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Some Studies on the Inhibition of Mediator Release from Mast Cells

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Some Studies on the Inhibition of Mediator Release from Mast Cells Some studies on the inhibition of mediator release from mast cells by Graham Angus Mackay A thesis presented to The University of London in partial fulfilment of the requirements for the degree of Doctor of Philosophy in the Faculty of Science. The Christopher Ingold Laboratories, University College London, London. July 1993 ProQuest Number: 10045774 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10045774 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Manu Forti n Acknowledgments I wish to particularly thank my supervisor Professor F. L. Pearce for his guidance and help throughout my studies. I am also very grateful to Dr K. J. Murray of SmithKline Beecham for his assistance and contribution to the project. Many thanks go out to Dr.'s H. Y. A. Lau and W. L. Liu for their intellectual and technical help throughout, especially during my 'formative years'. I also wish to thank Dr. Z. Jaffar for the hours of stimulating scientific debate and her proof reading of this thesis and 'constructive criticism'. In Dr. Murray's laboratories, I wish to thank Mrs A. Worby, Mr B. Connolly and Mr D. Mills for their excellent assistance during my frequent visits to 'The Fry the'. I am also grateful to Dr L. Sellers, presently at the University of Cambridge, for discussions and technical instruction. Use of the facilities in the Department of Chemistry and throughout University College London and at SmithKline Beecham, 'The Frythe', Welwyn Garden City, Herts, is gratefully acknowledged. I also thank the Science and Engineering Research Council and SmithKline Beecham for funding me during this study. On a more personal level, I wish to thank Dr Z. Jaffar, Mr B. Emadi-Khiav and Mr C. Galloway for their continual support and friendship throughout my period in London. I also wish to thank all of the research workers present during my stay in Professor Pearce's laboratories for contributing their knowledge, effort and humour into the daily routine. Together, you have made my stay at UCL immensely enjoyable and I will always carry many happy memories. Most importantly, I wish to offer my deepest thanks to my father and mother, Kenneth and Nancy, and sister Susan for the unfailing love, support and patience which they have given me throughout. Their enthusiastic support of my tertiary education has been constant throughout the years and I hope that this thesis and my future deeds will justify their effort and sacrifice. ni Abstract The mast cell has been implicated in the aetiology of a range of allergic and inflammatory diseases including asthma. However, the regulatory processes which control the cell's activity remain unclear. In the present study, the effect of cyclic nucleotide modulation on mast cell function was assessed. It was hoped that this would not only indicate the importance of both cyclic adenosine and guanosine monophosphate in cellular regulation but also give further information into the mode of action of a range of ariti-allergic agents particularly disodium cromoglycate (DSCG). Exogenously applied cyclic adenosine monophosphate produced negligible inhibition of histamine release from rat peritoneal mast cells (RPMC) unlike the cell permeable derivatives of the cyclic nucleotide which were effective inhibitors. Unexpectedly, cyclic guanosine monophosphate (cGMP) produced a dose-dependent attenuation of histamine release from RPMC. However, this inhibition was strikingly reduced if the cells were preincubated with cGMP before stimulation. Such inhibition and marked tachyphylaxis closely resembles the effects of DSCG on RPMC. Further comparison between cGMP and DSCG revealed that they shared parallel kinetics of tachyphylaxis, underwent cross-tachyphylaxis and were ineffective inhibitors of histamine release from mast cells isolated from the mouse, guinea-pig and human. These results suggest that cGMP and DSCG mediate mast cell stabilisation through similar mechanisms. Biochemical analysis of the RPMC phosphodiesterase (PDE) profile revealed that the predominant enzymes were PDE IV and PDE V although some PDE III was also present. Whole cell functional studies, using selective PDE inhibitors, demonstrated that the PDE V targeted drug, zaprinast, produced a particularly potent inhibition of RPMC secretion which paralleled the effects noted using both DSCG and cGMP. Zaprinast's attenuatory activity seems likely to be removed from an interaction with