50 results on '"Landis, R. C."'
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2. Integrins and their Activation
- Author
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Hogg, N., Cabañas, C., Harvey, J., McDowall, A., Stanley, P., Stewart, M., Landis, R. C., Gergely, János, editor, Benczúr, M., editor, Erdei, Anna, editor, Falus, A., editor, Füst, Gy., editor, Medgyesi, G., editor, Petrányi, Gy., editor, and Rajnavölgyi, Éva, editor
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- 1993
- Full Text
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3. Additional file 9 of Viral metagenomics reveals the presence of novel Zika virus variants in Aedes mosquitoes from Barbados
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Thannesberger, J., Rascovan, N., Eisenmann, A., Klymiuk, I., Zittra, C., Fuehrer, H. P., Scantlebury-Manning, T., Gittens-St.Hilaire, M., Austin, S., Landis, R. C., and Steininger, C.
- Subjects
viruses - Abstract
Additional file 9: Figure S1. Local environment at mosquito trapping spots characterized by satellite imagery (Google maps); photographs taken by the authors during trap assembly. Figure S2. Metagenomic sequencing results from Illumina HiSeq sequencing. a Fraction of assigned reads mapped to the indicated clade in the Basic Local Alignment Search Tool (BLAST) N analysis; b relative abundance of reads mapped to indicated clade, normalized to contig length and number of reads mapped in total (reads per kilobase per million mapped reads; RPKM); c richness in number of assigned clades. Figure S3. a Absolute and b relative quantification by real-time polymerase chain reaction (RT–PCR) assays of artificially spiked viruses before and after target enrichment (TE); human cytomegalovirus (HCMV), ZIKV, influenza virus (InfluA), West Nile virus (WNV), yellow fever virus (YFV). Figure S4. Quantitative RT–PCR targeting a conserved region in the ZIKV NS5 gene; ZIKV load in the unenriched library and in the arbovirus specific target-enriched library of pooled Ae. aegypti mosquitos (n = 27). Measurements were made for biological triplicates. Error bars indicate SEM.
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- 2021
- Full Text
- View/download PDF
4. Additional file 7 of Viral metagenomics reveals the presence of novel Zika virus variants in Aedes mosquitoes from Barbados
- Author
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Thannesberger, J., Rascovan, N., Eisenmann, A., Klymiuk, I., Zittra, C., Fuehrer, H. P., Scantlebury-Manning, T., Gittens-St.Hilaire, M., Austin, S., Landis, R. C., and Steininger, C.
- Abstract
Additional file 7: Table S7. Results of arbovirus target enrichment with reads mapping bait sequences and corresponding BLASTN hit.
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- 2021
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- View/download PDF
5. Additional file 8 of Viral metagenomics reveals the presence of novel Zika virus variants in Aedes mosquitoes from Barbados
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Thannesberger, J., Rascovan, N., Eisenmann, A., Klymiuk, I., Zittra, C., Fuehrer, H. P., Scantlebury-Manning, T., Gittens-St.Hilaire, M., Austin, S., Landis, R. C., and Steininger, C.
- Abstract
Additional file 8: Table S8. Mapping target enrichment-derived reads to Zika virus (ZIKV) reference genome (NC_012532.1).
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- 2021
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6. Additional file 1 of Viral metagenomics reveals the presence of novel Zika virus variants in Aedes mosquitoes from Barbados
- Author
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Thannesberger, J., Rascovan, N., Eisenmann, A., Klymiuk, I., Zittra, C., Fuehrer, H. P., Scantlebury-Manning, T., Gittens-St.Hilaire, M., Austin, S., Landis, R. C., and Steininger, C.
- Abstract
Additional file 1: Table S1. Locations of mosquito collection; 24-h period, BG Sentinel traps.
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- 2021
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7. The inflammatory effect of cardiopulmonary bypass on leukocyte extravasation in vivo
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Evans, B. J., Haskard, D. O., Finch, J. R., Hambleton, I. R., Landis, R. C., and Taylor, K. M.
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- 2008
8. Aprotinin and the Protease-Activated Receptor 1 Thrombin Receptor: Antithrombosis, Inflammation, and Stroke Reduction
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Day, J. R. S., Landis, R. C., and Taylor, K. M.
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- 2006
9. Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention
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Day, J R S, Malik, I S, Weerasinghe, A, Poullis, M, Nadra, I, Haskard, D O, Taylor, K M, and Landis, R C
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- 2004
10. Aprotinin: is it prothrombotic?
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Poullis, M, Landis, R C, and Taylor, K M
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- 2001
11. The S128R polymorphism of E-selectin mediates increased recruitment of leucocytes under flow conditions
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Rao, R. M., Clarke, J. L., Ortlepp, S., Robinson, M. K., Landis, R. C., and Haskard, D. O.
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- 2001
12. Persistence of TNFα in diabetic wounds
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Landis, R. C., Evans, B. J., Chaturvedi, N., and Haskard, D. O.
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- 2010
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13. Leukocyte integrin expression in patients undergoing cardiopulmonary bypass
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Asimakopoulos, G., Kohn, A., Stefanou, D. C., Haskard, D. O., Landis, R. C., and Taylor, K. M.
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Male ,Double-Blind Method ,Cardiopulmonary Bypass ,Serine Proteinase Inhibitors/*therapeutic use ,Humans ,Female ,Coronary Artery Bypass ,Leukocytes/*metabolism ,Middle Aged ,Aprotinin/*therapeutic use ,Flow Cytometry ,Antigens, CD18/*metabolism ,Antigens, CD29/*metabolism - Abstract
BACKGROUND: The recruitment of leukocytes to vascular endothelium is controlled by adhesion events mediated through the beta2 integrins, whereas the response of extravasated leukocytes within the tissues is controlled through the beta1 integrins. Although cardiopulmonary bypass (CPB) has been shown to be associated with a systemic inflammatory response and elevated levels of beta2 integrins on leukocytes, its effect on the beta1 integrins is not known. This study investigated the effect of the protease inhibitor aprotinin on the expression of the beta1 and beta2 integrins on circulating leukocytes in patients undergoing CPB. METHODS: Patients undergoing primary elective coronary artery bypass grafting were randomized into full-dose aprotinin or placebo groups. Blood samples were obtained at nine time points preoperatively, intraoperatively, and up to 6 days postoperatively. The surface expression of the beta1 integrins VLA-1, -3, -4, -5, and -6 and of the beta2 integrins CD11a/CD18, CD11b/CD18, and CD11c/CD18 was measured by flow cytometry on gated neutrophil and monocyte subpopulations in whole blood. RESULTS: Expression of the beta1 integrins was not significantly altered during the study period and, therefore, aprotinin had no effect on the expression of these molecules. Of the beta2 integrins, CD11b/CD18 expression was significantly increased on neutrophils at 15 minutes after onset of CPB in the placebo group (p < 0.01) but not in the aprotinin group. CONCLUSIONS: This study showed that expression of the beta1 integrins on neutrophils and monocytes did not alter during the first 6 days after CPB. Expression of the beta2 integrin CD11b/CD18 increased significantly on neutrophils during CPB in control patients but not in patients treated with full-dose aprotinin. Ann Thorac Surg
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- 2000
14. A preliminary examination of the effects of genetic variants of redox enzymes on susceptibility to oedematous malnutrition and on percentage cytotoxicity in response to oxidative stressin vitro
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Marshall, K G, primary, Swaby, K, additional, Hamilton, K, additional, Howell, S, additional, Landis, R C, additional, Hambleton, I R, additional, Reid, M, additional, Fletcher, H, additional, Forrester, T, additional, and McKenzie, C A, additional
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- 2011
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15. Tumor necrosis factor receptor-associated periodic syndrome P46L and bilateral amputation in diabetes
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Quimby, K. R., primary, Greenidge, A. R., additional, Hennis, A. J., additional, Harrison, D. K., additional, and Landis, R. C., additional
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- 2010
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16. DNAPL SOURCE TREATMENT USING HIGH PRESSURE JETTING TECHNIQUES
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Jensen, R. H., primary, Landis, R. C., additional, Griffith, R. J., additional, McDevitt, M. F., additional, and Shoemaker, S. C., additional
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- 2000
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17. Involvement of the "I" domain of LFA-1 in selective binding to ligands ICAM-1 and ICAM-3.
