9%, 56.6%, 53.6%, respectively, when all parameters were obtained at the maximal skin response. In contrast, the C5a-induced skin response was not affected by addition of 15-HETE, even when the final dose of 15-HETE was increased 10 times to 3 micrograms. The LTB4-induced reaction could last up to 18 h after injection. After the addition of 300 ng of 15-HETE the skin response resolved after 1 h. The present results demonstrate that 15-HETE is a specific inhibitor of the LTB4-induced skin response and brings additional evidence in support of the ability of 15-HETE to regulate the proinflammatory effects of LTB4 in vivo.

Adult↗