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PubMed1987

The inflammatory activity of activated complement in ovine and bovine mammary glands.

Infusion of zymosan-activated plasma (ZAP), a source of activated complement, induced inflammation in non-lactating mammary glands but not in lactating glands of ewes and cows. Interstitial injection of ZAP in lactating ovine glands also failed to induce inflammation as assessed by the neutrophil content of milk. The inflammatory activity of ZAP in non-lactating glands was inhibited by infusion of whole milk but not by skimmed milk. These results suggest that components of whole milk mask the inflammatory activity of activated complement. In addition, lactating mammary tissue of ewes and cows may lack sensitivity to the inflammatory effect of activated complement. Thus, activated complement cannot be an important mediator of inflammation in the lactating gland.

Animals↗
PubMed1991

The induction of plasma leakage in skin by histamine, bradykinin, activated complement, platelet-activating factor and serotonin.

Vascular leakage of [125I]-human serum albumin into the skin of sheep was measured in response to intradermal injection of histamine, bradykinin, zymosan-activated plasma (ZAP), platelet-activating factor (PAF) and serotonin. Potency of the mediators was PAF greater than ZAP greater than bradykinin approximately histamine greater than serotonin. Maximal leakage occurred in the first 10 min following injection of bradykinin, histamine and PAF, and for histamine and bradykinin had effectively ceased by 40 min. In contrast, ZAP and serotonin induced relatively constant plasma leakage over the first 40 min following their intradermal injection. Prostaglandins E1 and E2 enhanced plasma leakage induced by histamine and bradykinin thus confirming the applicability of the two-mediator hypothesis of vascular leakage to permeability responses in skin of sheep.

Animals↗
PubMed2001

N-terminal domains of plant poly(ADP-ribose) polymerases define their association with mitotic chromosomes.

Poly(ADP-ribos)ylation is a reversible protein modification that in higher plants is catalyzed by two structurally different poly(ADP-ribose) polymerases, App and Zap. In vivo imaging of green-fluorescent protein (GPF) fusions showed that both Zap and App were associated with chromatin through the cell cycle progression. The in vivo behaviour of the App-GFP protein fusions can be attributed to the activity of two NASA motifs that mediate protein-protein interactions and nucleic acid binding. Expression of Zap deletion variants revealed that both Zn fingers and helix-turn-helix domains contributed to the association with chromosomes, whereas the localization in the nucleoplasm was mostly determined by the Zn fingers. The results highlight novel properties of protein sequences found in plant poly(ADP-ribose) polymerases and suggest important functions for this class of nuclear enzymes in chromosome dynamics.

Amino Acid Sequence↗
PubMed2001

Differential association of CD45 isoforms with CD4 and CD8 regulates the actions of specific pools of p56lck tyrosine kinase in T cell antigen receptor signal transduction.

An investigation into the role of CD45 isoforms in T cell antigen receptor signal transduction was carried out by transfecting CD45-negative CD4(+)CD8(+) HPB-ALL T cells with the CD45R0, CD45RBC, and CD45RABC isoforms. Fluorescence resonance energy transfer analysis showed that the CD45R0 isoform, but not the CD45RBC or CD45RABC isoforms, was found as homodimers and also preferentially associated with CD4 and CD8 at the cell-surface. A comparison was therefore made of T cell antigen receptor signaling between sub-clones expressing either CD45R0 or CD45RBC. Under basal conditions CD4-associated p56(lck) tyrosine kinase activity and cellular protein tyrosine phosphorylation levels were higher in the CD45R0(+) than in the CD45RBC(+) sub-clones. Upon CD3-CD4 ligation, TCR-zeta phosphorylation, ZAP-70 recruitment to the p21/p23 TCR-zeta phosphoisomers, ZAP-70 phosphorylation, as well as p56(lck), c-Cbl and Slp-76 phosphorylation, were all markedly increased in CD45R0(+) compared with CD45RBC(+) cells. T cell antigen receptor (TCR) stimulation alone also promoted c-Cbl phosphorylation in CD45R0(+) but not in CD45RBC(+) cells. Our results are consistent with a model in which association of CD45R0 with CD4 generates a more active pool of CD4-associated p56(lck) kinase molecules. Upon CD3-CD4 co-ligation, the active p56(lck) increases the intensity of T cell antigen receptor signal transduction coupling by promoting TCR-zeta chain phosphorylation and ZAP-70 recruitment.

