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      C-Reactive Protein and Complement Are Important Mediators of Tissue Damage in Acute Myocardial Infarction

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          Abstract

          Myocardial infarction in humans provokes an acute phase response, and C-reactive protein (CRP), the classical acute phase plasma protein, is deposited together with complement within the infarct. The peak plasma CRP value is strongly associated with postinfarct morbidity and mortality. Human CRP binds to damaged cells and activates complement, but rat CRP does not activate complement. Here we show that injection of human CRP into rats after ligation of the coronary artery reproducibly enhanced infarct size by ∼40%. In vivo complement depletion, produced by cobra venom factor, completely abrogated this effect. Complement depletion also markedly reduced infarct size, even when initiated up to 2 h after coronary ligation. These observations demonstrate that human CRP and complement activation are major mediators of ischemic myocardial injury and identify them as therapeutic targets in coronary heart disease.

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          Metabolic and scintigraphic studies of radioiodinated human C-reactive protein in health and disease.

          D M Vigushin, M B Pepys, P. Hawkins (1993)
          Plasma and whole-body turnover studies of human C-reactive protein (CRP), isolated from a single normal healthy donor and labeled with 125I, were undertaken in 8 healthy control subjects and 35 hospitalized patients including cases of rheumatoid arthritis, systemic lupus erythematosus, infections, and neoplasia. Plasma clearance of 125I-CRP closely approximated to a monoexponential function and was similar in the control and all patient groups. There was no evidence for accelerated clearance or catabolism of CRP in any of the diseases studied. The 19-h half-life was more rapid than that of most human plasma proteins studied previously, and the fractional catabolic rate was independent of the plasma CRP concentration. The synthesis rate of CRP is thus the only significant determinant of its plasma level, confirming the validity of serum CRP measurement as an objective index of disease activity in disorders associated with an acute-phase response. Approximately 90% of injected radioactivity was recovered in the urine after 7 d, and scintigraphic imaging studies with 123I-labeled CRP in 10 patients with different focal pathology showed no significant localization of tracer. The functions of CRP are thus likely to be effected predominantly in the fluid phase rather than by major deposition at sites of tissue damage or inflammation.
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            Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein.

            M Pepys, Jay Baltz (1982)
            The acute phase response among plasma proteins is a normal response to tissue injury and is therefore a fundamental aspect of many diverse disease processes. It probably usually has a beneficial net function in limiting damage and promoting repair but in some circumstances it may have pathological consequences. Sustained high levels of acute phase proteins and especially SAA are associated with the development of amyloidosis in some individuals. Increased concentrations of CRP may, by activating the complement system, contribute to inflammation and enhance tissue damage. Failure of the normal or appropriate CRP response may also possibly have deleterious effects. SAA is a polymorphic protein which is normally present only in trace amounts but which, during the acute phase response, becomes one of the major apolipoproteins associated with high-density lipoprotein particles. The function of apoSAA is not known but it must have considerable physiological significance apart from its role as the putative precursor of amyloid A protein fibrils. CRP and SAP have been very stably conserved throughout vertebrate evolution and homologous proteins are apparently present even in vertebrates. This strongly suggests that they have important functions although these have not yet been precisely delineated. The main role of CRP may be to provide for enhanced clearance of inappropriate materials from the plasma whether these are of extrinsic origin, such as microorganisms and their products, or the autologous products of cell damage and death. The interaction between aggregated CRP and plasma low-density lipoprotein may play a significant part in the normal function of CRP and may also have a role in lipoprotein metabolism, clearance, and deposition. SAP is a normal tissue protein as well as being a plasma protein. Aggregated SAP selectively binds fibronectin and this may represent an aspect of the normal function of SAP. The deposition of SAP in amyloid is evidently not a normal function but it is not known whether this deposition is involved in the pathogenesis of amyloid or whether it is merely an epiphenomenon. In any case immunohistochemical staining for SAP is useful in the diagnosis of amyloid, in investigation of glomerulonephritis, and in studying disorders of elastic tissue. Regardless of its physiological or pathophysiological functions, the assay of serum CRP is a valuable aid to clinical management in a number of different situations and in different diseases provided results are interpreted in the light of full clinical information.(ABSTRACT TRUNCATED AT 400 WORDS)
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              C-reactive protein fifty years on.

              Mark Pepys (1981)
              The discovery of C-reactive protein (CRP) half a century ago led to the description of the acute-phase reaction which is a fundamental response of the body to injury. Recent work on the structure and function of CRP has revealed the existence of a unique plasma protein family, including CRP and serum amyloid P component (SAP). These proteins have been conserved throughout vertebrate evolution. CRP binds specifically to a wide range of substances derived both from damaged autologous cells and from microorganisms. Complexed CRP can activate the complement system and, by virtue of its dramatically increased production in response to tissue injury, it probably acts primarily as a protective mechanism. However, in some circumstances CRP may also initiate or exacerbate inflammatory lesions. Clinical measurement of serum CRP is valuable as a screening test for organic disease and as a sensitive object index of disease activity and response to therapy in some inflammatory, infective, and ischaemic conditions. SAP closely resembles CRP in structure but not an acute-phase reactant in man. An apparently identical protein, amyloid P component (AP), is always found in amyloid deposits. AP is also found in normal tissues, as an integral constituent of vascular basement membranes and is located on the peripheral microfibrillar mantle of elastic fibres throughout the body.
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                Author and article information

                Contributors
                :
                Dept. of Medicine, Royal Free Campus, Royal Free and University College Medical School, Rowland Hill St., London NW3 2PF, UK.44-20-7472-280344-20-7472-2801
                Journal
                Journal ID (nlm-ta): J Exp Med
                Title: The Journal of Experimental Medicine
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1007
                ISSN (Electronic): 1540-9538
                Publication date (Print): 20 December 1999
                Volume: 190
                Issue: 12
                Pages: 1733-1740
                Affiliations
                [a ]Immunological Medicine Unit, Division of Medicine,
                [b ]Cardiothoracic Unit, Department of Surgery
                [c ]Department of Histopathology, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom
                Article
                Publisher ID: 99-1186
                DOI: 10.1084/jem.190.12.1733
                PMC ID: 2195725
                PubMed ID: 10601349
                SO-VID: 633b27aa-45b4-4b92-8519-fa7bdaf8f626
                Copyright © © 1999 The Rockefeller University Press
                History
                Date received : 14 July 1999
                Date revision requested : 4 October 1999
                Date accepted : 8 October 1999
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Medicine
                Keywords: heart,ischemia,necrosis,inflammation,acute phase response
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: heart, ischemia, necrosis, inflammation, acute phase response

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