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PubMed1991

Regulation of leukocyte migration by activation of the leukocyte adhesion molecule-1 (LAM-1) selectin.

A central feature of host defence is the ability of leukocytes to enter tissues in response to immune or inflammatory stimuli. The leukocyte adhesion molecule-1 (LAM-1) regulates the migration of human leukocytes by mediating the binding both of lymphocytes to high endothelial venules of peripheral lymph nodes and of neutrophils to endothelium at inflammatory sites. As lymphocytes and neutrophils express the same LAM-1 protein, it is not clear how lineage-specific differences in leukocyte migration are controlled. We now report that the affinity of LAM-1 for a carbohydrate-based ligand, PPME, is dramatically increased following lymphocyte and neutrophil activation by lineage-specific stimuli. In addition, activation of lymphocytes by physiological stimuli enhanced LAM-1-dependent binding to high endothelial venules. Thus, transient changes in LAM-1 affinity after leukocyte stimulation probably directly influence leukocyte migration.

Antibodies, Monoclonal↗
PubMed1988

Possible changes in the leukocyte membrane as a mechanism of leukocyte adhesion to the venular walls induced by leukotriene B4 and fMLP in the microvasculature of the hamster cheek pouch.

Images of the microvasculature of the hamster cheek pouch were projected on TV monitor screen using a monochrome TV camera. Rolling and adhesion of the polymorphonuclear leukocytes on the venular wall were continuously recorded by a newly developed videodensitometer, as changes in average intensity of videosignals in a given detection window superimposed on the screen. Topical application (2.5, 5 and 10 nmol/50 microliter) of fMLP (formyl-methionyl-leucyl-phenylalanine) or superfusion of leukotriene (LT) B4 (0.3, 3 and 30 pmol/ml/min) caused dose-dependent increase in the number of leukocytes adhering to the venules, but a tendency of rolling leukocyte to decrease. Local pretreatment of the microvasculature with a selective 5-lipoxygenase inhibitor (AA-1777) prevented the leukocyte adhesion induced by fMLP (10 nmol/50 microliter), indicating that this adhesion was induced through generation of 5-lipoxygenase products. Selective injection of fMLP (10, 30 and 100 pmol/0.1 microliter) by micropipette into the connective tissue close to the capillary dose-dependently increased the number of leukocytes adhering to the venule downstream, but injection of the highest dose (100 pmol/0.1 microliter) close to the venular wall caused no adhesion to the same venule. Similar results were obtained with LTB4 (30 fmol/0.1 microliter). These findings suggest that fMLP or LTB4 applied topically is absorbed from the capillaries and induces membrane changes in the leukocytes, but not in the endothelial cells, resulting in their adhesion to the venular wall.

Animals↗
PubMed1990

Kinetics of leukocyte sequestration in the lungs of acutely septic primates: a study using 111In-labeled autologous leukocytes.

To further clarify the role of leukocytes in the pathogenesis of ARDS, we studied the localization and kinetics of leukocyte migration using 111In-labeled autologous white cell scans (111In wbc scans) in four primates made acutely septic with infusions of Escherichia coli. Whole body images were obtained with a gamma camera and were acquired on computer every 15 min beginning immediately after the E. coli infusion. Simultaneous measurements of C5a and peripheral blood leukocyte count were also obtained. Within 5 min of initiating sepsis, three major events occurred: complement activation as measured by the production of C5a, a profound fall in peripheral leukocyte count, and a significant increase in the sequestration of leukocytes in the lungs. The pulmonary sequestration reached a peak at 15 min with a mean of 152% of baseline activity. This sequestration consisted of a population that was predominantly neutrophils. Damage to the pulmonary capillary endothelium was demonstrated by an increase in extravascular lung water. The results support a role for neutrophils and complement as mediators in the pathogenesis of ARDS.

Acute Disease↗
PubMed2003

Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response.

Both the innate and adaptive immune responses are dependent on the migration of leukocytes across endothelial cells. The process of diapedesis, in which the leukocyte crawls between tightly apposed endothelial cells, is a unique and complex process. Several molecules concentrated at the junctions of endothelial cells, originally described as having a role in holding the endothelial monolayer together, have also been shown to have a role in the emigration of leukocytes. Several mechanisms have been proposed for 'loosening' the junctions between endothelial cells to enable leukocyte passage. These leukocyte-endothelial-cell adhesion molecules are probably involved in regulating the signaling as well as the adhesion events of diapedesis. In addition, this Review introduces a new and unified nomenclature for the junctional adhesion molecule (JAM) family.

