Hirschfield, G.M.; (2005) C-reactive protein and enhancement of tissue damage: a potential therapeutic target. Doctoral thesis , University of London.

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Abstract

Human C-reactive protein (CRP), the classical acute phase reactant, is a member of the pentraxin family of calcium dependent ligand binding proteins. When ligand bound, particularly to phosphocholine residues found in cell membranes, bacterial cell walls and lipoprotein particles, CRP activates the complement cascade through engagement of Clq. Prior studies have suggested an important role for CRP both epidemiologically and biologically in atherothrombosis and its consequences. In the largest study to date of the epidemiological association between CRP and future cardiac events in healthy individuals, we demonstrate in contrast to previous studies, that the additive value of this inflammatory marker is less than previously thought. Further study of the biology of this ancient molecule in a number of animal models of disease has failed to confirm a protective role for CRP in endotoxaemia, and despite evidence of upregulated production in a transgenic mouse strain prone to atherosclerosis, we have demonstrated no apparent effect of human CRP on atherogenesis. Finally we have clearly and robustly shown that decamerisation of pentameric CRP by a novel low molecular weight palindromic inhibitor effectively prevents the ligand binding properties of this protein. This has established a platform for pharmacological inhibition of CRP in myocardial infarction and stroke where the complement activation initiated by CRP binding to necrotic cells has been suggested to be pro-inflammatory and deleterious.

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