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1.
The haemopoietic recombinant human cytokines granulocyte and granulocyte-macrophage colony-stimulating factor (rhG-CSF and rhGM-CSF) are used to facilitate recovery of bone marrow function following cytotoxic chemotherapy. Recent clinical experience indicates that rhG-CSF is better tolerated than rhGM-CSF. Thus, we have compared the priming effects of rhG-CSF and rhGM-CSF on superoxide anion (O2-) generation and platelet-activating factor (PAF) synthesis by neutrophils. During a 60-min incubation of neutrophils with rhGM-CSF (1 nM) or recombinant human tumour necrosis factor-alpha (rhTNF-alpha; 0.3 nM), cell-associated PAF levels increased, and upon stimulation with FMLP (100 nM) there was a striking amplification of PAF formation (8-13-fold) and release (24-36-fold). In contrast, in rhG-CSF (1 nM)-primed cells, there was no increase in cell-associated PAF levels and neither PAF synthesis nor PAF release was amplified following stimulation with FMLP. On the other hand, each of rhG-CSF, rhGM-CSF or rhTNF-alpha increased subsequent FMLP (100 nM)-induced O2- generation (by 89%, 166% and 115%, respectively). These results suggest the existence of distinct intracellular signalling pathways for cytokine priming. Furthermore, some of the more severe adverse reactions to the administration of rhGM-CSF may be a result of the biosynthesis and/or release of the potent inflammatory mediator, PAF. 相似文献
2.
Regulation of the respiratory burst and its priming by recombinant human tumour necrosis factor-alpha (rhTNF-alpha) and platelet-activating factor (PAF) were investigated in human polymorphonuclear leucocytes (PMN). Adenosine (0.1-10 microM) pretreatment of PMN concentration-dependently inhibited the superoxide anion generation (O2-) in response to formyl-methionyl-leucyl-phenylalanine (FMLP). The priming by PAF (1 microM) for an increased O2- generation by FMLP-stimulated PMN was completely blocked by adenosine pretreatment. In contrast, rhTNF-alpha-induced priming was unaffected by adenosine. In addition, the direct stimulation of PMN O2- by rhTNF-alpha was also unaffected by adenosine as was rhTNF-alpha-induced PAF synthesis. FMLP-induced PAF synthesis was reduced by adenosine to a similar extent as the inhibition of the respiratory burst. Adenosine also inhibited PAF-, but not FMLP-induced increases in intracellular calcium in PMN. These findings indicate that short-term, direct stimulants (FMLP) or priming agents (PAF) are subject to modulation by the endothelial product adenosine, whereas the priming and direct stimulation of the respiratory burst by the longer-acting agent, rhTNF-alpha is unaffected. Moreover, differential inhibition of PMN activation by adenosine reveals important functional differences in the signalling mechanisms initiated by PAF, FMLP and rhTNF-alpha. 相似文献
3.
Endotoxin release may amplify the neutrophil (PMN) responses to bacterial infection through the release of monocyte-derived tumour necrosis factor (TNF). The present study was designed to assess the effect of recombinant human TNF-alpha (rhTNF-alpha) on the in vitro response of human PMN to two defined strains of pathogenic Escherichia coli. In the absence of rhTNF-alpha, a P-fimbriate strain caused significant release of the PMN secondary granule marker vitamin B12-binding protein (B12 BP), and a low level of release of leukotriene B4 (LTB4). Type 1-fimbriate strain 504, however, stimulated the release of the primary granule marker myeloperoxidase (MPO) and PMN chemiluminescence (CL), in addition to B12 BP and LTB4 release. Following rhTNF-alpha (10(-9) M) pretreatment, the release of LTB4 by PMN stimulated with the P-fimbriate strain was synergistically augmented, while B12 BP and MPO release were additively increased. In contrast, rhTNF-alpha did not significantly affect any of the responses by the type 1-fimbriate strain. These results suggest selectivity in the priming of PMN by rhTNF-alpha and confirm the independence of PMN responses to phagocytic stimuli. 相似文献
4.