Animals↗
PubMed1994

Complement, leukocytes, and leukocyte elastase in full-term neonates undergoing cardiac operation.

In 13 neonates undergoing cardiac operations for congenital cardiac defects, complement, leukocytes, and leukocyte elastase were studied during and after cardiopulmonary bypass. All but two neonates received prostaglandin E1 before the operation. The C3d/C3 ratio rose significantly during cardiopulmonary bypass from 0.86 +/- 0.55 to 1.40 +/- 0.56 (mean +/- standard deviation; p < 0.0001). Abnormally elevated C5a levels (18.6 +/- 7.3 micrograms/L) were measured at the end of cardiopulmonary bypass. C4 was not overtly consumed during the procedure. Leukocytes fell from a preoperative value of 10.06 +/- 3.15 x 10(9)/L to 3.21 +/- 0.64 x 10(9)/L after beginning of cardiopulmonary bypass (p < 0.0001) and rose at the end of the procedure from 2.33 +/- 0.67 x 10(9)/L to 7.19 +/- 1.84 x 10(9)/L, after protamine administration (p < 0.0001). Neutrophils fell from a preoperative value of 5.14 +/- 1.18 x 10(9)/L to 1.46 +/- 0.35 x 10(9)/L after beginning of cardiopulmonary bypass and rose at the end of extracorporeal circulation from 1.00 +/- 0.31 x 10(9)/L to 4.10 +/- 1.18 x 10(9)/L, after protamine administration (p < 0.005). Elastase release occurred in all neonates during cardiopulmonary bypass and averaged 331.5 +/- 175.7 micrograms/L. Complement activation and leukocyte stimulation did not correlate with postoperative complications or outcome. This study demonstrates complement activation and leukocyte stimulation in neonates undergoing cardiac operation.

Alprostadil↗
PubMedDate not supplied

Improved preparation of leukocytes for chemiluminescent study of human phagocytic leukocyte-generated reactive oxygen species.

Leukocyte oxidative function was investigated in a more physiological milieu than currently used in the chemiluminescence (CL) technique. Heparinized blood was mixed with 6% dextran-T70 (9:1) and the leukocyte-rich plasma obtained without centrifugation was used for the CL experiments (phagocyte count was adjusted to 0.7 x 10(6)/mL with Hanks' buffer) (method A). In this medium, phagocytes responded to stimulation by opsonized zymosan, producing strong luminescence in the presence of 0.5 mumol/L MCLA. CL was inhibited by superoxide dismutase, suggesting that the luminescence reaction was attributable to O2-. Granulocytes were also prepared by the usual method involving centrifugation and were then suspended in plasma (method B). Oxidative function of phagocytes prepared by the two methods was studied together with whole blood as aliquots diluted with Hanks' buffer up to a factor of 1000. Luminescence reached a peak value at a dilution factor of 16, but at very high dilutions luminescence decreased sharply. Significantly higher luminescence values were obtained with samples from method A. Luminescence of whole blood peaked at a dilution factor of 248 but it was less than the value obtained using samples prepared by method A or B. As samples prepared by method A contain all the leukocyte populations, platelets, residual red cells and plasma proteins, the assay of leukocyte-generated reactive oxygens using CL is attained in more physiological conditions than method B in which leukocytes may be damaged owing to repeated centrifugation and hypotonic shock.

Azides↗
PubMed2005

Dialyzable leukocyte extract differentially regulates the production of TNFalpha, IL-6, and IL-8 in bacterial component-activated leukocytes and endothelial cells.

OBJECTIVE: To investigate i) whether the Dialyzable Leukocyte Extract (DLE) modulates the production of proinflammatory cytokines in leukocytes activated by the bacterial cell wall components lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PGN); ii) the effect of DLE on LPS-stimulated endothelial cells; and iii) whether the regulatory effect of DLE on inflammatory mediators is related to the modulation of Toll-like receptors (TLRs), NF-kappaB and cAMP signaling pathways. METHODS: Leukocytes were stimulated with LPS, LTA, and PGN in the presence of DLE. Endothelial cells were stimulated with LPS and treated with DLE. The levels of Tumor Necrosis Factor-alpha(TNFalpha), Interleukin-6 (IL-6), and IL-8 in culture supernatants were evaluated by ELISA. The expression of Toll-like receptor 2 (TLR2) and 4 (TLR4), NF-kappaB activity and cAMP levels were evaluated by flow cytometry, EMSA, and EIA, respectively. RESULTS: The addition of DLE to leukocytes stimulated with cell wall constituents suppressed the production of TNFalpha. However, DLE induced IL-8 release in monocytes and enhanced IL-6 and IL-8 production by activated monocytes and endothelial cells. Also, DLE induced TLR2 and TLR4 expression, and increased cAMP levels, whereas NF-kappaB activity was inhibited. CONCLUSIONS: The present data indicate the differential regulation by DLE of the production of TNFalpha, IL-6, and IL-8 cytokines, associated with effects on TLR2 and TLR4 expression and NF-kappaB and cAMP activities. We suggest a putative mechanism for the biological effects of DLE in activated leukocytes and endothelial cells.