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Landis, R C, primary, McDowall, A, additional, Holness, C L, additional, Littler, A J, additional, Simmons, D L, additional, and Hogg, N, additional
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- 1994
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18. A novel LFA-1 activation epitope maps to the I domain.
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Landis, R C, primary, Bennett, R I, additional, and Hogg, N, additional
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- 1993
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19. A preliminary examination of the effects of genetic variants of redox enzymes on susceptibility to oedematous malnutrition and on percentage cytotoxicity in response to oxidative stress in vitro.
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Marshall, K G, Swaby, K, Hamilton, K, Howell, S, Landis, R C, Hambleton, I R, Reid, M, Fletcher, H, Forrester, T, and McKenzie, C A
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MALNUTRITION in children ,GENETICS of disease susceptibility ,OXIDATIVE stress ,CASE-control method ,GENETIC polymorphisms ,POLYPEPTIDES ,EPOXY compounds ,SUPEROXIDE dismutase ,CATALASE - Abstract
Background: The causes of oedematous vs non-oedematous childhood malnutrition (OM vs NOM) remain elusive. It is possible that inherited differences in handling oxidant stressors are a contributing factor. Aims: To test for associations between polymorphisms in five genes and (i) risk of OM, a case-control study, and (ii) percentage cytotoxicity in peripheral blood mononuclear cells (PBMCs) exposed to hydrogen peroxide (H 2 O2 ), an in vitro cell challenge study. Methods: Participants had been admitted previously for treatment of OM (cases, n = 74) or NOM (controls, n = 50), or were an independent set of healthy pregnant women (n = 47) who donated peripheral blood mononuclear cells. We tested for associations between genetic variation and outcome using single markers or a bivariate score constructed by counting numbers of deleterious alleles for each of 15 possible pairs of markers. Results: In the case-control study there were no significant single-marker associations with OM. We did find that higher bivariate scores were associated with OM for the pair of NAD(P)H:quinone oxidoreductase 1 and catalase (odds ratio 2·00, 95% CI 1·05-3·82). In the cell challenge experiments, there were no significant associations with percentage cytotoxicity. Conclusions: Variation in this small set of genes seems unlikely to have a large impact on either risk of OM or cytotoxicity after H2 O2 exposure. The use of larger sample sizes to test the effects of a much larger set of genetic variants will be required in order to determine whether genetic variation contributes to the risk of OM. Such studies have potential for improving our understanding of causal pathways in OM. [ABSTRACT FROM AUTHOR]- Published
- 2011
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20. Induction of human monocyte IL-1 mRNA and secretion during anti-CD3 mitogenesis requires two distinct T cell-derived signals.
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Landis, R C, primary, Friedman, M L, additional, Fisher, R I, additional, and Ellis, T M, additional
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- 1991
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21. Distinct yet complementary mechanisms of heparin and glycoprotein llb/Illa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention.
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Day, J. R. S., Malik, I. S., Weerasinghe, A., Poullis, M., Nadra, I., Haskard, D. O., Taylor, K. M., and Landis, R. C.
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BLOOD platelet activation ,GLYCOPROTEINS ,POLYSACCHARIDES ,BLOOD coagulation factors ,BLOOD platelets ,THROMBIN ,CYTOKINES ,CENTRAL nervous system - Abstract
Objective: To study the effect of unfractionated heparin (UFH) venus low molecular weight heparin (LMWH) in combination with glycoprotein (Gp) IIb/IIIa blockers on platelet activation and aggregation. Methods: Washed platelets were stimulated with thrombin in the presence or absence of UFH (monoparin), LMWH (enoxaparin), and a Gp IIb/IIIa blocker (abciximab, eptifibatide, or tirofiban). Results: Although Gp IIb/IIIa antagonists blocked the final common pathway of thrombin induced platelet aggregation, UFH and LMWH were better at blocking upstream platelet activation. UFH was significantly more effective than LMWH at inhibiting P selectin expression (p = 0.001) and platelet derived growth factor release from thrombin activated platelets (p = 0.012). Conclusions: UFH and LMWH exert complementary effects to Gp IIb/IIIa blockers by inhibiting afferent pathways of platelet activation. Coadministration of heparin with Gp IIa/IIIb blockers provides improved protection against persistent platelet activation, thereby improving outcome after percutaneous coronary intervention. Judging from these data, UFH may be more effective in this regard than LMWH, at least in vitro. The use of LMWH in preference to UFH during percutaneous coronary intervention, although initially attractive, may inadequately protect against platelet activation despise the presence of Gp IIb/IIIa blockers. [ABSTRACT FROM AUTHOR]
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- 2004
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22. Detection of group A streptococci by aerobic culture and a new simplified immunoassay in three pediatric practices and a hospital laboratory.
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Kellogg, James A., Bankert, David A., Schonauer, Thomas D., Landis, Robert C., Nussbaum, Allen S., Levisky, John S., Kellogg, J A, Bankert, D A, Schonauer, T D, Landis, R C, Nussbaum, A S, and Levisky, J S
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- 1991
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23. The Antithrombotic and Antiinflammatory Mechanisms of Action of Aprotinin
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Landis, R. C., Asimakopoulos, G., Poullis, M., Haskard, D. O., and Taylor, K. M.
