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PubMed1976

Modulation of human eosinophil polymorphonuclear leukocyte migration and function.

Eosinophil migration toward a concentration gradient of a chemotactic factor is regulated at four levels. Diverse immunologic pathways generate stimuli with eosinophil chemotactic activity, including the complement products C5a and a fragment of C3a and the peptide products of mast cells and basophils activated by IgE-mediated reactions, such as eosinophil chemotactic factor of anaphylaxis (ECF-A) and other oligopeptides. The intrinsic preferential leukocyte activity of the chemotactic stimuli represents the second level of modulation, with ECF-A and other mast cell-derived peptides exhibiting the most selective action on eosinophils. The third level of control of eosinophil chemotaxis is composed of inactivators and inhibitors of chemotactic stimuli and is exemplified by degradation of C5a by anaphylatoxin inactivator or chemotactic factor inactivator and of ECF-A by carboxypeptidase-A or aminopeptidases. The activity of ECF-A is uniquely suppressed by equimolar quantities of its NH2- terminal tripeptide substituent, presumably by eosinophil membrane receptor competition. Factors comprising the fourth level of regulation, which alter eosinophil responsiveness to chemotactic stimuli, include the chemotactic factors themselves, through deactivation; nonchemotactic inhibitors such as the COOH-terminal tripeptide substituent of ECF-A, the neutrophil-immobilizing factor (NIF), the phagocytosis-enhancing factor Thr-Lys-Pro-Arg, and histamine at concentrations greater than 400 ng/ml; and nonchemotactic enhancing principles represented by ascorbate and by histamine at concentrations of 30 ng/ml or less. Local concentrations of eosinophils called to and immobilized at the site of a hypersenitivity reaction may express their regulatory functions by degrading the chemical mediators elaborated including histamine, slow-reacting substance of anaphylaxis (SRS-A), and platelet-activating factor (PAF) by way of their content of histaminase, arylsulfatase B, and phospholipase D, respectively. Immunologic pathways may thus provide the capability for early and specific host defense reactions with a later influx of eosinophils preventing irreversible local tissue alterations or distant organ effects.

Anaphylaxis↗
PubMed1994

Tumor necrosis factor induces a selective shedding of its p75 receptor from human neutrophils.

The effect of tumor necrosis factor alpha (TNF) on the expression of its specific receptors (p55 TNF-R and p75 TNF-R) on the surface of human neutrophils (PMN) and mononuclear cells (MNC) was investigated and compared to the effect of various agonists. PMN and MNC express both p55 and p75 TNF-R on their membranes. Within minutes of incubation with chemotactic factors or calcium ionophore A23187, both types of TNF-R were down-regulated from the surface on both cell populations. At the same time, soluble forms of these TNF-R appeared in supernatants, in amounts proportional to the extent of down-regulation induced by each stimulus, suggesting that shedding is the major mechanism leading to loss of p55 and p75 TNF-R upon activation with these agonists. Likewise, TNF induced 60-80% and 73-90% decreases in PMN surface p55 TNF-R and p75 TNF-R, respectively. However, modulation of the two types of TNF-R by TNF proceeded through different mechanisms. TNF induced a selective shedding of the p75 TNF-R since, by both enzyme-linked immunosorbent assay and Western blot analysis, only the p75 TNF-R was detected in supernatants of cells stimulated with TNF. Down-modulation of surface p55 TNF-R most probably resulted from TNF-induced receptor internalization, since 125I-TNF bound to PMN p55 TNF-R was rapidly internalized with a t1/2 = 5 min and preincubation of PMN with TNF inhibited by 68 +/- 6% the release of p55 TNF-R triggered upon subsequent treatment with A23187. The apparently unique property of TNF to induce a differential modulation of the two types of TNF-R at the surface of PMN and MNC might play an important role in the control of peripheral blood cell responses to TNF.

Adult↗
PubMed1993

Eosinophil accumulation induced by human interleukin-8 in the guinea-pig in vivo.