Cells, Cultured↗
PubMedDate not supplied

Model studies of leukocyte-endothelium-blood interactions. I. The fluid flow drag force on the adherent leukocyte.

Using a large scale model and the concept of dimensional similarity, we have developed a dimensionless correlation which permits the estimation of the drag force of blood flow in an in vivo vessel on a leukocyte adherent to the vessel wall. This relationship is [formula: see text] where Re is a Reynolds number, Cd is a drag coefficient, and d/D is the leukocyte-to-vessel diameter ratio. This function increases rapidly with increasing d/D when d/D is greater than 0.5. A relationship between the drag force on the leukocyte, Ff, and the commonly used wall shear stress in the absence of the adherent cell, tau w, has also been developed, and is given by [formula: see text] This study shows that the discrepancy between the in vivo and in vitro critical wall stresses (above which leukocytes do not adhere to endothelial cell layers) is not due to misrepresentation of the corresponding drag forces on the leukocytes. The discrepancy must be due to real differences in the flow and/or cellular conditions between the in vivo and in vitro experiments.

Animals↗
PubMed1986

In vitro assessment of mononuclear leukocyte aggregation in response to sodium arachidonate and calcium ionophore A23187: comparison with polymorphonuclear leukocytes.

The effects of ionophore A23187 and sodium arachidonate (AASS) on mononuclear leukocyte (MNL) aggregation were evaluated and the results compared to those obtained with similarly challenged polymorphonuclear leukocytes (PMN). MNL aggregated in response to both ionophore A23187 (8-40 microM f.c.) and AASS (0.05-0.5 mM f.c.) and the response was comparable to that of similarly challenged PMN. The AASS induced aggregation of the two leukocyte subpopulations was inhibited by the presence of bovine serum albumin (BSA) in the incubation media and by calcium exogenously added. In contrast, this cation stimulated ionophore induced aggregation. When PMN and MNL aggregation was induced by AASS, a marked release of lactic dehydrogenase (LDH) was detected. The thromboxane-synthetase inhibitor UK 37248, inhibited both leukocyte aggregation and LDH release. When the response of leukocytes from male and female subjects was compared, in terms of aggregation, it appeared that the response of PMN from female volunteers was higher than that of PMN isolated from male donors, whereas no sex-related difference was detected when MNL aggregation was evaluated.

Adult↗
PubMed1999

Leukocyte adhesion--an integrated molecular process at the leukocyte plasma membrane.

Leukocyte adhesion is of pivotal functional importance, because most leukocyte functions depend on cell-cell contact. It must be strictly controlled, both at the level of specificity and strength of interaction, and therefore several molecular systems are involved. The most important leukocyte adhesion molecules are the selectins, the leukocyte-specific beta2-integrins and the intercellular adhesion molecules. The selectins induce an initial weak contact between cells, whereas firm adhesion is achieved through integrin intercellular adhesion molecular binding. Although studies during the past twenty years have revealed several important features of leukocyte adhesion much is still poorly understood, and further work dealing with several aspects of adhesion is urgently needed. In this short essay, we review some recent developments in the field.

Carbohydrate Metabolism↗
PubMed1995

Regulation of leukocyte-endothelium interaction and leukocyte transendothelial migration by intercellular adhesion molecule 1-fibrinogen recognition.