CD4 Antigens↗
PubMed1999

Association of the adaptor molecule LAT with CD4 and CD8 coreceptors identifies a new coreceptor function in T cell receptor signal transduction.

Linker for activation of T cells (LAT) is an adaptor protein whose tyrosine phosphorylation is critical for transduction of the T cell receptor (TCR) signal. LAT phosphorylation is accomplished by the protein tyrosine kinase ZAP-70, but it is not at all clear how LAT (which is not associated with the TCR) encounters ZAP-70 (which is bound to the TCR). Here we show that LAT associates with surface CD4 and CD8 coreceptors and that its association is promoted by the same coreceptor cysteine motif that mediates Lck binding. In fact, LAT competes with Lck for binding to individual coreceptor molecules but differs from Lck in its preferential association with CD8 rather than CD4 in CD4(+)CD8(+) thymocytes. Importantly, as a consequence of LAT association with surface coreceptors, coengagement of the TCR with surface coreceptors induces LAT phosphorylation and the specific recruitment of downstream signaling mediators to coreceptor-associated LAT molecules. These results point to a new function for CD4 and CD8 coreceptors in TCR signal transduction, namely to promote LAT phosphorylation by ZAP-70 by recruiting LAT to major histocompatibility complex-engaged TCR complexes.

Adaptor Proteins, Signal Transducing↗
PubMed1988

Prostacyclin biosynthesis and reduced 5-HT uptake after complement-induced endothelial injury in the dog isolated lung.

1. Pulmonary prostacyclin (PGI2) biosynthesis was evaluated in relation to endothelial integrity before and after complement activation in isolated plasma-perfused lung lobes of the dog. 2. The plasma was activated with zymosan (ZAP, n = 4), yeast cells (YAP, n = 4) or yeast with 3 microM indomethacin (Indo + YAP, n = 3). Immunoreactive 6-oxo-prostaglandin F1 alpha (i-6-oxo-PGF1 alpha) and thromboxane B2 (iTXB2) were measured to monitor PGI2 and TXA2 biosynthesis. 3. The kinetic parameters Km and Vmax of 5-hydroxytryptamine (5-HT) uptake were calculated on the basis of multiple indicator diffusion data to evaluate endothelial integrity. 4. YAP and ZAP induced a biphasic increase of the arterial perfusion pressure. The immediate pressure peak was partly mediated by TXA2 and the TXB2 was subsequently cleared by the lung. 5. The apparent Vmax of 5-HT uptake remained constant throughout the experiment. Thus, complement activation did not affect the number of endothelial 5-HT carrier sites available to the perfusate. 6. The apparent Km of 5-HT uptake was enhanced in 9 lungs exposed to activated plasma complement for 20 min. This decreased affinity for 5-HT probably reflects endothelial injury. It was transient as the apparent Km had returned to the baseline value after 60 min. 7. PGI2 clearance and biosynthesis were virtually absent in the control period. PGI2 formation increased drastically after infusion of ZAP or YAP and was proportional to the endothelial injury expressed as elevated Km or pulmonary oedema. Thus, PGI2 biosynthesis might be a marker of severe endothelial distress.

Animals↗
PubMed1994

Effects of phosphodiesterase isoenzyme inhibitors on cutaneous inflammation in the guinea-pig.