Interleukin-8 (IL-8) is a neutrophil chemoattractant cytokine. Initially IL-8 appeared to exhibit specificity for neutrophils over other cells of the immune system. However, several recent studies have shown that this mediator can also activate other leucocyte types in vitro. In this study we have used an in vivo model of local [111In]leucocyte accumulation in the guinea-pig and an in vitro assay of leucocyte activation (changes in cytosolic-free Ca2+) to investigate the eosinophil chemoattractant activity of IL-8. The intradermal injection of recombinant human (rh)IL-8 induced a dose-dependent accumulation of intravenously administered [111In]eosinophils into the skin sites over 4 hr. Time-course experiments revealed that this cell infiltration was delayed in onset, occurring between 1 and 2 hr after injection of IL-8. The delay may indicate that IL-8 operates via an indirect mechanism. In contrast, eosinophil accumulation induced by the complement fragment C5a occurred within the first hour following injection. Other human cytokines, IL-1, IL-3, IL-5, tumour necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), were not eosinophil chemoattractants in this in vivo test system. Direct activation of eosinophils by IL-8 was demonstrated in vitro by a transient elevation in cytoplasmic-free Ca2+ levels where it was less potent than either rhC5a or leukotriene B4 (LTB4). Experiments using [111In]neutrophils in vivo indicated that rhIL-8 and rhC5a were similar in potency in inducing local neutrophil infiltration into guinea-pig skin. The demonstration of the eosinophil chemoattractant activity of IL-8 in vivo raises the possibility that this cytokine, or a structurally related molecule, contributes towards eosinophil infiltration in a number of inflammatory conditions such as asthma, helminthic infections and adult respiratory distress syndrome.

Animals↗
PubMed1993

Effects of alpha 1-proteinase inhibitor on chemotaxis and chemokinesis of polymorphonuclear leukocytes: its possible role in regulating polymorphonuclear leukocyte recruitment in human subjects.

A variety of biologic products derived from bacteria, inflammatory cells, and active degraded proteins have been identified as having chemotactic activity essential for polymorphonuclear leukocyte (PMN) recruitment to the site of inflammation. Little is known, however, concerning factors responsible for regulating the intensity and duration of PMN recruitment. Evidence is growing that proteinase inhibitors modify the migrating ability of PMNs, although the physiologic implications of this have eluded clarification. In an attempt to hypothesize a role of alpha 1-proteinase inhibitor (alpha 1-Pi) in PMN recruitment to inflammatory sites, we examined the effects of alpha 1-Pi in different physiologic concentrations on PMN migration with a microchemotaxis chamber technique. Alpha 1-proteinase inhibitor had both stimulatory and inhibitory effects on cell migration, depending on its concentration. The inhibitor was active in inducing both directed locomotion (chemotaxis) and nondirected locomotion (chemokinesis) in concentrations of 0.02, 0.2, and 2 mg/ml, with maximum potency in both cases at 0.2 mg/ml (corresponding to the normal alveolar surface fluid level in the lung). Alpha 1-proteinase inhibitor impaired chemotactic responsiveness to known chemoattractants at 2 and 10 mg/ml (corresponding to normal and inflammatory blood levels, respectively) in order of potency. These results suggest that alpha 1-Pi may play a role in regulating inflammatory processes, especially in the lung, through its stimulatory and inhibitory effects, depending on its concentration.

Chemotaxis, Leukocyte↗
PubMed1993

Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators.