Although primarily recognized for its role in hemostasis, fibrinogen is also required for competent inflammatory reactions in vivo. It is now shown that fibrinogen promotes adhesion to and migration across an endothelial monolayer of terminally differentiated myelomonocytic cells. This process does not require chemotactic/haptotactic gradients or cytokine stimulation of the endothelium and is specific for the association of fibrinogen with intercellular adhesion molecule 1 (ICAM-1) on endothelium. Among other adhesive plasma proteins, fibronectin fails to increase the binding of leukocytes to endothelium, or transendothelial migration, whereas vitronectin promotes the binding but not the migration. The fibrinogen-mediated leukocyte adhesion and transendothelial migration could be inhibited by a peptide from the fibrinogen gamma-chain sequence N117NQKIVNL-KEKVAQLEA133, which blocks the binding of fibrinogen to ICAM-1. This interaction could also be inhibited by new anti-ICAM-1 monoclonal antibodies that did not affect the ICAM-1-CD11a/CD18 recognition, thus suggesting that the fibrinogen binding site on ICAM-1 may be structurally distinct from regions previously implicated in leukocyte-endothelium interaction. Therefore, binding of fibrinogen to vascular cell receptors is sufficient to initiate (i) increased leukocyte adhesion to endothelium and (ii) leukocyte transendothelial migration. These two processes are the earliest events of immune inflammatory responses and may also contribute to atherosclerosis.

Amino Acid Sequence↗
PubMed1975

Migration inhibition of human leukocytes mixed with phytohemagglutinin-preincubated mononuclear leukocytes.

An in vitro test able to demonstrate phytohemagglutinin (PHA)-induced migration inhibition of human peripheral blood leukocytes was investigated. The migration inhibition was demonstrated by the agarose migration technique. Purified mononuclear leukocytes which had been incubated for 30 min with PHA, then washed and added to non-separated leukocytes induced migration inhibition of the mixed cell population. Since no PHA was added to the non-separated leukocytes, a direct PHA effect on polymorph migration was avoided. If the PHA-preincubated mononuclear leukocytes were heated at 56 degrees C for 30 min, their ability to cause migration inhibition was abolished. This suggests that the inhibition was caused by migration inhibitory factor (MIF) produced by the PHA-stimulated lymphocytes.

Cell Migration Inhibition↗
PubMed1982

Study of the immunopotentiator effects of dialyzable leukocyte extracts obtained out of leukocytes previously used for interferon production.

The existence of immunopotentiator factors able to induce blastogenesis, chemotaxis and able of inhibiting migration of leukocytes was investigated in alcohol precipitates of different batches of dialyzed leukocyte extracts (DLE). These were prepared either out of fresh leukocytes from a large pool of buffy coats obtained from all blood collected from healthy donors with irrelevant antigen sensitiveness (DLE-NS) or from similar leukocytes which were incubated during 19 h for interferon production (DLE-NS-I). Alternatively, the same factors were investigated on a batch of DLE obtained from a donor exquisitely sensitive to Candida antigen (C-DLE-CS). It was observed that all the three batches contained equal amounts of either specific or nonspecific immunological enhancing factors. The similarity of the intensity of specific factors between the so-called nonspecific batches (DLE-NS and DLE-NS-I) and the specific batch (C-DLE-CS) was interpreted to be the result of the random selection of the donors for the preparation of the nonspecific batches, which consequently contain randomized relevant specificities. It is postulated, therefore, that batches of DLE which represent a large waste of leukocytes used for interferon production can be a useful tool for double-blind DLE therapy purposes.

Adjuvants, Immunologic↗
PubMedDate not supplied

Percoll density gradient centrifugation and consecutive flow cytometry do not identify leukocytes and leukocyte subtypes in ejaculate specimens.

This paper describes an attempt to establish a new combined method of leukocyte analysis in human ejaculate by Percoll density gradient centrifugation and consecutive flow cytometry. As a first step, leukocyte separation was performed by Percoll density gradient centrifugation with consecutive enrichment of leukocytes, especially granulocytes, in the 40%/60% and 60%/80% Percoll interfaces. Then these fractions were stained with specific monoclonal antibodies and analysed in a Facscan flow cytometer. Flow cytometric analysis did not demonstrate identifiable leukocyte populations, indicating a questionable cross-reaction with spermatozoal elements. Therefore, the combined technique of Percoll density gradient centrifugation and flow cytometric analysis were considered unsuitable for clinical leukocyte determination.

Antibodies, Monoclonal↗
PubMed1991

Detection of aggregated leukocytes in the circulating pool during stress-demargination is not necessarily a result of decreased leukocyte adhesiveness.