The aim of the present work was to study interactions between the synthesis of platelet-activating factor (PAF) and leukotriene B 4 (LTB 4) in human polymorphonuclear leukocytes (PMNs) in vitro. PAF, at nanomolar concentrations, stimulated calcium ionophore A23187-activated PMNs to release LTB 4 and 5-hydroxyeicosatetraenoic acid (5-HETE). This seems to be a receptor-mediated process as it was blocked by a PAF receptor antagonist WEB 2086 (IC 50 6.6±3.9 M). Moreover, LTB 4 stimulated the formation of PAF in activated PMNs. WEB 2086 did not, however, alter PMN migration towards either LTB 4 or the chemotactic peptide FMLP. This suggests that the enhancement of PAF synthesis in response to LTB 4 is a concomitant event rather than a mediating process in LTB 4-induced chemotactic movement of PMNs. These effects are implicated in the complex network of interactions between inflammatory mediators that results accumulation and activation of PMNs in the exacerbation of inflammatory processes. 相似文献
5.
BACKGROUND: In vitro eosinophil (EOS) adhesion to recombinant human (rh)-vascular cell adhesion molecule (VCAM)-1 stimulates superoxide anion (O2-) generation and enhances formyl-methionyl-leucyl phenylalanine (FMLP)-activated O2- generation. Therefore, EOS adhesion via VLA-4 to VCAM-1 expressed on endothelium may be instrumental in the selective recruitment and function of EOS in airway inflammation. OBJECTIVE: We hypothesized that EOS interaction with endothelial cells expressing VCAM-1 will undergo an enhancement in inflammatory function. METHODS: To determine this possibility, human umbilical vein endothelial cells (HUVEC) were stimulated with either a combination of interleukin (IL)-4 and tumour necrosis factor (TNF)-alpha (100 pM) or medium alone for 24 h; the expression of adhesion proteins on HUVEC and their effect on EOS O2- generation was subsequently determined. RESULTS: As determined by both enzyme-linked immunosorbent assay and flow cytometry, IL-4 and TNFalpha acted synergistically to induce VCAM-1 expression on HUVEC. Treating HUVEC with IL-4/TNFalpha also increased EOS adhesion and primed subsequent FMLP (0.1 microM) activated EOS O2- generation. Although EOS adhesion was partially inhibited by both antialpha4 and antibeta2 monoclonal antibodies (MoAbs), O2- generation was completely inhibited by either antialpha4 integrin MoAb (HP1/2) or anti-VCAM MoAb (BBIG-V1). Furthermore, enhanced O2- generation, but not adhesion, associated with IL-4 + TNFalpha-treatment of HUVEC was inhibited when EOS were treated with the platelet activating factor (PAF)-antagonist WEB 2086 (20 microM), thus suggesting an involvement of PAF in priming EOS. However, paraformaldehyde fixation of IL-4/TFN-alpha treated HUVEC did not significantly alter EOS function. CONCLUSIONS: These results suggest EOS adhesion to endothelial cells via an VLA-4/VCAM-1 interaction may be important in the development of the function of this cell. Furthermore, our results suggest that modulation of EOS function involves two priming factors: EOS adhesion to HUVEC expressing VCAM-1 and PAF. 相似文献
6.
Neutrophil (PMN) activation by the yeast component zymosan involves the complement receptor type 3 (CD11b/CD18). Recombinant human tumour necrosis factor-alpha (rhTNF-alpha) augmented the zymosan-stimulated leukotriene B4 (LTB4) release from PMN, reaching a fourfold increase at 10(-9) M. Co-incubation of PMN with 10(-9) M rhTNF-alpha and staurosporine resulted in a further dose-dependent increase, which became significantly greater than a purely additive effect at a staurosporine concentration of 10 nM. This synergy was maintained at all doses of staurosporine tested. In addition, doses of phorbol 12-myristate 13-acetate (PMA) that do not activate protein kinase C (PKC) (below 10(-9) M) also augmented the zymosan-stimulated release of LTB4. However, doses of PMA above 10(-9) M progressively inhibited the response to levels below that of zymosan alone. Staurosporine at 50 nM completely prevented, and 10(-9) M rhTNF-alpha partially but significantly (P less than 0.02 at 10(-8) M PMA, P less than 0.01 at 10(-7) M PMA) reversed, this high-dose PMA inhibition. PKC activation thus opposes the priming effect of rhTNF-alpha on neutrophils, while PKC inhibition may enhance the ability of rhTNF-alpha to prime PMN for zymosan activation. The combined effect of rhTNF-alpha and staurosporine suggests an intracellular synergy rather than simply a direct action due to increased zymosan receptor expression. Thus there appear to be mechanisms whereby the responses of neutrophils may be augmented without activating PKC. Indeed, kinase activation may even exert a degree of feedback control that is antagonized by rhTNF-alpha treatment. 相似文献
7.