Neutrophil apoptosis leads to macrophage ingestion of intact senescent neutrophils. This may represent a neutrophil removal mechanism that is important both in the control of inflammatory tissue injury and for the normal resolution processes of inflammation. Because apoptosis is likely to be a key control process in cell and tissue homeostasis, a number of inflammatory mediators were tested for their ability to modulate the rate of apoptosis in populations of neutrophils aging in culture. Endotoxic lipopolysaccharide, human recombinant complement factor 5a, and human recombinant granulocyte-macrophage colony-stimulating factor all markedly inhibited the rate of neutrophil apoptosis in a concentration-dependent fashion, without inducing necrosis (as assessed by trypan blue exclusion). This inhibitory effect on the rate of neutrophil apoptosis was shown by morphological criteria and confirmed by gel electrophoresis of extracted DNA. Inhibition of apoptosis of aging neutrophil populations was associated with prolongation of the functional life span of the population as assessed by the ability of neutrophils to spread on glass surfaces, to polarize in response to deliberate stimulation with N-formyl-Met-Leu-Phe (fMLP), and to release the granule enzyme marker myeloperoxidase on fMLP stimulation. These observations show that inflammatory mediators prolong the functional life span of neutrophils through modulation of apoptosis. Further elucidation of these mechanisms will lead to a better understanding of the processes controlling neutrophil residence and function in inflamed tissues and may provide further insights into the molecular mechanisms of apoptosis, which is of widespread importance in tissue biology.

Apoptosis↗
PubMed1995

Continuous hemofiltration as blood purification in sepsis.

Continuous hemofiltration was first described as a new form of renal replacement for critically ill patients in the late 1970s. Since then, it has undergone remarkable technical and conceptual modifications and has become a widely used form of dialytic therapy in the ICU. More recent insights into the pathogenesis of sepsis and the role of soluble molecules in the mediation of organ injury during septic shock have led to a resurgence of the concept of blood purification during life-threatening infection. Recent studies have confirmed that cytokine extraction occurs in vivo in humans during continuous hemofiltration and that other smaller, potentially noxious molecules such as platelet-activating factor, complement factors C5a and C3a, and thromboxane are also removed from the circulation of septic patients or animals. Experimental studies have shown that continuous hemofiltration has beneficial hemodynamic effects in septic animals and that such effects may correlate with the intensity of ultrafiltration. Cardiac function also appears to improve and myocardial depressant factors are removed from the circulation. Continuous hemofiltration offers some promise as an adjunctive form of treatment in severe sepsis.

Animals↗
PubMed1996

Possible involvement of C5/C5a in the efferent and elicitation phases of contact sensitivity.

The elicitation of 24-h contact sensitivity (CS) in mice requires a serotonin-dependent, 2-h response called CS initiation. We studied the role of complement (C) by comparing CS in DBA/1 (C5-normal) vs DBA/2 (C5-deficient) mice and found impaired 2-h, but not 24-h, CS. We showed previously that 2-h responses represent CS initiation and are required for elicitation of 24-h responses. Treatment of C5-deficient mice with absent macroscopic responses (ear swelling) with a selective serotonin antagonist inhibited 24-h CS, suggesting that C5-deficient mice had submacroscopic (i.e., microscopic), serotonin-dependent CS initiation. When normal mouse serum was used as a source of C5 to reconstitute C5-deficient mice, significant 2-h responses were restored. Furthermore, heat treatment of normal mouse serum to inactivate C abrogated restoration of 2-h responses. Thus, C5 was suggested to be involved in CS initiation. Using a suboptimal immunizing dose of Ag revealed an impaired 24-h component of CS in DBA/2 mice, but not in DBA/1 mice, and also in C5-deficient B10.D2/o mice compared with C5-normal B10.D2/n mice with a suboptimal eliciting dose of Ag. Again, reconstitution of B10.D2/o mice with normal mouse serum restored deficient 24-h CS responses. Thus, 2-h and classical 24-h CS probably depend in part on C5. These results imply that C5 may play a role in the elicitation of 24-h CS, probably via required preceding CS initiation.

Animals↗
PubMed1996

Priming of eosinophil recruitment in vivo by LPS pretreatment.