Leukocyte endothelial interactions are essential for a normal immune response. It is known that this response is influenced by stress and that the latter induces demargination. We examined the question of whether stress demargination results from a decreased state of leukocyte adhesiveness. Included were various volunteers and patients under different degrees of stress. 66 young athletes before beginning their daily exercises, 67 middle-aged healthy volunteers, 25 patients before ergometry for evaluation of chest pain, 75 patients who were referred to the emergency room with chest pain without ischemia/infarction, 78 patients with ischemia/infarction, 65 patients with minor trauma, 25 with a fracture and 12 with polytrauma. The leukocyte adhesiveness/aggregation (LAA) values were measured with a direct slide test. The respective LAA values were 7.4 +/- 4.7, 6.3 +/- 4.4, 5.8 +/- 3.6, 5.2 +/- 3.5, 10.8 +/- 8.5, 9.1 +/- 5.8, 12.2 +/- 6.6 and 19 +/- 12.6% of aggregated leukocytes. We conclude that an increase in aggregated white blood cells can be detected in the circulating pool during major stress. It is therefore suggested that stress demargination is not necessarily a result of diminished leukocyte adhesiveness.

Adolescent↗
PubMed1997

Homing of mucosal leukocytes to joints. Distinct endothelial ligands in synovium mediate leukocyte-subtype specific adhesion.

Inflammation and infection of the gut can be followed by reactive arthritis at a distant joint. Leukocyte recruitment into synovium is essential for this process, but nothing is known about the endothelial adhesion molecules in synovial membrane which direct the homing of activated, gut-derived leukocytes to joints. Here we analyzed the expression of the known endothelial adhesion molecules in inflamed synovium and their function in binding of mucosal leukocytes. Intercellular adhesion molecule-1 (ICAM-1/CD54) and vascular adhesion protein-1 (VAP-1) were most prominently expressed in synovial vessels. All other adhesion molecules were found at lower levels in inflamed synovia, except mucosal addressin which was absent. Binding of macrophages isolated from lamina propria of the gut to synovial endothelium was almost entirely P-selectin-dependent. In contrast, small intestinal lymphocytes and immunoblasts both relied mainly on VAP-1 in recognition of synovial vessels. Thus, endothelial P-selectin and VAP-1 mediate binding of mucosal effector cells to synovium in a leukocyte subtype-selective manner. Antiadhesive therapy against these inducible molecules should ablate the pathogenetic cascade leading to inappropriate homing of leukocytes to joints in arthritis.

Amine Oxidase (Copper-Containing)↗
PubMed1983

Inheritance of high leukocyte folate binding activity. Relationship between folate binding in leukocytes and serum.

Folate binding was determined in leukocyte lysates from relatives of three persons whose leukocytes contained large amounts of folate binding protein. A pedigree analysis showed that high leukocyte folate binding activities occurred with great frequency in these families suggesting a dominant mode of inheritance. Folate binding in serum varied within narrow limits (0.2-0.5 nmol folate/l serum) in persons with leukocyte folate binding activities less than 0.8-1.0 nmol folate per 10(9) cells. A shift to a higher level of serum folate binding (greater than or equal to 1.0 nmol/l serum) was, however, observed at leukocyte folate binding activities above that value.

Carrier Proteins↗
PubMed1982

An altered response by peripheral leukocytes to synthesize or release leukocyte endogenous mediator in critically ill, protein-malnourished patients.

LEM derived from fixed and circulating macrophages is involved in certain aspects of the metabolic response to infection. A reduction in the synthesis or release of LEM from leukocytes of nonstressed, protein-malnourished patients has been demonstrated. In this study, blood leukocytes from 15 protein-malnourished patients (serum albumin less than 2.5 gm/dl) who were critically ill were assayed for their in vitro capacity to produce LEM. Samples were taken before (day 0) and 3 or 7 days after the institution of parenteral nutrition. Hospitalized patients were judged capable of producing LEM (responders) if the percentage of polymorphonuclear leukocytes in the blood of the rats injected with their LEM was greater than 52% ( the minimum value obtained when LEM from 10 human volunteers was injected into the rats). With this criterion, eight patients were responders and only one died during their hospital stay, whereas five of seven nonresponders expired (p less than 0.05). On day 0, prior to intravenous nutritional support, there was no difference in the capacity to produce LEM between responding and nonresponding patients. However, those patients whose leukocytes were capable of responding received significantly greater quantities of dietary protein and calories over the 7-day study period than nonresponders (p less than 0.05). There was a correlation between the polymorphonuclear leukocyte response to LEM in rats and the patients' dietary protein intake (r = 0.719, p less than 0.005). these findings suggest that an appreciable fraction of severely ill, protein-malnourished patients have a reduced capacity to synthesize LEM, as judged by bioassay and an increased risk of mortality. The in vitro capacity to produce LEM in a critically ill population appears to be associated with the dietary intake of the patient.

Animals↗