1. Inflammation is central to the pathophysiology of asthma. The recent findings that different inflammatory cells may express different phosphodiesterase (PDE) isoenzymes have centered attention on inhibitors of these isoenzymes as new drugs for the treatment of asthma. In this study, we investigated the effect of different PDE isoenzyme inhibitors on the accumulation of 111In-labelled eosinophils and local oedema formation at sites of allergic- and mediator-induced inflammation in guinea-pig skin. 2. Systemic treatment with SK&F 94120, a type III PDE inhibitor, or zaprinast, a type V PDE inhibitor, had no effect on the 111In-eosinophil accumulation and oedema formation induced by i.d. injection of zymosan-activated plasma (ZAP), PAF, histamine or in a passive cutaneous anaphylaxis (PCA) reaction. 3. Systemic treatment with rolipram, a type IV PDE inhibitor, effectively inhibited 111In-eosinophil accumulation induced by ZAP, PAF, histamine and in a PCA reaction. However, oedema formation measured in the same sites was not affected. Systemic administration of higher doses of theophylline produced similar results. In contrast, 111In-neutrophil accumulation induced by ZAP or in a PCA reaction was not altered by systemic treatment with rolipram. 4. Locally-injected rolipram had little effect on 111In-eosinophil accumulation and oedema formation induced by histamine, PAF and in a PCA reaction. 5. These data show that systemic, but not local, treatment with rolipram effectively inhibits allergic- and mediator-induced 111In-eosinophil accumulation but not oedema formation or 111In-neutrophil accumulation. This, taken together with the potent inhibitory effects of PDE type IV inhibitors on eosinophil function in vitro, suggest that this class of drugs may be beneficial in disease states such as asthma where eosinophils are thought to play a major pathophysiological role.

Animals↗
PubMed2006

Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic subgroups most likely to undergo disease progression.

OBJECTIVE: Serum thymidine kinase (TK) levels have been shown to be correlated with survival in many malignancies, including chronic lymphocytic leukaemia (CLL). This study was designed to investigate associations between TK levels and other prognostic markers, in newly and previously diagnosed Binet stage A patients. Furthermore, the use of serum TK measurement to identify subcategories of disease within those defined by IgV(H) mutational status, gene usage and chromosomal aberrations was investigated. METHODS: Ninety-one CLL patients were enrolled. Serum TK levels were measured using a radioenzyme assay. IgV(H) mutational status and V(H) gene usage were determined using BIOMED-2 primers and protocol. Recurring chromosomal abnormalities were detected by interphase fluorescent in situ hybridisation (FISH). Flow cytometry and reverse transcriptase polymerase chain reaction (RT-PCR) determined CD38 and Zap-70 expression, respectively. RESULTS: Significantly higher serum TK levels were found in IgV(H) unmutated, compared with IgV(H) mutated, patients (P < 0.001). Elevated TK levels were also found in patients with CD38 and Zap-70 positivity (P = 0.004, P < 0.001, respectively), short lymphocyte doubling time (LDT) (P = 0.044) and poor or intermediate prognosis chromosomal aberrations (P < 0.001). CONCLUSION: A TK level of >8.5 U/L best identified patients with progressive disease. Elevated TK levels could identify patients categorised, at diagnosis, into good prognosis subgroups by the various biological markers (mutated IgV(H), good prognosis chromosomal aberrations, Zap-70(-) and CD38(-)) who subsequently showed disease progression. Additionally, patients with V(H)3-21 gene usage showed high TK levels, irrespective of mutational status, and serum TK measurement retained predictive power as disease progressed in all subcategories studied.

ADP-ribosyl Cyclase 1↗
PubMed2002

Polymerization efficiency of LED curing lights.