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- 2001
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24. Circulating adhesion molecules and inflammatory mediators in demyelination: A review
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Hartung, H. -P, Archelos, J. J., Zielasek, J., Gold, R., Koltzenburg, M., Reiners, K. -H, Toyka, K. V., Raine, C. S., Hafler, D. A., Weiner, H. L., Chang, J., Utz, U., Mcfarland, H. F., Thomas, P. K., Hartung, H. P., Pollard, J. D., Harvey, G. K., Taylor, W. A., Hughes, R. A. C., Reiners, K., Schmidt, B., Khalili-Shirazi, A., Brostoff, S. W., Burns, J., Krasner, L. J., Rostami, A., Pleasure, D., Pette, M., Gengaroli, C., Linington, C., Brosnan, C. F., Claudio, R. A., Martiney, J. A., Sobel, R. A., Mitchell, M. E., Fondren, G., Hickey, W. F., Shingu, M., Hashimoto, M., Ezaki, I., Nobunaga, M., Springer, T. A., Bevilacqua, M. P., Nelson, R. M., Hynes, R. O., Picker, J., Gearing, A. J. H., Newman, W., Pigott, R., Dillon, L. P., Hemingway, I. H., Brustein, M., Kraal, G., Mebius, R. E., Watson, S. R., Schleiffenbaum, B., Spertini, O., Tedder, T. F., Leeuwenberg, J. F. M., Smeets, E. F., Neefjes, J. J., Seth, R., Raymond, F. D., Makgoba, M. W., Rothlein, R., Manolfi, E. A., Czaikowski, M., Martin, D. S., Tsukada, N., Miyaagi, K., Matsuda, M., Michels, M., Jander, S., Heidenreich, F., Stoll, G., Sharief, M. K., Noori, M. A., Ciardi, M., Rieckmann, P., Weichselbraun, I., Albrecht, M., Mccarron, R. M., Wang, L., Racke, M. K., Jemison, L. M., Williams, S. K., Lublin, F. D., Kim, K. S., Wass, C. A., Cross, A. S., Opal, S. M., Wilcox, C. E., Ward, A. M., Evans, A., Frohman, E. M., Frohman, T. C., Dustin, M. L., Wong, D., Dorovini-Zis, K., Fabry, Z., Waldschmidt, M. M., Hendrickson, D., Satoh, J., Kim, S. U., Kastrukoff, L. F., Takei, F., Whitaker, J. N., Herman, P. K., Sparacio, S. M., Cannella, B., Cross, A. H., Dopp, J. M., Breneman, S. M., Olschowska, J. A., Lindsey, J. W., Steinman, L., Steffen, B. J., Butcher, E. C., Engelhardt, B., Osborn, L., Hession, C., Tizard, R., Baron, J. L., Madri, J. A., Ruddle, N. H., Kuchroo, V. K., Martin, C. A., Greer, J. M., Tanaka, M., Satom, A., Makino, M., Tabira, T., Yednock, T. A., Cannon, C., Fritz Zimprich, Jung, S., Maurer, M., Willenborg, D. O., Simmons, R. D., Tamatani, T., Miyasaka, M., Seventer, G. A., Shimizu, Y., Damle, N. K., Aruffo, A., Dang, L. H., Michalek, M. T., Dougherty, G. J., Murdock, S., Hogg, N., Landis, R. C., Oka, N., Akiguchi, I., Kawasaki, T., Staunton, D. E., Ockenhouse, C. F., Ellison, M. D., Merchant, R. E., Selmaj, K., Zeman, A., Mclean, B., Thompson, E. J., Powell, M. B., Mitchell, D., Lederman, J., Hershkoviz, R., Mor, F., Gilat, D., Kuroda, Y., Shimamoto, Y., Bergman, C. M., Mcgrath, K. M., Chung, I. Y., Norris, J. G., Benveniste, E. N., Hofmann, F. M., Hinton, D. R., Johnson, K., Merrill, J. E., Strom, S. R., Ellison, G. W., Myers, L. W., Rudick, R. A., Ransohoff, R. M., Hentges, R., Trotter, J. L., Collins, K. G., Veen, R. C., Hauser, S. L., Doolittle, T. H., Lincoln, R., Beck, J., Rondot, P., Catinot, L., Chofflon, M., Juillard, C., Juillard, P., Kitze, B., Tracey, K. J., Cerami, A., Miyagi, K., Yanagisawa, N., Selmaj, K. W., Farooq, M., Norton, W. T., Fierz, W., Endler, B., Reske, K., Sun, D., Schafer, B., Meide, P. H., Strigard, K., Holmdahl, R., Meide, P., Tsai, C. P., Armati, P. J., Billiau, A., Duong, T. T., St Louis, J., Gilbert, J. J., Voorthuis, J. A. C., Uitdehaag, B. M. J., Groot, C. J. A., Steiniger, B., Vass, K., Lassmann, H., Vethna, M., Lampson, L. A., Karpus, W. J., Swanborg, R. H., Renno, T., Lin, J. Y., Piccirillo, C., Olsson, T., Wang, W. -Z, Hojeberg, B., Voskuhl, R. R., Martin, R., Bergman, C., Link, J., Soderstrom, M., Colton, C. A., Gilbert, D. L., Sonderer, B., Wild, P., Wyler, R., Nathan, C. F., Heininger, K., Stevens, A., Lang, R., Schabet, M., Bowern, N. A., Danta, G., Doherty, P. D., Griot, C., Burge, T., Vandervelde, M., Peterhans, E., Chia, L. S., Thompson, J. E., Moscarello, M. A., Konat, G. W., Wiggins, R. C., Offner, H., Richard, A., Kolb, H., Kolb-Bachofen, V., Tausch, M., Simmons, M. L., Murphy, S., Macmickin, J. D., Weidenmann, M. J., Koprowski, H., Zheng, Y. M., Heber-Katz, E., Bo, L., Dawson, T. M., Wesselingh, S., Misko, T. P., Lin, R. F., Ignarro, L. J., Sherman, M. P., Levi-Strauss, M., Mallat, M., Compston, D. A., Morgan, B. P., Campbell, A. K., Scolding, N., Noble, M., Koski, C. L., Oleesky, D., Sanders, M. E., Swoveland, P. T., Robbins, D., Schwenke, C., Bitter-Suermann, D., Griffin, J. W., Li, C. Y., Feasby, T. E., Hahn, A. F., Neilson, M., Scolding, N. J., Sawant-Mane, S., Clark, M. B., Piddlesden, S., Zimprich, F., Shin, N. L., and Carney, D. F.
25. Dear SIRS ... unfaithfully yours.
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Landis, R. C. and Durandy, Y.
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SYSTEMIC inflammatory response syndrome , *SEPSIS , *BLOOD cell count , *CARDIOPULMONARY bypass - Abstract
A letter to the editor about systemic inflammatory response syndrome is presented.
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- 2017
26. RECOMBINANT APROTININ VARIANTS BLOCK PLATELET ACTIVATION VIA PAR 1.
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Day, I. R. S., Haskard, D., Taylor, K. M., and Landis, R. C.
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APROTININ ,ANTICOAGULANTS ,BLOOD platelets ,CARDIAC surgery ,THROMBIN ,CARDIOLOGY - Abstract
This article focuses on a study related to recombinant aprotinin variants block platelet activation via protease activated receptors (PAR1). Cardiopulmonary bypass causes platelet dysfunction and aprotinin helps prevent this. Thrombin signalling on platelets is mediated by PAR1 and 4 and aprotinin inhibits thrombin induced platelet activation by preventing activation of PAR1. Low dose thrombin activates PAR1 alone. Aprotinin muteins block PAR1 induced platelet aggregation. With more understanding of the mechanism of action, safer and more efficacious aprotinin variants may become available for clinical use.
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- 2004
27. THROMBIN MEDIATED INDUCTION OF DECAY ACCELERATING FACTOR ON HUMAN ENDOTHELIAL CELLS IS PREDOMINANTLY MEDIATED THROUGH A PROTEASE ACTIVATED RECEPTOR 2 PROTEIN KINASE C EPSILON DEPENDENT PATHWAY.
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Lidington, F., Mankoff, R., Landis, R. C., Kindederer, A., Ohba, M., Haskard, D., and Mason, J.
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PROTEIN kinases ,THROMBIN ,THROMBOSIS ,CARDIOVASCULAR diseases ,BLOOD coagulation ,VASCULAR endothelium ,PHOSPHORYLATION - Abstract
The article reports that the serine protease thrombin, is an important mediator of thrombosis, which also has pro-angiogenic, permeability inducing and cytoprotective effects on vascular endothelium. These actions are mediated by members of the protease activated receptor family. Researchers have now explored in detail the signaling pathways mediating thrombin induced cytoprotection. Using pharmacological inhibitors they found that protein kinase C and the mitogen activated protein kinases are required for thrombin induction of DAF surface expression and were rapidly phosphorylated by thrombin. However, blockade of PKC did not prevent these phosphorylation events, suggesting that thrombin can signal to MAPK independently of PKC.
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- 2004
28. SUSCEPTIBILITY TO DIABETIC CARDIOVASCULAR DISEASE IS INFLUENCED BY HAPTOGLOBIN (HP) PHENOTYPE DEPENDENT ANTI-INFLAMMATORY PATHWAYS IN MACROPHAGES (Mϕ).
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Philippidis, P., Nadra, I., Evans, B., Taylor, K. M., Haskard, D. O., and Landis, R. C.
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HAPTOGLOBINS ,ALPHA globulins ,CARDIOVASCULAR diseases ,BLOOD proteins ,HEMOGLOBINS ,MYOCARDIAL infarction - Abstract
The article focuses on a study that explores the hypothesis that haptoglobin (HP) phenotype exerts its differential effect on cardiovascular risk by modulating the inflammatory response within plaques following hemoglobin clearance. Hp is a plasma protein polymer genetically encoded by two allelic variants. Recent studies show that diabetics homozygous for the Hp 2 allele have a fivefold increased risk of developing myocardial infarction, stroke, and cardiovascular death compared with Hp 1-1 individuals.