Eosinophils are important inflammatory cells in allergic diseases. Recent evidence suggests that priming mechanisms in the blood may be important for effective eosinophil recruitment to sites of allergic inflammation. We have investigated whether priming an inflammatory site could enhance eosinophil recruitment in vivo. Pretreatment of skin sites in the guinea pig with a low dose (30 ng) of LPS, which had little effect on eosinophil accumulation alone, enhanced by up to threefold the 111In-eosinophil accumulation in response to a passive cutaneous anaphylactic reaction and to intradermally injected eosinophil chemoattractants (leukotriene B4, PAF, and C5ades Arg). In contrast, LPS pretreatment did not enhance accumulation of 111In-neutrophils. Priming was seen only with a 1-h pretreatment time and was not associated with an increase in local edema or a change in cutaneous blood flow. It was independent of local protein synthesis, as assessed using cycloheximide, and was unaffected by a PAF antagonist, a 5-lipoxygenase inhibitor, and the IL-1 receptor antagonist. The priming response was, however, reduced by co-injection with the LPS of TNFR-IgG, but not of CD4-IgG. Blockade of CD18 showed this adhesion molecule to be critical for eosinophil accumulation, and LPS-primed sites were inhibited as effectively as nonprimed sites. In conclusion, low dose LPS pretreatment of guinea pig skin sites primes for eosinophil accumulation induced by intradermally injected inflammatory mediators and cutaneous anaphylactic reaction. This may be an important process by which eosinophil recruitment is modulated in vivo.

Animals↗
PubMed1996

The role of basophils in allergic disease.

During allergic disease, leucocytes infiltrate the affected tissues and release their mediators and cytokines. In this way, the local inflammatory process is induced and maintained. Basophilic granulocytes have been demonstrated in lung and sputum of allergic asthmatics, in nasal mucosa and secretion of allergic rhinitis patients, and in skin lesions of atopic dermatitis patients. The number of basophils correlates with the severity of the disease. Analysis of mediator profiles and cellular contents of lavages of nose, skin and lung during allergic late-phase reactions (LPR) have demonstrated histamine, but not tryptase or prostaglandin D2. The histamine-containing cells have been characterized as basophilic granulocytes. This indicates that infiltrating basophils but not mast cells are activated and release their inflammatory contents in the LPR. We are interested in the cellular mechanisms that determine the degranulation of basophils during LPR. Basophil activators, such as allergens and activated complement, are not present at these sites. However, cytokines that prime basophils but do not induce degranulation, such as interleukin-5 (IL-5) and granulocyte/macrophage colony-stimulating factor (GM-CSF), have been detected at sites of LPR. We have now observed that after emptying intracellular Ca2+ stores by means of the Ca2+ adenosine triphosphatase (ATPase) inhibitor, thapsigargin, basophils become extremely sensitive to stimuli that do not affect the Ca2+ stores themselves but that induce degranulation, such as the phorbolester, phorbol myristate acetate (PMA). The most interesting finding was that although both thapsigargin and IL-3, IL-5 or GM-CSF do not induce basophil degranulation by themselves, a 2 min preincubation of basophils with thapsigargin followed by addition of one of these cytokines resulted in extensive histamine release: IL-3 induced 71 +/- 7% histamine release (conc1/2max 6 pM), IL-5 induced 43 +/- 8% histamine release (conc1/2max 41 pM) and GM-CSF induced 57 +/- 10% histamine release (conc1/2max 140 pM). Interestingly, the effect of thapsigargin could be mimicked by platelet-activating factor (PAF) (range 10(-9) to 10(-6) M), although to a lesser extent. Our results indicate that basophil degranulation in tissues during late-phase reactions might be caused by a combination of mediators or cytokines depleting Ca2+ stores, as platelet-activating factor or thapsigargin do, concurrent with activation by interleukin-3, interleukin-5 or granulocyte/macrophage colony-stimulating factor. The response of the basophils towards these cytokines might also be influenced by cell adhesion events, such as binding of basophils via integrins. This is the subject of further study.

Asthma↗
PubMed1996

The effect of salmeterol and nimesulide on chemotaxis and synthesis of PAF and LTC4 by human eosinophils.