PDE V as a range of equipotent PDE V inhibitors had variable inhibitory effects on RPMC. Thus, modulation of cyclic nucleotide levels at both intra- and extra- cellular sites can have marked effects on the activation state of mast cells. Moreover, the results yield useful information to the elucidation of DSCG's mechanism of action. The uncovering of this mechanism may result in the development of more effective anti-allergic agents which share DSCG's low in vivo toxicity. IV Table of Contents Pages Title Page I Acknowledgements m Abstract IV Table of Contents V-XI Chapter 1 Introduction 1-41 1.1 Historical synopsis 2-3 1.2 Involvement of the mast cell in health and disease 3-5 1.3 Morphological aspects of mast cells and basophils - mast cell heterogeneity 5-6 1.4 Control of secretion and the mast cell high affinity IgE receptor FceRI 6-9 1.5 Activation of m ast cells 1.5.1 Immunological stimulation by antibody-antigen reactions 9-10 1.5.2 Non-im m unological activation 10 1.6 Mast cell m ediators 11 1.6.1 Pre-formed mediators 1.6.1.1 Proteoglycans 11-12 1.6.1.2 Histamine 12-13 1.6.1.3 Serotonin 13-14 1.6.1.4 Neutral proteases 14-15 V 1.6.1.5 Chemotactic factors 15 1.6.2 Newly generated mediators 16 1.6.2.1 Eicosanoids 16-19 1.6.2.3 PAF 19-20 1 .6.2.4 Cytokines 2 0 -2 1 1.7 Mast cell degranulation and the intracellular processes controlling it 2 1 1.7.1 Elevation of intracellular divalent calcium (Ca^+) 21-22 1.7.1.1 The role of phosphatidyl inositol (PI) turnover 22-24 1.7.2 Guanosine triphosphate (GTP) binding proteins (G proteins) 24-26 1.7.3 The role of cyclic nucleotides 26-27 1.7.4 The role of protein-tyrosine phosphorylation 28-29 1.7.5 Activation of a membrane serine esterase 29 1.7.6 Mast cell membrane ion channels 29-30 1.7.7 Sum m ary 30 1.8 Clinical treatment of allergic conditions- mast cell stabilisation 30-31 1.9 Aims of the present study 31 Chapter 2 Methods and materials 42-64 2.1 A nim als 43 2.2 Human subjects 43 2.3 Buffers 2.3.1 Buffers used in the isolation of mast cells and in whole cell experiments 43-44 2.3.2 Buffers used for enzyme extraction and analysis 44-45 VI 2.3.3 Buffers and solutions used in protein purification and phosphorylation experiments 45-46 2.4 Isolation and purification of mast cells and basophils 46-48 2.5 Mast cell num ber and purity 48 2.6 Extraction and purification of phospho­ diesterase (PDE) and cAMP dependent protein kinase (cAMP-PrK) enzymes 49-50 2.7 Histamine and tryptase release from isolated mast cells 50 2.8 Inhibition of histamine and PGD 2 release from isolated mast cells and basophils 50-51 2.9 Protein phosphorylation experiments 51-52 2.10 Measurement of histamine 2.10.1 Manual assay 52 2.10.2 Automated assay 52-53 2.11 Prostaglandin D2 assay 53-54 2.12 Tryptase assay 54-55 2.13 Phosphodiesterase assay 55-56 2.14 cAMP-PrK activity ratio 56-57 2.15 Protein phosphorylation assay 57-59 2.16 Active sensitization 2.16.1 Sensitization with N. brasiliensis 59 2.16.2 Preparation of L3 larvae 59-60 VII 2.16.3 Preparation of secretory allergen 60 2.17 Materials 2.17.1 Secretagogues used 60 2.17.2 Inhibitors used 60-61 2.17.3 Nucleotides used 61 2.17.4 Novel PDE inhibitors and cAMP-PrK activators used 61 2.17.5 Miscellaneous compounds used 62 2.17.6 Materials for buffers 62 2.17.7 Materials for SDS-PAGE 62 2.17.8 Radioactive materials 63 2.17.9 Other materials 63 2.18 Stock solutions used 63-64 2.19 Numerical analysis 64 Chapter 3 The effect of purification on rat peritoneal mast cell reactivity to a range of secretory and inhibitory agents 65-85 3.1 Introduction 66-68 3.2 M ethods and materials 68 3.3 Results 68-70 3.3.1 Comparison of the efficiency of the Percoll and Path-O-Cyte 4 purification techniques 6 8 3.3.2 Comparison of the reactivity of non-purified and purified rat peritoneal mast cells to a range of secretagogues 68-69 3.3.3 The effect of Percoll purification on rat peritoneal mast cell reactivity to secretory drugs 69 3.3.4 The effect of purification on the sensitivity of RPMC to inhibition by a range of compounds VIII 3.3.4.1 Cyclic nucleotide phosphodiesterase inhibitors 69-70 3.3.4.2 Chromone and related drugs 70 3.4 Discussion 70-73 Chapter 4 Effect of a range of nucleotides on mast cell and basophil activation 86-129 4.1 Introduction 87-90 4.2 Methods and materials 90 4.3 Results 90-99 4.3.1 Effect of cAMP and its derivatives 90-91 4.3.2 Effect of cGMP and its derivatives 91 4.3.3 Effect of a range of cyclic and guanine nucleotides 92 4.3.3.1 Cyclic nucleotides 92-93 4.3.3.2 Guanosine nucleotides 93-94 4.3.4 A more complete analysis of the inhibitory effects of cGMP on
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