PURPOSE: The purpose of this study was to compare the curing efficiency of three commercially available light-emitting diode (LED)-based curing lights with that of a quartz tungsten halogen (QTH) curing light by means of hardness testing. In addition, the power density (intensity) and spectral emission of each LED light was compared with the QTH curing light in both the 380- to 520-nm and the 450- to 500-nm spectral ranges. MATERIALS AND METHODS: A polytetrafluoroethylene mold 2 mm high and 8 mm in diameter was used to prepare five depth-of-cure test specimens for each combination of exposure duration, composite type (Silux Plus [microfill], Z-100 [hybrid]), and curing light (ZAP Dual Curing Light, LumaCure, VersaLux, Optilux 401). After 24 hours, Knoop hardness measurements were made for each side of the specimen, means were calculated, and a bottom/top Knoop hardness (B/T KH) percentage was determined. A value of at least 80% was used to indicate satisfactory polymerization. A linear regression of B/T KH percentage versus exposure duration was performed, and the resulting equation was used to predict the exposure duration required to produce a B/T KH percentage of 80% for the test conditions. The power densities (power/unit area) of the LED curing lights and the QTH curing light (Optilux 401) were measured 1 mm from the target using a laboratory-grade, laser power meter in both the full visible light spectrum range (380-780 nm) and the spectral range (between 450 and 500 nm), using a combination of long- and short-wave edge filters. RESULTS: The emission spectra of the LED lights more closely mirrored the absorption spectrum of the commonly used photoinitiator camphorquinone. Specifically, 95% of the emission spectrum of the VersaLux, 87% of the LumaCure, 84% of the ZAP LED, and 78% of the ZAP combination LED and QTH fell between 450 and 500 nm. In contrast, only 56% of the emission spectrum of the Optilux 401 halogen lamp fell within this range. However, the power density between 450 and 500 nm was at least four times greater for the halogen lamp than for the purely LED lights. As a result, the LED-based curing lights required from 39 to 61 seconds to cure a 2-mm thick hybrid resin composite and between 83 and 131 seconds to adequately cure a microfill resin composite. By comparison, the QTH light required only 21 and 42 seconds to cure the hybrid and microfill resin composites, respectively. CLINICAL SIGNIFICANCE: The first-generation LED-based curing lights in this study required considerably longer exposure durations than the QTH curing light to adequately polymerize a hybrid and a microfill resin composite.

Composite Resins↗
PubMed1994

Ig alpha and Ig beta are functionally homologous to the signaling proteins of the T-cell receptor.

Signal transduction by antigen receptors and some Fc receptors requires the activation of a family of receptor-associated transmembrane accessory proteins. One common feature of the cytoplasmic domains of these accessory molecules is the presence is at least two YXXA repeats that are potential sites for interaction with Src homology 2 domain-containing proteins. However, the degree of similarity between the different receptor-associated proteins varies from that of T-cell receptor (TCR) zeta and Fc receptor RIIIA gamma chains, which are homologous, to the distantly related Ig alpha and Ig beta proteins of the B-cell antigen receptor. To determine whether T- and B-cell antigen receptors are in fact functionally homologous, we have studied signal transduction by chimeric immunoglobulins bearing the Ig alpha or Ig beta cytoplasmic domain. We found that Ig alpha and Ig beta cytoplasmic domains were able to activate Ca2+ flux, interleukin-2 secretion, and phosphorylation of the same group of cellular substrates as the TCR in transfected T cells. Chimeric proteins were then used to examine the minimal requirements for activation of the Fyn, Lck, and ZAP kinases in T cells. Both Ig alpha and Ig beta were able to trigger Fyn, Lck, and ZAP directly without involvement of TCR components. Cytoplasmic tyrosine residues in Ig beta were required for recruitment and activation of ZAP-70, but these amino acids were not essential for the activation of Fyn and Lck. We conclude that Fyn and Lck are able to recognize a clustered nonphosphorylated immune recognition receptor, but activation of these kinases is not sufficient to induce cellular responses such as Ca2+ flux and interleukin-2 secretion. In addition, the molecular structures involved in antigen receptor signaling pathways are conserved between T and B cells.

Amino Acid Sequence↗
PubMed1992

Downregulation of blood and bone marrow neutrophils decreases expression of acute lung injury in sheep.

We have shown that infusion of zymosan-activated plasma (ZAP) in sheep causes acute lung injury and downregulates peripheral blood neutrophils in that elicited superoxide release is reduced for at least 24 h after the infusion. The present study was designed to test the following hypotheses: 1) peripheral blood neutrophils are representative of neutrophils marginated in the pulmonary circulation, 2) blood neutrophils are downregulated because neutrophils developing in bone marrow are similarly affected, and 3) downregulated neutrophils have a reduced capacity to produce tissue injury. In a series of experiments in 21 sheep, we showed that elicited superoxide release was similar in peripheral blood neutrophils and in marginated neutrophils washed out of the pulmonary vascular bed. Measurements of superoxide release from blood and bone marrow neutrophils collected 2-24 h after ZAP infusion revealed progressive downregulation with time and greater downregulation of superoxide release in bone marrow neutrophils compared with peripheral blood neutrophils. Finally, after downregulating peripheral blood neutrophils, subsequent infusion of ZAP in conscious sheep produced sequestration of neutrophils in the pulmonary circulation but failed to produce a sustained increase in lung lymph protein clearance. The results suggest that neutrophil downregulation, as measured in vitro, is expressed in vivo as reduced ability of neutrophils to produce tissue injury when challenged by an activating agent.