The degranulation response of purified human eosinophils to platelet-activating factor (PAF) has been studied. PAF induced release of eosinophil peroxidase (EPO) and beta-glucuronidase from highly purified human eosinophils with an EC50 of 0.9 nM. The order of release was comparable with that induced by phorbol myristate acetate (PMA). The new specific PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-H-thieno[3,2-f] [1,2,4]triazolo-[4,3a][1,4]-diazepin-2-yl](4-morpholinyl)- 1-propane-one (WEB 2086) inhibited the PAF-induced enzyme release by human eosinophils in a dose-dependent manner. The viability of eosinophils were unaffected both by PAF and WEB 2086. The results suggest that PAF may amplify allergic and inflammatory reactions by release of preformed proteins from eosinophil granules. 相似文献
8.
A critical role for leukotriene B(4) (LTB(4)) and/or platelet-activating factor (PAF) in regulating polymorphonuclear cell (PMN) trafficking to inflammatory sites has been reported in a number of experimental inflammatory models. In vitro, newly synthesized LTB(4) and PAF were shown to act in an autocrine/paracrine or intracrine fashion to enhance intracellular arachidonic acid availability and leukotriene biosynthesis. This suggested potentially cooperative effects of these lipid mediators in regulating PMN extravasation. The present study aimed to elucidate whether endogenous LTB(4) and PAF may both act to regulate plasma extravasation and PMN trafficking to inflammatory sites in experimental inflammation. With this aim, we have used selective and potent PAF and LTB(4) receptor antagonist pretreatments in dermal and pulmonary inflammation models in rats. Our results show additive inhibitory effects of dual LTB(4) and PAF receptor blockade in either PAF- or LTB(4)-elicited cutaneous PMN accumulation compared to single-drug administration. Furthermore, the combined administration of the drugs inhibited the PMN accumulation induced by the chemically unrelated soluble agonists tumour necrosis factor-alpha and C5a. Finally, in a model of pulmonary inflammation induced by the intravenous injection of Sephadex beads, lung neutrophilia was reduced by 63% following the administration of LTB(4) and PAF antagonists, in contrast with the lack of effect of single drug administration. Our results strongly support a role of both endogenous LTB(4) and PAF in regulating PMN trafficking to inflammatory sites in various experimental conditions. 相似文献
9.
Nedocromil sodium (Tilade) is an effective therapeutic agent against asthma and has been shown to exhibit antiinflammatory activity in vitro; however, its mode of action is yet to be described fully. Using an in vitro assay designed to mimic the extravasation of neutrophils from the peripheral circulation through cellular barriers to sites of inflammation, the effect of nedocromil sodium on chemoattractant-stimulated neutrophil migration was examined. We also examined the effects of WEB 2086, a platelet-activating factor (PAF) receptor antagonist, in parallel. Neutrophils and the cellular barrier were pretreated and/or co-incubated with nedocromil or WEB 2086 and the effects on neutrophil chemotaxis measured. In all treatments, nedocromil did not significantly affect chemotaxis through cellular or noncellular barriers to N-formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4), or PAF. In contrast, WEB 2086 inhibited PAF-induced neutrophil migration through both naked filters and endothelial and epithelial monolayers cultured on these filters. We conclude that while nedocromil has been shown to have inhibitory effects on neutrophils and is an effective therapeutic agent for asthma and inflammatory conditions, its activity is not primarily mediated by inhibition of neutrophil chemotaxis. Platelet-activating factor antagonists may partially be effective in asthma through inhibitory effects on neutrophil chemotaxis. 相似文献
10.