Salmeterol is a long-acting beta 2-adrenoceptor agonist, with several antiasthma properties. Nimesulide is a nonsteroidal anti-inflammatory drug, supposed to act by inhibition of phosphodiesterase type IV. This might indicate that the effects of both drugs are mediated by an increase in cyclic adenosine monophosphate (cAMP). For salmeterol, it has been shown that it inhibits the influx of eosinophils into the lungs of guinea-pigs after platelet-activating factor (PAF) challenge, suggesting an effect of cAMP on eosinophil migration. For neutrophils, it has been shown that PAF synthesis is inhibited by cAMP. In the present study, we have, therefore, measured the effect of salmeterol and nimesulide on two important human eosinophil functions: chemotaxis; and synthesis of PAF and leukotriene C4 (LTC4). Both drugs were found to be inhibitors of the chemotactic responses of human eosinophils. However, at comparable concentrations, only nimesulide was able to inhibit the synthesis of PAF and LTC4 in activated eosinophils. These results indicate that although the effects of both drugs are thought to be mediated by an increase in cyclic adenosine monophosphate, they have differential effects on eosinophil chemotaxis and synthesis of lipid mediators.

Adrenergic beta-Agonists↗
PubMed1996

[Effects of injectio reduqing on plasma IL-8 and nitric oxide levels in rabbits with endotoxin induced disseminated intravascular coagulation].

Experiments were performed for investigating the effects of Injectio Reduqing (RDQ) on plasma interleukin-8 (IL-8), NO2-/NO3-, complement 5a(C5a) and polymorphonuclear neutrophilic leukocyte (PMN) Chemotaxis Index (CI) in rabbits with endotoxin-induced disseminated intravascular coagulation (DIC). The results showed that plasma IL-8, NO2-/NO3-, C5a and CI levels of PMN increased markedly in model group, which were confirmed pathologically with obvious damage of tissues or organs. While in RDQ group the abov-mentioned parameters and damage of tissues or organs were reduced significantly (P < 0.01). The results suggested that the IL-8 and NO might be involved in pathogenesis of endotoxin-induced DIC, and RDQ could be used in preventing or treating DIC through mechanism of regulation of cytokines network.

Animals↗
PubMed1998

Phosphatidylinositol 3-kinase mediates chemoattractant-stimulated, CD11b/CD18-dependent cell-cell adhesion of human neutrophils: evidence for an ERK-independent pathway.

We examined the role of phosphatidylinositol 3-kinase (PI 3-K) in FMLP-stimulated cell-cell adhesion of human neutrophils. The specific PI 3-K inhibitors wortmannin and LY294002 inhibited neutrophil homotypic aggregation stimulated by chemoattractants such as FMLP (50% inhibitory concentration (IC50) approximately 11 nM and 13 microM, respectively) but not PMA. Wortmannin also inhibited FMLP-stimulated adhesion of neutrophils to human endothelial cell monolayers, suggesting a common signaling pathway for homotypic and heterotypic adhesion. Neither CD11b/CD18 expression nor expression of an activation-specific epitope of CD11b/CD18 was affected by wortmannin in FMLP-stimulated cells. Moreover, wortmannin also inhibited the aggregation of egranulate neutrophil cytoplasts that lack the capacity for CD11b/CD18 up-regulation. Although wortmannin inhibited neutrophil lysosomal enzyme release, it had no effect on FMLP-stimulated up-regulation of CD35 in intact neutrophils, suggesting discrepant signaling pathways for specific granule degranulation and secretory vesicle release. Aggregation of human neutrophils is associated with activation of the mitogen-activated protein kinases Erk1 and -2, and Erk is activated in response to PI 3-K in some cell types. However, wortmannin inhibited FMLP stimulation of neutrophil Erk only at concentrations (IC50 > or = 1 microM) inconsistent with an effect on PI 3-K. Our data indicate that PI 3-K mediates neutrophil adhesion by a mechanism independent of CD11b/CD18 up-regulation, suggesting that PI 3-K acts either parallel to, or downstream of, Erk.

Androstadienes↗
PubMed1998

Adhesion-dependent release of elastase from human neutrophils in a novel, flow-based model: specificity of different chemotactic agents.