Acute Disease↗
PubMed1990

Failure of therapy with 2,3-dihydroxybenzoic acid to modify the course of sepsis-induced lung injury.

Oxidant-induced injury of the pulmonary microvasculature reportedly contributes to an increase in microvascular permeability and pulmonary hypertension, both of which are principal features of acute lung injury (ALI). We tested the hypothesis that antioxidant therapy with 2,3-dihydroxybenzoic acid (DHB), initiated in awake sheep after the development of sepsis-induced ALI, would ameliorate the progression of these lesions. DHB has many actions that suggested to us the potential for demonstrating benefit in ALI complicating sepsis; it is a nontoxic hydroxyl-radical scavenger that also inhibits the cyclooxygenase pathway and acts as a weak iron chelator. In preliminary experiments, we demonstrated that pretreatment with DHB prevented an increase in mean pulmonary arterial pressure, plasma thromboxane A2, measured as its metabolite thromboxane B2, and lymph total protein clearance that otherwise followed an infusion of zymosan-activated plasma (ZAP) in sheep. In subsequent experiments, 12 additional sheep were rendered septic by cecal ligation and perforation. Twenty-four to 36 h after cecal ligation and perforation, an increase in lung microvascular permeability was confirmed, because pulmonary lymph flow had increased by 82% while the mean lymph-to-plasma total protein ratio was unchanged from baseline. At this point, six sheep were then treated with parenteral DHB and six with DHB vehicle for the subsequent 24 h. In contrast to the demonstrated benefit of DHB pretreatment in preventing ALI secondary to an infusion of ZAP, the progressive increase in lymph total protein clearance that complicated septic lung injury in the DHB vehicle group throughout this 24-h study period was not ameliorated in the DHB treatment group. However, DHB did prevent a modest increase in mean pulmonary arterial pressures that was demonstrated in the DHB vehicle group throughout this 24-h treatment period. Although pretreatment prevented ALI after a ZAP infusion, we conclude that DHB only incompletely modified disease progression when administered after the onset of sepsis-induced ALI because it ameliorated the pulmonary hypertensive response without concurrently modifying an increase in lung microvascular fluid flux.

Animals↗
PubMed2004

Variability in the degree of expression of phosphorylated IkappaBalpha in chronic lymphocytic leukemia cases with nodal involvement.

PURPOSE: Based on previous preliminary observations, we hypothesize that the molecular and clinical variability of chronic lymphocytic leukemia (CLL) reflects differences in the degree of nuclear factor (NF)-kappaB activation, as determined by the expression of phosphorylated IkappaBalpha (p-IkappaBalpha). EXPERIMENTAL DESIGN: The expression profile (mRNA and protein expression) was analyzed with the Centro Nacional de Investigaciones Oncologicas Oncochip, a cDNA microarray containing 6386 cancer-related genes, and a tissue microarray (TMA). The results were correlated with the IgV(H) mutational status, ZAP-70 expression, cytogenetic alterations, and clinical outcome. RESULTS: We found correlations between the presence of p-IkappaBalpha, a surrogate marker of NF-kappaB activation, and changes in the expression profile (mRNA and protein expression) and clinical outcome in a series of CLL cases with lymph node involvement. Activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, was associated with the expression of a set of genes comprising key genes involved in the control of B-cell receptor signaling, signal transduction, and apoptosis, including SYK, LYN, BCL2, CCR7, BTK, PIK3CD, and others. Cases with increased expression of p-IkappaBalpha showed longer overall survival than cases with lower expression. A Cox regression model was derived to estimate some parameters of prognostic interest: IgV(H) mutational status, ZAP-70, and p-IkappaBalpha expression. The multivariate analysis disclosed p-IkappaBalpha and ZAP-70 expression as independent prognostic factors of survival. CONCLUSIONS: A variable degree of activation of NF-kappaB, as determined by the expression of p-IkappaBalpha, is an identifiable event in CLL, and is correlated with changes in the expression profile and overall survival.