The spontaneous and stimulated generation of fatty acid cyclo-oxygenase pathway-derived products of arachidonic acid from highly purified (91.6 +/- 1.3%, n = 23) human blood eosinophils obtained from asthmatics were examined using combined gas chromatography/mass spectrometry. Under resting conditions, eosinophils spontaneously generated 0.24 +/- 0.10 pg prostaglandin E2 (PGE2), 0.51 +/- 0.20 prostaglandin D2 (PGD2), 0.35 +/- 0.10 pg prostaglandin F2 alpha (PGF2 alpha) and 8.5 +/- 2.2 pg thromboxane B2 (TXB2), the stable metabolite of TXA2 per 10(6) cells. In contrast, 6-keto-prostaglandin F1 alpha and 9 alpha,11 beta-prostaglandin F2 were not detectable. Stimulation of eosinophils with platelet-activating factor (PAF) for 5 min induced a two- to sixfold increase in the biosynthesis of prostanoids. More than 95% of the generated prostanoids were released into the surrounding medium. The response to PAF was inhibited by the PAF receptor antagonist WEB 2086 (1 microM). The fatty acid cyclo-oxygenase inhibitor, ibuprofen, abolished both the spontaneous and PAF-stimulated generation of prostanoids by eosinophils. LTB4, PMA and calcimycin also produced an increase in prostanoid production, whereas lyso-PAF, the PAF precursor and metabolite, failed to induce prostanoid generation over basal production. In conclusion, the results demonstrate that PAF potently activates human eosinophils to generate and release several fatty acid cyclo-oxygenase metabolites of the arachidonic acid pathway, with TXB2 being the most abundant. These data are in agreement with previous observations suggesting that PAF may be an important stimulus for prostanoid release by the eosinophil in allergic diseases such as asthma. 相似文献
11.
WEB 2086, an antagonist of platelet-activating factor (PAF), was assessed against the cutaneous response in vivo and the aggregation of platelets ex vivo induced by PAF in a double-blind, placebo-controlled, crossover study in 12 normal male volunteers. Wheal-and-flare responses to intradermal PAF (200 ng) and histamine (1 microgram) were measured 1 hour after placebo or control administration. Wheal volumes were significantly reduced by 66% +/- 8.7% (mean +/- SEM), 86% +/- 8.3%, and 90% +/- 6.0% after 10, 40, and 100 mg of WEB 2086 compared to placebo administration (p less than 0.005). Flare responses were correspondingly inhibited by 66% +/- 8.3%, 82% +/- 8.7%, and 84% +/- 7.8% at 10, 40, and 100 mg of WEB 2086, respectively. Cutaneous responses to histamine were unaffected. Ex vivo platelet responses to PAF were significantly inhibited at all three doses of WEB 2086. Oral WEB 2086 is a potent and specific inhibitor of cutaneous and platelet responses to PAF in man. 相似文献
12.
We observed that human monocytes (MO) and polymorphonuclear neutrophils (PMN) stimulated by lipopolysaccharide (LPS) produce platelet-activating factor (PAF) in a pattern characterized by an early and a delayed peak of synthesis. The early peak of PAF synthesis was due to a direct stimulation of these cells through mCD14 receptor as it was inhibited by anti-CD14 monoclonal antibody. The delayed and sustained peak of PAF synthesis was dependent on protein synthesis and cytokine production as shown by the inhibitory effect of cycloheximide on both MO and PMN, and of anti-tumour necrosis factor-alpha (anti-TNF-alpha) and of anti-interleukin-8 (anti-IL-8) neutralizing antibodies on MO and PMN respectively. IL-10 completely prevented this second, cytokine-dependent peak of PAF synthesis. In contrast, IL-10 markedly enhanced the first peak of PAF synthesis both in MO and PMN. Moreover, IL-10 was shown to modulate the production of superoxide anions (O2-) on both MO and PMN. As suggested by previous studies, IL-10 inhibited the delayed production of O2-. In the present study, we observed that IL-10 directly stimulated an early production of O2-. In addition, IL-10 enhanced the synthesis of O2- by MO and PMN challenged with LPS. The IL-10-induced O2- production was dependent, at least in part, from its effect on PAF synthesis, as it was inhibited by the PAF receptor antagonist WEB 2170. These results suggest that IL-10 may upregulate the early synthesis of PAF and O2- triggered by direct LPS stimulation, whereas it may downregulate the delayed production of these mediators. 相似文献
13.