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- 2004
29. APROTININ PREVENTS PLATELET DYSFUNCTION AFTER CARDIOPULMONARY BYPASS (CPB) BY PROTECTING PAR 1.
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Day, J. R. S., Haskard, D. O., Taylor, K. M., and Landis, R. C.
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APROTININ ,ANTICOAGULANTS ,BLOOD platelets ,FIBRINOLYTIC agents ,HEMATOLOGIC agents ,CARDIOLOGY - Abstract
This article focuses on a study that shows aprotinin prevents platelet dysfunction after cardiopulmonary bypass (CPB) by protecting PAR1. CPB causes the activation of platelets, rendering them dysfunctional. The return of these platelets to the circulation contributes to excessive postoperative bleeding. Researchers have demonstrated that aprotinin preserve platelet function in vivo by protecting the platelet PAR1 receptor from stimulation. This action of aprotinin may synergise with its anti-fibrinolytic effect, further limiting requirements for postoperative blood and platelet transfusion.
- Published
- 2004
30. ANTI-INFLAMMATORY MONOCYTES ARE INDUCED FOLLOWING CARDIOPULMONARY BYPASS SURGERY.
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Philippidis, P., Taylor, K. M., Haskard, D. O., and Landis, R. C.
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ANTI-inflammatory agents ,CARDIOPULMONARY system ,CARDIOPULMONARY bypass ,MONOCYTES ,CARDIAC surgery ,CARDIOLOGY - Abstract
This article focuses on a study that shows anti-inflammatory monocytes are induced following cardiopulmonary bypass surgery. Circulating monocyte activation at 2-4 hours following the onset of cardiopulmonary bypass surgery is commonly thought to potentiate systemic inflammatory responses and impair patient recovery. These in vivo observations demonstrate the induction of anti-inflammatory circulating monocytes at 24-48 hours. Therapeutic strategies to induce such circulating monocytes may improve clinical outcome and promote wound healing postoperatively.
- Published
- 2004
31. DISTINCT YET COMPLEMENTARY ROLES OF IIB/IIIA INHIBITORS AND HEPARIN DURING PLATELET ACTIVATION: IMPLICATIONS FOR RESTENOSIS FOLLOWING PERCUTANEOUS CORONARY INTERVENTIONS (PCI).
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Day, J. R. S., Malik, I. S., Weerasinghe, A., Poullis, M., Nadra, I., Haskard, D. O., Taylor, K. M., and Landis, R. C.
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BLOOD platelets ,CORONARY disease ,HEPARIN ,CORONARY arteries ,MEDICAL research ,CLINICAL trials - Abstract
This article focuses on a study that explores distinct yet complementary roles of IIb/IIIa inhibitors and heparin during platelet activation with implications for restenosis following percutaneous coronary interventions (PCI). Unfractionated heparin produces significantly greater inhibition of platelet activation and smooth muscle proliferation than LMWH, at least in vitro, thus cautioning against the adoption of LMWH as the standard during PCI before clinical trials are completed. Results of the study are also discussed in the article.
- Published
- 2004
32. ATHEROSCLEROTIC CALCIFICATION AS A HIDDEN SOURCE OF INFLAMMATION: PROTEIN KINASE Cα AND ϵ, ERK-1/2 AND NFκB SIGNALLING PATHWAYS MEDIATE CALCIUM HYDROXYAPATITE CRYSTAL INDUCED...
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Nadra, I., Philippidis, P., Mason, J. C., McCarthy, G. M., Landis, R. C., and Haskord, D. O.
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MACROPHAGES ,INFLAMMATION ,CALCIUM ,HYDROXYAPATITE ,ATHEROSCLEROTIC plaque ,CALCIFICATION - Abstract
This article focuses on a study related to atherosclerotic calcification as a hidden source of inflammation. Within atherosclerotic lesions macrophages have been shown to colocalise with calcium hydroxyapatite (HAP) deposits. Several studies have also demonstrated that through the secretion of TNFα macrophages are also capable of inducing further calcification. Researchers are the first to report that HAP deposits within atherosclerotic lesions are likely to enhance atherogenesis and calcification through the release of macrophages.
- Published
- 2004
33. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery.
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Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, and Taylor KM
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- Humans, Thrombin metabolism, Aprotinin therapeutic use, Cardiopulmonary Bypass, Receptor, PAR-1 antagonists & inhibitors
- Abstract
Background: Protease-activated receptor-1 (PAR1) is the principal thrombin receptor in the vasculature, and antagonists against this receptor are in preclinical trials. Aprotinin, already approved for clinical use to reduce transfusion requirements in cardiopulmonary bypass (CPB) surgery, has been shown to inhibit PAR1 activation in vitro. Here, we exploit CPB as a model for thrombin generation in humans to examine whether aprotinin can inhibit platelet PAR1 activation clinically., Methods and Results: PAR1 expression and function on platelets was examined in coronary artery bypass grafting (CABG) patients randomized into 2 groups: (1) those receiving saline infusion during CPB (n=17) and (2) those receiving aprotinin (2x10(6) kallikrein inhibitor units [KIU] in pump prime, 2x10(6) KIU loading dose, followed by 0.5x10(6) KIU/h [n=13]). Platelets in the saline group showed loss of PAR1-specific function at 2 hours after CPB, but this was preserved in the aprotinin group (P<0.001). These effects were most likely targeted at PAR1 receptor cleavage, because (1) the level of thrombin generated during CPB did not vary significantly between groups, (2) expression of SPAN12, which detects only uncleaved PAR1 receptors, was preserved in the aprotinin but not the placebo group (P<0.05), and (3) supporting evidence in vitro showed reduced thrombin-induced PAR1 cleavage (P<0.001) and platelet aggregation (P<0.001) in the presence of aprotinin., Conclusions: This study demonstrates that platelet PAR1 activation by thrombin can be inhibited by aprotinin. Our results extend the clinical mechanism of action of aprotinin and provide the first proof of principle that PAR1 can be inhibited clinically. This has implications beyond cardiac surgery for the development of therapeutic PAR1 blockade.
- Published
- 2004
- Full Text
- View/download PDF
34. Heparin is much more than just an anticoagulant.
- Author
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Day JR, Landis RC, and Taylor KM
- Subjects
- Anticoagulants adverse effects, Blood Platelets drug effects, Heparin adverse effects, Humans, Anticoagulants pharmacology, Blood Coagulation drug effects, Heparin pharmacology
- Published
- 2004
- Full Text
- View/download PDF
35. Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery.
