The effect of glycosaminoglycans on cytokine-mediated inflammatory cell recruitment
The effect of glycosaminoglycans on cytokine-mediated inflammatory cell recruitment
The results show that heparin but not heparan sulphate, significantly inhibited the binding and chemotactic response of neutrophils to IL-8, while alpha2-macroglobulin reversed the inhibitory effect. Mast cell degranulation is central to the pathophysiology of allergic airways disease. Heparin measurements in nasal lavage following allergen challenge of the upper airways indicated the different kinetics of mast cell mediator release and diffusion. Heparin, derived solely from mast cells, apparently remained bound by proteins of the extracellular matrix, indicating the importance of measuring markers of disease activity within the tissue compartment, where their effects may be localised during inflammation. It is likely that the interactions described have an important physiological parallel and that heparin and alpha2-macroglobulin play a role in the co-regulation of IL-8 bioactivity.
The catabolism of heparin and heparan sulphate was postulated to have an important regulatory role in the inflammatory process. In order to test this theory a novel, non-radioactive zymographic technique was developed to quantify and characterise heparinase activity in biological samples. Heparinase activity in sputum from CF and asthmatic patients was significantly higher compared to normal subjects. Conversely, heparin concentrations were significantly lower in the sputum of the patients groups than levels detected in normal sputum. Heparin concentrations significantly correlated negatively with the level of heparinase activity. This indicates that an imbalance between heparinases and their natural inhibitor, heparin may influence the progression of inflammation.
Using an immunocytochemical approach, heparinase (NAP-2) in CF lung tissue was localised to endothelial and epithelial basement membranes, suggesting that it has been released by structural or infiltrating inflammatory cells and bound by its substrate in the matrix. This confirms our analysis of supernatants from endothelial cells in culture, which release constitutive low levels of heparinase activity contributing to the turnover of the predominantly heparan sulphate glycocalyx. Further, during the interaction of platelets, neutrophils and eosinophils with EC in culture, increased concentrations of activated matrix metalloprotease-9 and heparinase were detected in culture supernatants, which correlated with the number of adherent leucocytes.
University of Southampton
1998
Ramdin, Lara S.P
(1998)
The effect of glycosaminoglycans on cytokine-mediated inflammatory cell recruitment.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
The results show that heparin but not heparan sulphate, significantly inhibited the binding and chemotactic response of neutrophils to IL-8, while alpha2-macroglobulin reversed the inhibitory effect. Mast cell degranulation is central to the pathophysiology of allergic airways disease. Heparin measurements in nasal lavage following allergen challenge of the upper airways indicated the different kinetics of mast cell mediator release and diffusion. Heparin, derived solely from mast cells, apparently remained bound by proteins of the extracellular matrix, indicating the importance of measuring markers of disease activity within the tissue compartment, where their effects may be localised during inflammation. It is likely that the interactions described have an important physiological parallel and that heparin and alpha2-macroglobulin play a role in the co-regulation of IL-8 bioactivity.
The catabolism of heparin and heparan sulphate was postulated to have an important regulatory role in the inflammatory process. In order to test this theory a novel, non-radioactive zymographic technique was developed to quantify and characterise heparinase activity in biological samples. Heparinase activity in sputum from CF and asthmatic patients was significantly higher compared to normal subjects. Conversely, heparin concentrations were significantly lower in the sputum of the patients groups than levels detected in normal sputum. Heparin concentrations significantly correlated negatively with the level of heparinase activity. This indicates that an imbalance between heparinases and their natural inhibitor, heparin may influence the progression of inflammation.
Using an immunocytochemical approach, heparinase (NAP-2) in CF lung tissue was localised to endothelial and epithelial basement membranes, suggesting that it has been released by structural or infiltrating inflammatory cells and bound by its substrate in the matrix. This confirms our analysis of supernatants from endothelial cells in culture, which release constitutive low levels of heparinase activity contributing to the turnover of the predominantly heparan sulphate glycocalyx. Further, during the interaction of platelets, neutrophils and eosinophils with EC in culture, increased concentrations of activated matrix metalloprotease-9 and heparinase were detected in culture supernatants, which correlated with the number of adherent leucocytes.
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Published date: 1998
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Local EPrints ID: 463479
URI: http://eprints.soton.ac.uk/id/eprint/463479
PURE UUID: 85ab8ed4-0fb0-4da4-ba16-7b8b8cf124a3
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Date deposited: 04 Jul 2022 20:52
Last modified: 04 Jul 2022 20:52
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Author:
Lara S.P Ramdin
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