In the present study, we have investigated the effect of the short-term incubation of polymorphonuclear leucocytes (PMN) with infectious Epstein-Barr virus (EBV) on leukotriene B(4) (LTB(4)) biosynthesis. Pre-exposure of PMN to EBV led to an increased production of LTB(4) upon stimulation with either the ionophore A23187, the chemotactic peptide fMLP, or phagocytic particles (zymosan). Experiments performed with viral particles pretreated with a neutralizing antibody raised against the gp350 of the viral envelope revealed that a specific interaction between the PMN surface and the viral glycoprotein gp350 is required for the priming effect of EBV. Preincubation of PMN with EBV resulted in an increased release of arachidonic acid upon stimulation with a second agonist. Moreover, LTB(4) biosynthesis in EBV/A23187-treated PMN was greatly diminished in the presence of an inhibitor of the cytosolic phospholipase A2 (cPLA(2)), suggesting that cPLA(2) plays a critical role in the priming effect of EBV. Accordingly, EBV by itself promoted Ser-505 phosphorylation of cPLA(2) and strongly enhanced fMLP-induced phosphorylation of p38 MAP kinase, an enzyme known to phosphorylate cPLA(2) in human PMN. Furthermore, fMLP-induced translocation of cPLA(2) was strongly enhanced when PMN were previously exposed to EBV. These data indicate that binding of EBV to human PMN results in the activation of intracellular events involved in the release of pro-inflammatory lipid mediators. 相似文献
14.
We studied the influence of a selective 5-lipoxygenase inhibitor, AA861, on the generation of the superoxide anion (O2-) and the lipoxygenase metabolites by human polymorphonuclear leukocytes (PMN). PMN produce O2- in a dose-dependent manner following stimulation with arachidonic acid (AA), leukotriene B4 (LTB4), or C5a. When PMN were stimulated with one of those three agents in the presence of high doses of AA861 (1-10 micrograms/ml), a significant reduction of O2- release was observed. In contrast, the generation of O2- by PMN stimulated by LTB4 was potentiated at lower concentrations of AA861 (0.025-0.25 micrograms/ml). However, stimulation with AA or C5a did not influence O2- generation in the presence of AA861 at the same concentration range. Furthermore, treating the PMN with the cyclooxygenase inhibitor, acetylsalicylic acid, did not potentiate the generation of O2- by stimulation with LTB4 over a wide range of concentrations. Quantification of lipoxygenase metabolites by reverse-phase high-performance liquid chromatography revealed that a high concentration of AA861 (0.5-5 micrograms/ml) completely inhibited the production of LTB4 and its omega-oxidative metabolites by PMN following stimulation with 100 microM AA, but only partially inhibited that of 5-hydroxyeicosatetraenoic acid (5-HETE). AA861 at a concentration of 5 micrograms/ml significantly increased the production of 15-HETE by PMN following the same stimulation. AA861 did not influence catabolism of LTB4 added to the reaction mixture to its omega-oxidative products by PMN over a wide range of concentrations. These findings suggest that the inhibition of 5-lipoxygenase metabolism may stimulate 15-lipoxygenase in human PMN.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
15.
Stimulation of human neutrophils with zymosan particles resulted in a dose-response release of IL-8 in the 24 h culture supernatant, measured using a specific radioimmunoassay. IL-8 was detected after 8 h (0.11±0.08 nM) and peaked at 24 h (2.81±0.85 nM). Two distinct PAF receptor antagonists, WEB 2086 and UK 74505 produced a dose-dependent inhibition of zymosan-induced IL-8 release. This inhibitory action was maximal (68% 10−6
M WEB 2086; 71% 10−8
M UK 74505) when the drug was co-administered with zymosan, becoming progressively less effective when administered at increasing intervals after addition of zymosan. In contrast, a specific LTB4 antagonist, LY 255283, an IL-1 receptor antagonist and an anti-human TNFα antibody were unable to modulate the response indicating that these mediators are not involved. This study provides the first direct evidence of a central role for the phospholipid mediator PAF in the pathway of IL-8 release, following neutrophil activation by a particulate stimulusin vitro. 相似文献
16.