- Author
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Philippidis P, Mason JC, Evans BJ, Nadra I, Taylor KM, Haskard DO, and Landis RC
- Subjects
- Aged, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Autocrine Communication, Blister immunology, Cells, Cultured, Coronary Artery Bypass, Female, Haptoglobins metabolism, Heme Oxygenase-1, Hemoglobins metabolism, Humans, Inflammation enzymology, Inflammation metabolism, Macrophages enzymology, Male, Membrane Proteins, Middle Aged, Monocytes enzymology, Receptors, Cell Surface metabolism, Antigens, CD physiology, Antigens, Differentiation, Myelomonocytic physiology, Cardiopulmonary Bypass, Heme Oxygenase (Decyclizing) biosynthesis, Interleukin-10 biosynthesis, Macrophages immunology, Monocytes immunology, Receptors, Cell Surface physiology
- Abstract
The recently described hemoglobin scavenger receptor CD163 mediates the endocytosis of hemoglobin:haptoglobin (Hb:Hp) complexes and thereby counters Hb-induced oxidative tissue damage after hemolysis. Although CD163 has been indirectly associated with antiinflammatory and atheroprotective activity, no ligand-receptor-effector pathway has yet been described for this receptor. To understand the significance of CD163 and more clearly define downstream pathways linked to inflammatory resolution, we studied the expression and function of CD163 in human monocytes/macrophages using both in vitro and in vivo models. Differentiation of human blood monocytes into macrophages either by in vitro culture or in resolving cantharidin-induced skin blisters led to an equivalent increase (>15x) in CD163 expression. Elevated CD163 levels were also noted on circulating monocytes in cardiac surgical patients during the resolution phase of the systemic inflammatory response to cardiopulmonary bypass surgery. In each case, binding of Hb:Hp to CD163-bearing cells elicited potent interleukin-10 secretion, and this was inhibited by the anti-CD163 antibody RM3/1. Release of interleukin-10, in turn, induced heme oxygenase-1 stress protein synthesis via an autocrine mechanism. Such induction of heme oxygenase-1 was observed in vivo 24 to 48 hours after the onset of cardiopulmonary bypass surgery. These results identify novel antiinflammatory and cytoprotective effector pathways in human monocytes/macrophages related to Hb scavenging and metabolism, which may have relevance in atheroprotection, wound healing, and patient recovery postoperatively.
- Published
- 2004
- Full Text
- View/download PDF
36. New antiinflammatory and platelet-preserving effects of aprotinin.
- Author
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Landis RC, Haskard DO, and Taylor KM
- Subjects
- Blood Platelets drug effects, Cardiopulmonary Bypass, Cell Adhesion drug effects, Endothelium, Vascular drug effects, Humans, Leukocytes drug effects, Receptor, PAR-1, Receptors, Thrombin antagonists & inhibitors, Anti-Inflammatory Agents pharmacology, Aprotinin pharmacology, Platelet Aggregation Inhibitors pharmacology
- Abstract
The clinical benefit of aprotinin with respect to improved hemostasis, platelet function, and inflammatory response to cardiopulmonary bypass (CPB) surgery has been well documented, but these benefits have been overshadowed by the concern that such a potently hemostatic agent might also be prothrombotic. In this article, we discuss recent advances in the understanding of the basic mechanism of aprotinin that have led to the identification of new antiinflammatory targets and the discovery that aprotinin is, in fact, antithrombotic with respect to platelets. Its antithrombotic action is mediated by the selective blocking of the major thrombin receptor, the protease-activated receptor 1 (PAR1), but not other receptors of platelet activation (ie, collagen, adenosine diphosphate [ADP], or epinephrine receptors). The selective targeting of PAR1 enables aprotinin to protect platelets from unwanted activation by thrombin generated during CPB surgery (consistent with a role in platelet-preservation), while permitting the participation of platelets in the formation of hemostatic plugs at wound and suture sites, where collagen, ADP, and epinephrine are most likely to be expressed. Aprotinin therefore exerts a subtle hemostatic yet antithrombotic mechanism of action, which, when allied with its multitiered antiinflammatory effect, makes this drug a valuable companion to cardiac surgery.
- Published
- 2001
- Full Text
- View/download PDF
37. Aprotinin administration in the pericardial cavity does not prevent platelet activation.
- Author
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Landis RC and Taylor KM
- Subjects
- Aprotinin administration & dosage, Cardiopulmonary Bypass, Hemostatics administration & dosage, Humans, Pericardium, Aprotinin pharmacology, Hemostatics pharmacology, Platelet Activation drug effects
- Published
- 2001
- Full Text
- View/download PDF
38. Effect of aprotinin on endothelial cell activation.
- Author
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Asimakopoulos G, Lidington EA, Mason J, Haskard DO, Taylor KM, and Landis RC
- Subjects
- Cardiopulmonary Bypass, Cell Adhesion Molecules drug effects, Cells, Cultured, E-Selectin drug effects, Endothelium, Vascular cytology, Endothelium, Vascular physiology, Flow Cytometry, Humans, Inflammation Mediators physiology, Intercellular Adhesion Molecule-1 drug effects, Vascular Cell Adhesion Molecule-1 drug effects, Aprotinin pharmacology, Endothelium, Vascular drug effects, Serine Proteinase Inhibitors pharmacology, Tumor Necrosis Factor-alpha physiology
- Abstract
Background: Cardiopulmonary bypass surgery is often accompanied by a systemic inflammatory response, which can lead to postoperative complications in high-risk patients. This is mediated in part through a systemic rise in inflammatory cytokine levels and the sequestration of leukocytes within organs. Aprotinin has previously been shown to exert an anti-inflammatory effect by preventing the capacity of leukocytes to transmigrate through vascular endothelium. Here we have focused on whether aprotinin has an effect on endothelial cell activation and adhesion molecule expression in response to tumor necrosis factor-alpha, particularly with reference to whether aprotinin inhibits tumor necrosis factor-stimulated neutrophil transendothelial migration., Methods and Results: Intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expression was studied in tumor necrosis factor-alpha-activated human umbilical vein endothelial cells in the presence of aprotinin at 200, 800, and 1600 kIU/mL. Aprotinin inhibited tumor necrosis factor-alpha-stimulated expression of intercellular adhesion molecule-1 (P =.019 at 1600 kIU/mL) and vascular cell adhesion molecule-1 (P =.003 at 1600 kIU/mL) but not E-selectin. Similar results were obtained in the dermal microvascular endothelial cell line, HMEC-1, which exhibited diminished intercellular adhesion molecule-1 expression in the presence of aprotinin (P =.040 at 800 kIU/mL and P <.001 at 1600 kIU/mL). Aprotinin also significantly inhibited neutrophil transmigration across tumor necrosis factor-alpha-activated human umbilical vein endothelial cells (P =.046 at 1600 kIU/mL)., Conclusions: We have demonstrated that aprotinin inhibits intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, but not E-selectin, expression on tumor necrosis factor-alpha-activated endothelial cells and that transendothelial migration by neutrophils is also specifically suppressed under these conditions. Our results indicate that endothelial cells can be specifically targeted by aprotinin, therefore adding to our understanding of the anti-inflammatory mechanism of action of aprotinin during cardiopulmonary bypass.
- Published
- 2001
- Full Text
- View/download PDF
39. Pathogenesis of crystal-induced inflammation.
- Author
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Landis RC and Haskard DO
- Subjects
- Crystallization, Humans, Macrophages physiology, Monocytes physiology, Neutrophils physiology, Synovial Fluid chemistry, Synovial Fluid metabolism, Uric Acid adverse effects, Uric Acid blood, Arthritis chemically induced, Arthritis metabolism, Gout chemically induced, Gout metabolism
- Abstract
Crystals are an important cause of inflammatory rheumatic diseases and provide relatively simple paradigms for modelling inflammatory responses in general. Thus, in the case of gout, we know that hyperuricemia leads to precipitation of monosodium urate (MSU) crystals in joints, which are taken up by leukocytes, and then an acute attack of arthritis is triggered. However, fundamental questions remain unanswered. Why are only certain hyperuricemic individuals, and then only certain joints, affected? What factors maintain joints in a quiescent state, what prompts the resolution of an inflammatory attack, and are these related? This article draws on developments during the past year to support the idea that the mononuclear phagocyte may play a key role within the synovial compartment, tipping the balance from the asymptomatic state to acute inflammation, or vice versa, depending on their state of monocyte to macrophage differentiation.
- Published
- 2001
- Full Text
- View/download PDF
40. Effect of aprotinin (trasylol) on the inflammatory and thrombotic complications of conventional cardiopulmonary bypass surgery.