Adult↗
PubMed2006

The GNAS1 T393C polymorphism is associated with disease progression and survival in chronic lymphocytic leukemia.

PURPOSE: B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of monoclonal mature B cells. The G protein Galphas subunit has been linked to proapoptotic processes in cancer cell lines. The TT genotype of the GNAS1 T393C polymorphism is associated with increased Galphas transcript levels and a more favorable clinical course in different solid cancers. EXPERIMENTAL DESIGN: We retrospectively genotyped 144 patients with B-CLL to examine a potential association between T393C genotypes with progression-free survival (time from diagnosis to initiation of chemotherapy) and overall survival. RESULTS: The C-allele frequency in the patient group was 0.57 and not significantly different from that of healthy blood donors. Median progression-free survival was significantly different between genotypes (TT 130 months; TC 100 months; CC 31 months; P = 0.0066). Multivariable analysis showed that besides of ZAP-70 (P = 0.005) and Binet stage (P < 0.001), the T393C polymorphism was an independent prognostic factor for progression-free survival [hazard ratio (HR) CC versus TT 2.7; P = 0.010]. In Binet A stages, ZAP-70-positive patients with CC genotypes had a HR of 4.4 to receive first therapy compared with ZAP-70-negative patients with T-alleles (P = 0.0001). Regarding overall survival, CC genotypes (median overall survival, 197 months) were at highest risk for death compared with T-alleles (median overall survival, 310 months) in both univariate (HR, 4.8; P < 0.0001) and multivariable analysis (HR, 5.6; P = 0.002). CONCLUSIONS: Here, we show that the GNAS1 T393C status is a novel independent prognostic marker in patients with B-CLL. These results could help to define patients who could benefit from an early individualized therapy.

Adult↗
PubMed2006

Roles of leukocytosis and cysteinyl leukotriene in polymorphonuclear leukocyte-dependent plasma extravasation.

The PMN-dependent plasma extravasation is a major mechanism of permeability enhancement in acute inflammation. To reveal the pathophysiological significance of the PMN-dependent plasma extravasation, we prepared a systemic leukocytotic guinea pig model by a daily injection of recombinant human (rh)G-CSF. The extent of the PMN-dependent plasma extravasation, regarded as the late-phase permeability induced by an intradermal injection of zymosan-activated guinea pig plasma (ZAP) or of rhC5a, clearly correlated to the circulating PMN number. The augmentation of local response following the systemic response seemed to be the characteristic feature of the PMN-dependent plasma extravasation. We then revealed the molecular mechanism of the PMN-dependent plasma extravasation. Neither the antihistaminic agent diphenhydramine, nor the bradykinin B2 receptor antagonist, HOE140, affected the ZAP-induced, late-phase extravasation. In contrast to this, pretreatment with an antagonist of cysteinyl leukotriene (cys-LT) 1 receptor, pranlukast, significantly reduced the late-phase extravasation. Similarly, it was reduced by pretreatment with a 5-lipoxygenase inhibitor, MK-886, indicating the participation of cys-LTs in the PMN-dependent plasma extravasation. Histologically, pretreatment with pranlukast or MK-886 did not affect the ZAP-induced PMN infiltration. Consistently, a combined treatment with pranlukast and diphenhydramine completely suppressed the early-phase extravasation. As pranlukast pretreatment did not affect plasma extravasation induced by mast cell degranulation, and depletion of platelets did not influence the pranlukast-inhibitable plasma extravasation induced by rhC5a injection, cys-LTs are most likely produced by transcellular biosynthesis involving PMNs and vascular wall cells.

Adrenergic beta-Antagonists↗
PubMed2002

Oral antivirals revisited in the treatment of herpes zoster: what do they accomplish?