Neutrophils must adhere to the vessel wall, migrate, and degranulate in an ordered manner to perform their protective function. Disruption of these processes may be pathogenic. Current knowledge of the degranulation process is derived almost exclusively from studies on neutrophils in suspension, in which priming with the nonphysiological agent cytochalasin B is necessary to obtain elastase release in response to activating agents. To avoid this, we have adopted a different approach. Using a novel flow-based adhesion system, we have been able to quantify the release of elastase from the primary granules of activated neutrophils adherent to immobilized platelets or purified receptors without priming. Comparing stimuli, formyl tripeptide (fMLP), interleukin-8 (IL-8), activated complement fragment C5a, and platelet-activating factor (PAF) all induced rapid conversion to CD11b/CD18 (MAC-1) -mediated stationary adhesion when perfused over neutrophils already rolling on platelet monolayers or purified P-selectin. However, fMLP, C5a, and IL-8, but not PAF, induced release of elastase from the adherent cells in minutes. Neutrophils stimulated in suspension showed little degranulation. Treatment of neutrophils with an inhibitor of 5-lipoxygenase-activating protein (MK886) and thus synthesis of leukotrienes (LTs) or with an antagonist of the LTB4 receptor (LY223982) blocked the release of elastase. This indicated that endogenous synthesis of 5-lipoxygenase products such as LTs and autocrine activation of neutrophils was required for fMLP-driven elastase release. We hypothesize that the differential ability of PAF and fMLP to induce elastase release from surface-adherent neutrophils could arise from differential ability to generate leukotrienes, such as LTB4, and would be an appropriate mechanism for the control of elastase release during inflammation in vivo, where it is important that cytotoxic agents are not released until activated neutrophils have migrated into the extravascular tissues.

Blood Platelets↗
PubMed1999

Chemotactic migration triggers IL-8 generation in neutrophilic leukocytes.

Neutrophils recovered from inflammatory exudates possess increased levels of IL-8, but exposure of neutrophils to chemoattractants results in only a modest stimulation of IL-8 generation. This study was undertaken to explore the hypothesis that IL-8 generation in these cells is dependent upon the process of migration. Neutrophils synthesized up to 30 times as much IL-8 during migration in response to a gradient of diverse chemoattractants than they did when stimulated directly by the attractants in the absence of a gradient. This IL-8 response was dependent on migration since it was not observed in cells exposed to concentration gradients of chemoattractants under conditions that prevented cell movement. While actinomycin-D (1 microg/ml) had little influence on the generation of IL-8 during chemotaxis, the protein synthesis inhibitor cycloheximide (10 microg/ml) markedly blunted the accumulation of cell-associated IL-8, suggesting that new protein synthesis from preexisting mRNA was responsible for the effect. Consistent with this interpretation, migrating cells incorporated over 10 times as much [3H]leucine into IL-8 as did nonmotile neutrophils exposed to chemoattractants. A substantial portion of the IL-8 generated during chemotaxis was released upon subsequent metabolic stimulation. Thus, the IL-8 synthesized during chemotaxis is uniquely positioned to exert a regulatory influence on inflammatory processes governed by neutrophilic leukocytes responding to inflammatory and infectious stimuli.

Animals↗
PubMedDate not supplied

Inhibition of chemotactic migration of human neutrophilic granulocytes by recombinant human granulocyte-macrophage colony-stimulating factor.

Human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) was analysed for effects on the migration of human neutrophilic granulocytes by the Boyden chamber assay. At concentrations ranging from 0.1 to 10,000 U/ml (or 10(-12) to 10-mol/l) GM-CSF had neither chemokinetic nor chemotactic activity. When added to the cells in the upper compartment of the chamber GM-CSF dose-dependently inhibited the chemotactic migration towards the tripeptide f-Met-Leu-Phe and the complement split product C5a. Chemotaxis towards f-Met-Leu-Phe was inhibited more efficiently by GM-CSF than C5a-induced migration.

Chemotaxis, Leukocyte↗