- Author
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Landis RC, Asimakopoulos G, Poullis M, Thompson R, Nourshargh S, Haskard DO, and Taylor KM
- Subjects
- Animals, Aprotinin pharmacology, Hemostatics pharmacology, Humans, Inflammation prevention & control, Intracranial Embolism etiology, Leukocytes drug effects, Systemic Inflammatory Response Syndrome etiology, Aprotinin therapeutic use, Cardiopulmonary Bypass adverse effects, Hemostatics therapeutic use, Intracranial Embolism prevention & control, Systemic Inflammatory Response Syndrome prevention & control
- Abstract
Before the discovery of its hemostatic properties, aprotinin was thought of as a potential anti-inflammatory agent. Its clinical introduction in 1987 to prevent blood loss during cardiac surgery [Royston 1987, van Oeveren 1987] led to its anti-inflammatory benefits being largely overlooked in favor of a vigorous debate centering on whether aprotinin may be pro-thrombotic when given to patients. In this article, we summarize evidence for the anti-inflammatory activity of aprotinin and discuss our recent contributions in this area. We also summarize the state of the thrombosis debate and discuss our recent evidence from purified platelets which shows that aprotinin is simultaneously hemostatic yet anti-thrombotic.
- Published
- 2001
41. Inhibition of neutrophil L-selectin shedding: a potential anti-inflammatory effect of aprotinin.
- Author
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Asimakopoulos G, Taylor KM, Haskard DO, and Landis RC
- Subjects
- Aprotinin pharmacology, Cardiopulmonary Bypass adverse effects, Dose-Response Relationship, Drug, Flow Cytometry, Humans, Inflammation prevention & control, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Neutrophil Activation drug effects, Platelet Activating Factor pharmacology, Serine Proteinase Inhibitors pharmacology, L-Selectin drug effects, L-Selectin metabolism, Neutrophils metabolism
- Abstract
The cardiopulmonary bypass (CPB)-related inflammatory response involves leucocyte activation and increased leucocyte-endothelial cell interaction. L-selectin is an adhesion molecule expressed on the surface of leucocytes which participates in the initial rolling step of the leucocyte-endothelial cell adhesion cascade. L-selectin is proteolytically cleaved off the surface of leucocytes when they become activated, an event that is regarded as a marker of leucocyte activation. Aprotinin is a protease inhibitor that has been used in cardiac surgery as a haemostatic agent and also exhibits certain anti-inflammatory properties. In this study, peripheral venous blood from volunteers was pre-incubated with aprotinin at 200, 800 and 1600 kallikrein inhibiting units (kiu)/ml and stimulated with the chemoattractants N-formyl-methyl-leucyl-phenylalanine (fMLP) or platelet activating factor (PAF). Surface expression of L-selectin on neutrophils was measured using a monoclonal antibody and flow cytometry. The results demonstrate that aprotinin inhibits shedding of L-selectin in a dose-dependent fashion (p=0.0278 and 0.0005, respectively, at 800 and 1600 kiu/ml for fMLP-stimulated shedding; p=0.0017 and 0.0010, respectively, at 200 and 800 kiu/ml for PAF-stimulated shedding). This effect may be of significance with respect to the anti-inflammatory action of aprotinin in patients undergoing CPB.
- Published
- 2000
- Full Text
- View/download PDF
42. Cloning of porcine intercellular adhesion molecule-1 and characterization of its induction on endothelial cells by cytokines.
- Author
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Stocker CJ, Sugars KL, Yarwood H, Delikouras A, Lechler RI, Dorling A, Landis RC, Morley BJ, and Haskard DO
- Subjects
- Amino Acid Sequence, Animals, COS Cells, Cell Adhesion, Endothelium, Vascular drug effects, Gene Library, Humans, Intercellular Adhesion Molecule-1 chemistry, Intercellular Adhesion Molecule-1 physiology, Interferon-gamma pharmacology, Interleukins pharmacology, Kinetics, Lymphocytes physiology, Molecular Sequence Data, Recombinant Proteins biosynthesis, Recombinant Proteins chemistry, Recombinant Proteins pharmacology, Sequence Alignment, Sequence Homology, Amino Acid, Swine, Transcription, Genetic, Transfection, Tumor Necrosis Factor-alpha pharmacology, Cytokines pharmacology, Endothelium, Vascular metabolism, Gene Expression Regulation drug effects, Intercellular Adhesion Molecule-1 genetics
- Abstract
Background: The transplantation of pig organs into humans requires a detailed knowledge of similarities and differences between the two species in the molecular physiology of host defense mechanisms. We therefore set out to identify porcine intercellular adhesion molecule (ICAM)-1 and to characterize its expression by endothelial cells., Methods: Porcine ICAM-1 cDNA was isolated from an endothelial cell cDNA library. An anti-pig ICAM-1 monoclonal antibody was generated and used to investigate the regulation by cytokines of ICAM-1 expression by porcine aortic endothelial cells (PAEC), using flow cytometry., Results: We found that porcine ICAM-1 was similar in primary structure to human ICAM-1, with five Ig-like domains. COS-7 cells transfected with porcine ICAM-1 supported beta2 but not alpha4 integrin-dependent adhesion of human T lymphoblasts. There was a low-level surface expression of ICAM-1 on unstimulated PAEC and increased expression after stimulation with tumor necrosis factor (TNF)-alpha. However expression of ICAM-1 seemed to be significantly lower than that of vascular cell adhesion molecule-1, both on unstimulated and TNF-alpha-activated PAEC. Recombinant porcine interferon-gamma weakly stimulated ICAM-1 expression when incubated alone with PAEC but had an inhibitory effect on the increase in ICAM-1 due to TNF-alpha, both at 8 and 24 hr., Conclusions: Our observations confirm the existence of ICAM-1 in the pig and provide novel insights into how porcine and human endothelial cells differ in terms of adhesion molecule expression and cytokine responsiveness. Such differences are potentially important in interpreting models of inflammation in the pig and also in understanding the process of rejection of porcine xenografts.
- Published
- 2000
- Full Text
- View/download PDF
43. Noninflammatory phagocytosis of monosodium urate monohydrate crystals by mouse macrophages. Implications for the control of joint inflammation in gout.
- Author
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Yagnik DR, Hillyer P, Marshall D, Smythe CD, Krausz T, Haskard DO, and Landis RC
- Subjects
- Animals, Arthritis, Gouty, Cell Differentiation, Cell Extracts pharmacology, Cell Line drug effects, Cell Line metabolism, Endothelium, Vascular chemistry, Endothelium, Vascular cytology, Endothelium, Vascular metabolism, Intercellular Adhesion Molecule-1 biosynthesis, Macrophages cytology, Macrophages immunology, Mice, Phagocytosis, Tumor Necrosis Factor-alpha metabolism, Uric Acid immunology
- Abstract
Objective: We have hypothesized that the process of monocyte to macrophage differentiation may alter the inflammatory response of mononuclear phagocytes to the uptake of monosodium urate monohydrate (MSU) crystals., Methods: Eight mouse monocyte/macrophage cell lines were arranged in increasing order of differentiation, as judged by expression of the macrophage markers F4/80 and BM 8 and by phagocytic capacity. Secretion of tumor necrosis factor alpha (TNFalpha) in response to MSU was measured by enzyme-linked immunosorbent assay., Results: The panel of monocyte/macrophage cell lines revealed a close linkage between the state of differentiation and the capacity of the cells to ingest MSU crystals. TNFalpha production, however, was not linked to phagocytic ability. Peak TNFalpha levels were synthesized by cells at an intermediate state of differentiation (3.2-14.1 ng/ml), whereas mature macrophages, which efficiently phagocytosed crystals, did not secrete TNFalpha. Mature cell lines produced TNFalpha when stimulated with zymosan (5.9-6.2 ng/ml), but this was abolished by coincubation with MSU crystals. Suppression of the zymosan response was not due to apoptosis or steric hindrance by MSU crystals. Culture supernatants from mature macrophages did not stimulate endothelial cell activation, in contrast to MSU-treated cells at an earlier stage of differentiation, which stimulated intercellular adhesion molecule 1 expression on sEND endothelioma cells through the release of TNFalpha (inhibited 80.6% by anti-TNFa)., Conclusion: We demonstrated that phagocytosis and TNFalpha production are distinct events in the response of mononuclear phagocytes to urate crystals, and these events can be distinguished at the level of macrophage differentiation. The noninflammatory removal of urate crystals by mature macrophages defines a new pathway that may be important in controlling the development of acute gout in patients with hyperuricemia.