Oral antiviral agents currently represent the most important therapeutic keystone in the treatment of herpes zoster. Three oral antiviral agents are available for the treatment of herpes zoster: acyclovir, its derivative valacyclovir, and famciclovir. Meta-analysis of published data has shown that oral acyclovir significantly reduces various herpes zoster-related symptoms as well as the duration, intensity and prevalence of zoster-associated pain (ZAP). However, this drug does not influence postherpetic neuralgia. The newer agents famciclovir and valacyclovir exhibit a better oral bioavailability than acyclovir. These agents have demonstrated similar efficacy to acyclovir with ZAP and they require less frequent administration. When initiated within 72 hours, oral antiviral therapy of herpes zoster is beneficial in selected, elderly immunocompetent patients, reducing the duration and intensity of ZAP and providing more rapid skin lesion healing. Oral antivirals are also of benefit in immunocompromised patients with uncomplicated herpes zoster. However, signs of cutaneous and visceral dissemination should be monitored; if signs occur, intravenous antiviral therapy is indicated.

Administration, Oral↗
PubMed1986

The effect of steroidal and nonsteroidal anti-inflammatory agents on granulocyte migration into bovine pulmonary artery intimal explants.

To determine whether steroidal or non-steroidal anti-inflammatory agents inhibit granulocyte migration, we measured granulocyte adherence to and migration across the intact endothelial layer of bovine pulmonary artery intimal explants. Explants were placed endothelium uppermost in chemotaxis chamber with either fetal calf serum (FCS) or zymosan activated plasma (ZAP) in medium 199 in the lower well and 5 X 10(6) separated 51Cr labelled granulocytes/ml in medium 199 + FCS in the upper well. Methylprednisolone (0.3 and 3.0 mg/ml), indomethacin (5 and 50 microM) and ibuprofen (10 and 100 microM) were also added to the upper well of some chambers. After 30, 60, 120 or 180 minutes of incubation the chambers were dismantled. Granulocyte adherence was assessed by rinsing the explant in 0.1% trypsin; the number of radioactive counts in the trypsin wash represented the number of adherent cells. Those remaining in the explant represented the number of granulocytes that migrated into the explant. At each time studied, chemotaxin-induced granulocyte migration was 2-3 times that of unstimulated or random migration (180 min incubation with FCS = 30.5% +/- S.E. 2.1; with ZAP in lower well = 61.6 +/- 3.4). Both unstimulated and chemotaxin-induced migration was significantly decreased from 30 minutes by 3.0 mg/ml of methylprednisolone (180 min incubation with ZAP in lower well = 22.3 +/- 5.8), but not by 0.3 mg/ml. However, one hour pretreatment of either the granulocytes or the explant with 3.0 mg/ml methylprednisolone had no significant effect on granulocyte migration. In contrast, granulocyte migration was unaltered by treatment with either indomethacin or ibuprofen. Methylprednisolone, indomethacin and ibuprofen had little effect on granulocyte adherence. We conclude that granulocyte migration across an intact endothelial layer is inhibited by high dose corticosteroids but not by cyclooxygenase inhibitors. This suggests a plausible rationale for use of high doses of corticosteroids in clinical states where granulocytes may mediate tissue injury.

Animals↗
PubMed1990

Potent and selective inhibition of in vitro lymphocyte migration by cyclosporine and dexamethasone.

We have studied the in vitro effects of cyclosporine A (CsA) and dexamethasone on lymphocyte migration, which is considered to play an important role in the pathogenesis of inflammatory and auto-immune disorders. Using a 48-well microchemotaxis assay, dose-related migratory responses of mixed peripheral blood lymphocytes (PBL) to recombinant interleukin (rIL)-1 alpha, rIL-2, leukotriene B4 (LTB4) and zymosan activated plasma (ZAP) were demonstrated. When preincubated with PBL under plasma free conditions and in the presence of undiluted autologous plasma, CsA in the dose range 4 x 10(-13)-1.6 x 10(-7) M caused concentration related inhibition of lymphocyte migration in response to fixed concentrations of rIL-1 alpha and rIL-2. CsA in the same dose range had no effect on the migration of PBL in response to ZAP and LTB4. Under plasma-free conditions dexamethasone (1 x 10(-11)-4 x 10(-6) M) caused concentration related inhibition of PBL migration in response to rIL-1 alpha and LTB4, but had no effect on the responses to rIL-2 and ZAP. These data provide evidence that CsA and dexamethasone are potent and selective inhibitors of in vitro lymphocyte migration, effects which may contribute to their therapeutic efficacy in vivo.

Chemotaxis, Leukocyte↗