Platelet-activating factor (PAF) is a potent contractile agonist in guinea pig peripheral lung strips. Whether PAF acts via specific receptor sites in the lung has not been fully established. To determine if specific receptor sites could be demonstrated in guinea pig peripheral lung tissue, we performed direct radioligand binding studies in tissue homogenates with [3H]C16-PAF (1-O-hexadecyl-sn-glyceryl-3-phosphorylcholine) and the PAF antagonists [3H]WEB 2086 and [3H]RP52770. These studies demonstrated binding sites for [3H]C16-PAF of high affinity (Kd of 2.6 nM from saturation isotherms and 0.9 nM from kinetic experiments) and a mean density of 200 fmol/mg protein. Binding was inhibited to the same degree with unlabeled C16-PAF, WEB 2086, and RP52770, all with pseudo-Hill slopes of unity. [3H]WEB 2086 binding demonstrated a receptor density similar to that of [3H]C16-PAF (226 fmol/mg protein) and was inhibited to the same degree by unlabeled C16-PAF, C18-PAF, WEB 2086, and RP52770. Although antagonist inhibition yielded pseudo-Hill slopes near unity, agonist inhibition slopes were shallow, suggesting two types or states for the PAF receptors. Direct binding studies with [3H]RP52770 revealed a much larger density of binding sites (1,200 fmol/mg protein), and this binding was not inhibited with C16-PAF, C18-PAF, WEB 2086, or lyso-PAF. These results indicate that guinea pig lung has specific binding sites for [3H]C16-PAF, that WEB 2086 is an effective antagonist of C16- and C18-PAF binding at these sites, and that RP52770 binds to the PAF site but, in addition, binds to another site with a much greater density. 相似文献
17.
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. 相似文献
18.
The phospholipid inflammatory mediator platelet activating factor (PAF) has been shown to stimulate certain functions of polymorphonuclear leukocytes (PMN). However, the effect of PAF on surface complement receptors of PMN has not been described. Using monoclonal antibodies and flow cytometry, we have assessed the effects of PAF on surface expression of membrane receptors for C3bi (CR3) and C3b (CR1) in human PMN. PAF (optimal concentration of 1 x 10(-8) M) increased CR3 190% and CR1 174% compared with unstimulated cells at 37 degrees C, while the PAF analogue lyso-PAF had no stimulatory effect. Both CR3 and CR1 responses to PAF reached maximum levels at 15-30 min. PAF effects were comparable to peak effects induced by LTB4 but less than induced by FMLP. A PAF receptor antagonist, SRI 63-441, blocked the increased complement receptor expression in a dose-dependent manner with maximal inhibition of 80-95% at 5 x 10(-6) M. Extracellular calcium had no effect on CR1 expression but slightly enhanced and EGTA partially inhibited the PAF-induced increase in CR3 expression. Simultaneous incubation with PAF and LTB4 enhanced CR3 and CR1 expression more than either agent alone. These findings indicate that PAF, alone and in combination with LTB4, can induce altered expression of complement receptors on the surface of PMN. This effect may enhance adhesion and phagocytosis by PMN at inflammatory reaction sites. 相似文献
19.
We have examined the interaction between the cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor α (TNFα) on polymorphonuclear leukocyte (PMN) function and on PMN responses to further stimulation with formyl Met Leu Phe (fMLP). Incubation of PMN with TNFα (0.3 nM) and, to a lesser extent, with GM-CSF (1 nM) directly stimulated superoxide anion (O
−2
) generation and increased the response to subsequent stimulation of PMN by fMLP (100 nM). However, the combination of GM-CSF and TNFα did not result in increased O
−2
generation and there was no synergistic effect of the combination of these cytokines on the priming of fMLP-induced O
−2
generation. The combination of TNFα and GM-CSF did result in a striking synergism in the stimulation of PAF generation, and, whereas neither stimulus alone resulted in detectable PAF release, the combination elicited the release of significant levels of PAF. The observation of significant PAF release from PMN exposed to TNFα and GM-CSF indicates that overt neutrophil stimulation with phagocytic or soluble stimuli may not be required for expression of at least some of the PMN pro-inflammatory capacity. 相似文献
20.
Platelet activating factor (PAF) mimics the effects of Culicoides antigen by inducing oedema and inflammatory cell accumulation in the dermis of horses with the allergic skin disease, sweet itch. PAF could therefore contribute to antigen-induced inflammatory changes in these horses. We now report that intravenous administration of the PAF receptor antagonist WEB 2086 (3mgkg –1), at a dose that inhibited the vascular and cellular responses to PAF in sweet itch horses, reduced Culicoides antigen-induced oedema at 1 h by 73% and at 8h by 71% (p<0.05). Neutrophil accumulation and eosinophil recruitment were not significantly reduced by WEB 2086 or a second hetrazepine PAF receptor antagonist WEB 2170 (0.1mgkg –1). These findings suggest a key role for PAF in oedema formation, but not inflammatory cell accumulation, induced by Culicoides antigen in the skin of sweet itch horses. 相似文献
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