- Published
- 2000
- Full Text
- View/download PDF
44. The antithrombotic effect of aprotinin: actions mediated via the proteaseactivated receptor 1.
- Author
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Poullis M, Manning R, Laffan M, Haskard DO, Taylor KM, and Landis RC
- Subjects
- Analysis of Variance, Blood Platelets metabolism, Calcium metabolism, Humans, Receptor, PAR-1, Signal Transduction, Thrombin pharmacology, Trypsin pharmacology, Aprotinin pharmacology, Platelet Aggregation drug effects, Receptors, Thrombin metabolism, Serine Proteinase Inhibitors pharmacology
- Abstract
Background: Despite aprotinin being in widespread clinical use to prevent bleeding during cardiac surgery, there remains concern that such a powerful hemostatic agent may also be prothrombotic, particularly in relation to coronary vein graft occlusion. The major thrombin receptor on platelets, protease-activated receptor 1 (PAR1) requires proteolytic cleavage to transmit activating signals. Here we have investigated the effect of aprotinin on thrombin-induced PAR1 activation of platelets., Methods and Results: Proteolysis-dependent and -independent responses of washed platelets were studied in vitro. Platelet aggregation induced by trypsin was dependent on PAR1 (inhibited by the PAR1-specific antagonist peptide, FLLRN) and was completely blocked by aprotinin at doses more than 100 KIU/mL. Aggregation in response to thrombin, 1 nmol/L, was predominantly mediated through PAR1 and was inhibited 42.6% to 86.6% (P <.05-.001) by pharmacologic doses of aprotinin (50-160 KIU/mL). Aprotinin did not inhibit the nonproteolytic agonists collagen, epinephrine, adenosine diphosphate, or phorbol 12-myristate 13-acetate. Furthermore, blockade of the thrombin response by aprotinin did not prevent subsequent platelet aggregation through collagen or epinephrine. Experiments with intraplatelet Ca(2+) fluxes, which provided an earlier measure of platelet activation, placed the effect of aprotinin proximal to the PAR1 activation event. Since aprotinin did not inhibit platelet responses to the nonproteolytic PAR1 agonist peptide, SFLLRN, this implied that aprotinin acted by preventing PAR1 receptor cleavage by thrombin., Conclusions: Aprotinin inhibits thrombin-induced platelet activation by preventing proteolysis of the PAR1 receptor. These findings argue against aprotinin being prothrombotic and suggest instead that aprotinin may have significant antithrombotic effects.
- Published
- 2000
- Full Text
- View/download PDF
45. An anti-inflammatory property of aprotinin detected at the level of leukocyte extravasation.
- Author
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Asimakopoulos G, Thompson R, Nourshargh S, Lidington EA, Mason JC, Ratnatunga CP, Haskard DO, Taylor KM, and Landis RC
- Subjects
- Analysis of Variance, Animals, Cell Adhesion physiology, Dose-Response Relationship, Drug, Endothelium, Vascular drug effects, Endothelium, Vascular physiology, Enzyme-Linked Immunosorbent Assay, Humans, Leukocytes physiology, Male, Microcirculation, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Neutrophils physiology, Peroxidase blood, Rats, Rats, Sprague-Dawley, Splanchnic Circulation, Statistics, Nonparametric, Aprotinin pharmacology, Cell Adhesion drug effects, Leukocytes drug effects, Serine Proteinase Inhibitors pharmacology
- Abstract
Background: Aprotinin is a serine protease inhibitor used extensively in cardiac operations to reduce postoperative bleeding. It has also been used in trials aimed at reducing the systemic inflammatory response to cardiopulmonary bypass. It remains unclear whether the anti-inflammatory action of aprotinin is related to its general ability to suppress leukocyte activation or whether aprotinin can exercise effects during the leukocyte-endothelial cell adhesion cascade., Methods: We used intravital microscopy to study the 3 main stages of the adhesion cascade (leukocyte rolling, firm adhesion, and extravasation) within the mesenteric microcirculation of rats. This in vivo technique allows leukocyte recruitment to be viewed directly through the transparent mesentery of anesthetized animals., Results: Aprotinin, given by continuous infusion at a clinically relevant dose, exerted no effect on the rolling or firm adhesion responses toward local chemoattractant N -formyl-methyl-leucyl-phenylalanine but significantly inhibited extravasation of leukocytes (73% at 40 minutes, P =.04) into surrounding tissues. In parallel in vitro experiments, aprotinin (used at 200, 800, and 1600 kIU/mL) dose dependently inhibited neutrophil transmigration through cultured endothelial cells in response to 3 different chemoattractants: N -formyl-methyl-leucyl-phenylalanine (P <.001 at 800 and 1600 kIU/mL), interleukin 8 (P <.05 at 200 kIU/mL and P <.001 at 800 and 1600 kIU/mL), and platelet-activating factor (P <.05 at 1600 kIU/mL)., Conclusions: Our studies have therefore revealed a novel anti-inflammatory mechanism of aprotinin operating at the level of leukocyte extravasation. These findings may be relevant in the prevention of systemic inflammation after cardiopulmonary bypass through the use of protease inhibitors.
- Published
- 2000
- Full Text
- View/download PDF
46. Leukocyte integrin expression in patients undergoing cardiopulmonary bypass.
- Author
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Asimakopoulos G, Kohn A, Stefanou DC, Haskard DO, Landis RC, and Taylor KM
- Subjects
- Coronary Artery Bypass, Double-Blind Method, Female, Flow Cytometry, Humans, Male, Middle Aged, Aprotinin therapeutic use, CD18 Antigens metabolism, Cardiopulmonary Bypass, Integrin beta1 metabolism, Leukocytes metabolism, Serine Proteinase Inhibitors therapeutic use
- Abstract
Background: The recruitment of leukocytes to vascular endothelium is controlled by adhesion events mediated through the beta2 integrins, whereas the response of extravasated leukocytes within the tissues is controlled through the beta1 integrins. Although cardiopulmonary bypass (CPB) has been shown to be associated with a systemic inflammatory response and elevated levels of beta2 integrins on leukocytes, its effect on the beta1 integrins is not known. This study investigated the effect of the protease inhibitor aprotinin on the expression of the beta1 and beta2 integrins on circulating leukocytes in patients undergoing CPB., Methods: Patients undergoing primary elective coronary artery bypass grafting were randomized into full-dose aprotinin or placebo groups. Blood samples were obtained at nine time points preoperatively, intraoperatively, and up to 6 days postoperatively. The surface expression of the beta1 integrins VLA-1, -3, -4, -5, and -6 and of the beta2 integrins CD11a/CD18, CD11b/CD18, and CD11c/CD18 was measured by flow cytometry on gated neutrophil and monocyte subpopulations in whole blood., Results: Expression of the beta1 integrins was not significantly altered during the study period and, therefore, aprotinin had no effect on the expression of these molecules. Of the beta2 integrins, CD11b/CD18 expression was significantly increased on neutrophils at 15 minutes after onset of CPB in the placebo group (p < 0.01) but not in the aprotinin group., Conclusions: This study showed that expression of the beta1 integrins on neutrophils and monocytes did not alter during the first 6 days after CPB. Expression of the beta2 integrin CD11b/CD18 increased significantly on neutrophils during CPB in control patients but not in patients treated with full-dose aprotinin.
- Published
- 2000
- Full Text
- View/download PDF
47. TNF-alpha, IL-4, and IFN-gamma regulate differential expression of P- and E-selectin expression by porcine aortic endothelial cells.
- Author
-
Stocker CJ, Sugars KL, Harari OA, Landis RC, Morley BJ, and Haskard DO
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Monoclonal biosynthesis, Aorta, Cell Adhesion immunology, Cells, Cultured, Cloning, Molecular, DNA, Complementary isolation & purification, Down-Regulation immunology, E-Selectin metabolism, Endothelium, Vascular cytology, Endothelium, Vascular immunology, Humans, Interleukin-1 physiology, Interleukin-4 antagonists & inhibitors, Leukocytes immunology, Leukocytes metabolism, Ligands, Membrane Glycoproteins physiology, Molecular Sequence Data, P-Selectin immunology, P-Selectin metabolism, Swine, Time Factors, Tumor Necrosis Factor-alpha antagonists & inhibitors, E-Selectin biosynthesis, Endothelium, Vascular metabolism, Interferon-gamma physiology, Interleukin-4 physiology, P-Selectin biosynthesis, Tumor Necrosis Factor-alpha physiology
- Abstract
P- and E-selectin are surface glycoproteins that mediate leukocyte rolling on the surface of endothelium in inflammation. We have cloned porcine P-selectin cDNA and generated a mAb, 12C5, with which to examine P-selectin expression by porcine aortic endothelial cells (PAEC) in comparison with that of E-selectin. Basal expression by PAEC of P-selectin was greater than that of E-selectin, whereas E-selectin expression was more prominently enhanced than that of P-selectin by stimulation with TNF-alpha or IL-1alpha. Both human or porcine IL-4 led to an increase in P-selectin expression, with kinetics that were delayed compared with those seen following stimulation with TNF-alpha or IL-1alpha, but IL-4 did not stimulate expression of E-selectin. When cells were stimulated with TNF-alpha in the presence of IL-4, we observed enhanced P-selectin expression with a parallel reduction in E-selectin expression. Finally, the increase in P-selectin expression due to human IL-4 was reduced in the presence of porcine but not human IFN-gamma. These observations show that E-selectin and P-selectin expression are differentially regulated in PAEC, and that IL-4 leads to a shift in the relative surface density of the two molecules toward P-selectin. The ability of porcine IFN-gamma to inhibit IL-4-induced P-selectin expression suggests that the balance between Th1 and Th2 cytokine production may determine the relative densities of the two selectins in chronic immune-mediated inflammation. Because the increased expression of P-selectin induced by human IL-4 was not inhibited by human IFN-gamma, this balance may be shifted toward P-selectin expression in porcine xenografts infiltrated by human lymphocytes.
- Published
- 2000
- Full Text
- View/download PDF
48. Control of leukocyte integrin activation.
- Author
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Hogg N, Harvey J, Cabanas C, and Landis RC
- Subjects
- Animals, Binding Sites, Antibody immunology, Cell Adhesion Molecules immunology, Humans, Intercellular Adhesion Molecule-1, Ligands, Lymphocyte Function-Associated Antigen-1 immunology, Signal Transduction immunology, Integrins immunology, Leukocytes immunology, Lymphocyte Activation immunology
- Abstract
The integrin receptors on leukocytes are transiently activated by "triggering" molecules that may be other leukocyte membrane structures such as the T-cell receptor complex or small molecules such as PAF, which bind to their own specific receptors. This "inside out" signaling is essential for high affinity integrin/ligand pairing. In the example of LFA-1/ICAM-1, binding is positively supported by Mg2+ but negatively supported by Ca2+. How specific divalent cations affect receptor activation and subsequent ligand binding has still to be fully understood. However, the fact that activation can be mimicked from outside the cell via special anti-LFA-1 monoclonal antibodies such as MEM-83 suggests that activated integrins undergo conformational changes. Further alteration occurs as a result of the interaction of integrin with ligand, and the resulting novel epitopes are named "ligand-induced binding sites." For a brief period of time the integrin/ligand complex is able to transmit signals from "outside in." The transient activation of leukocyte integrins determines that cell-cell adhesion will be short lived and serves the purpose of permitting recycling of effector cells with their targets.
- Published
- 1993
- Full Text
- View/download PDF
49. Adhesion molecules in cell interactions.
- Author
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Hogg N and Landis RC
- Subjects
- Animals, Antibodies therapeutic use, Antibodies, Monoclonal immunology, Antigens, Neoplasm physiology, Cadherins physiology, Cell Adhesion, Cell Adhesion Molecules classification, Cell Adhesion Molecules immunology, E-Selectin, Humans, Integrins physiology, Intercellular Adhesion Molecule-1, L-Selectin, Lectins physiology, Ligands, Lymphocyte Function-Associated Antigen-1 immunology, Mice, Multigene Family, P-Selectin, Platelet Membrane Glycoproteins physiology, Protein-Tyrosine Kinases physiology, Receptors, Immunologic physiology, Receptors, Lymphocyte Homing physiology, Signal Transduction, Cell Adhesion Molecules physiology, Lymphocytes immunology
- Abstract
During a successful immune response, several families of adhesion molecules participate in a cascade of binding events that lead to the binding of leukocytes, both to each other and to cell types such as the endothelium and epithelium. A central theme emerging from recent studies is that the function of an adhesion receptor cannot be inferred from its expression alone; rather, adhesion receptors are 'selected' to perform distinct effector functions based on their cell-background and factors present in the local microenvironment. Thus, adhesion receptors expressed on different cell-types may find themselves in different states of 'activation-readiness' and may be further selected by prevailing conditions in the microenvironment to bind tissue-specific ligands and mediate leukocyte effector functions such as homing or transendothelial migration.
- Published
- 1993
- Full Text
- View/download PDF
50. Performance of an enzyme immunoassay test and anaerobic culture for detection of group A streptococci in a pediatric practice versus a hospital laboratory.
- Author
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Kellogg JA, Landis RC, Nussbaum AS, and Bankert DA
- Subjects
- Adolescent, Adult, Antigens, Bacterial analysis, Bacteria, Anaerobic, Bacteriological Techniques, Child, Child, Preschool, Clinical Laboratory Techniques, Culture Media, Humans, Immunoenzyme Techniques, Infant, Office Visits, Oropharynx microbiology, Pharyngitis microbiology, Reagent Kits, Diagnostic, Streptococcus pyogenes immunology, Streptococcus pyogenes isolation & purification
- Abstract
The ability of pediatricians and hospital laboratory personnel to detect group A streptococci in patients with suspected streptococcal pharyngitis was evaluated using the TestPack Strep A and anaerobic culture. Duplicate throat specimens (for similar processing by both the pediatricians and laboratory technologists) were simultaneously collected on rayon-tipped swabs from patients with symptoms of pharyngitis. Each swab was first inoculated to a 5% sheep blood agar plate, then tested for group A streptococcus antigen using the TestPack Strep A according to the manufacturer's instructions. Cultures were incubated anaerobically at 35 degrees C for 2 nights unless positive after 1 night. Group A streptococci were identified using specific antisera. Pediatric office or laboratory cultures from 112 (31.3%) of the 358 patients contained group A streptococci. Of the patients with positive cultures, 96 (85.7%) and 107 (95.5%) were detected by the pediatricians and laboratory, respectively. Respective findings with the TestPack Strep A by the pediatricians and laboratory were sensitivity 68.8% and 74.8%, specificity 94.3% and 95.6%, predictive value of a positive result 81.5% and 87.9%, and predictive value of a negative result 89.2% and 89.9%. Anaerobic culture was significantly more sensitive than the TestPack Strep A for detection of group A streptococci by both the pediatricians (P less than 0.005) and laboratory personnel (P less than 0.05).
- Published
- 1987
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