Functional and clinical aspects of the myelomonocyte protein calprotectin.
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Antifungal Agents↗
Biomedical subjects
M K Fagerhol
Publications and source records attributed to M K Fagerhol.
[Plasma calprotectin. A new prognostic marker of survival in alcoholic liver cirrhosis].
The purpose of this study was to determine plasma concentrations of calprotectin in patients with different severity of alcoholic cirrhosis. Additionally, the prognostic value of calprotectin for recurrent infections and for survival was investigated after a median observation period of 19 months. No difference was found in calprotectin levels when comparing healthy controls (n = 16), compensated (n = 50) and decompensated cirrhotics (n = 34). However, high calprotectin concentrations (> median) was a significant prognostic marker of poor survival (p = 0.001, Log-rank test). Calprotectin levels (> median) showed an independent and much higher prognostic value than variables of liver disease (multivariate Cox model). During follow-up calprotectin levels (> median) were also a predictor of recurrent infection (p = 0.009, Log-rank test). Thus, in patients with alcoholic cirrhosis, plasma calprotectin appears to be a new prognostic marker of survival, which seems independent of severity of liver disease. Furthermore, high plasma calprotectin levels may characterize a group of cirrhotics with recurring bacterial infections.
Adult↗
Calprotectin as a marker of inflammation in cystic fibrosis.
Calprotectin is an abundant neutrophil cytosolic protein released during neutrophil activation or death. The use of plasma calprotectin concentration as a marker of pulmonary inflammation was tested in 31 children with cystic fibrosis, none of whom was acutely unwell or pyrexic. Twenty three were receiving antibiotics, 21 had positive sputum cultures, but none of the traditional tests clearly diagnosed ongoing infection. Plasma calprotectin was significantly higher in the cystic fibrosis group than in matched controls. Sixteen children with cystic fibrosis had values above the control range (320-1570 micrograms/l). Their chest radiograph Northern score, an index of accumulated pulmonary involvement, and their plasma copper, an index of acute phase response, both correlated with plasma calprotectin. Plasma gamma-glutamyltransferase also correlated weakly with plasma calprotectin: thus, hepatic pathology may be a confounding variable. However, the data still suggested that plasma calprotectin is a better index of inflammation than the traditional indices in general use.
Adolescent↗
Nomenclature for proteins: is calprotectin a proper name for the elusive myelomonocytic protein?
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Journal Article↗
The leucocyte protein L1 (calprotectin): a putative nonspecific defence factor at epithelial surfaces.
The L1 protein occurs at high concentrations in neutrophils, monocytes, certain reactive tissue macrophages, squamous mucosal epithelia, and reactive epidermis. It constitutes in fact about 60% of the neutrophilic cytosol protein fraction. The two L1 chains (L1H and L1L) are referred to by a bewildering collection of names, various authors having different preferences (MRP-8 and MRP-14; CFA or calgranulin A and B). The most recent proposal is calprotectin because of its calcium-binding properties and antimicrobial effect shown in vitro. L1 belongs to the S-100 protein family and may be involved in the regulation of keratinocyte proliferation and differentiation. It exists at high levels in blood and interstitial tissue fluid in several infectious, inflammatory, and malignant disorders, and it is released abundantly in foci of granulocytes and macrophages. The C-terminal sequence of the L1H chain has been shown to be identical to the N-terminus of peptides known as neutrophil immobilizing factors. Such an activity of L1 could be important for the accumulation of vital granulocytes, while L1 released from neutrophils, macrophages and epithelial cells might exert antimicrobial activity, perhaps by depriving microorganisms of zinc. The minimum inhibitory concentrations of L1 in vitro were found to be 4-32 mg/l for Candida albicans, 64 mg/l for Staphylococcus aureus, 64-256 mg/l for S. epidermidis, and 256 mg/ml for Escherichia coli and Klebsiella spp. Killing was observed at 2-4 times higher concentrations. In patients with HIV infection, those who developed oral candidiasis had significantly lower parotid L1 levels than those who did not (67 micrograms/l vs. 216 micrograms/l).
AIDS-Related Opportunistic Infections↗
Effects of calprotectin in avridine-induced arthritis.
Plasma levels of calprotectin correlate with disease activity and clinical assessments of arthritis in various rheumatic diseases, and high levels have been demonstrated in the synovial fluid of patients with rheumatoid arthritis. However, the role of calprotectin in rheumatic inflammation is unclear. The purpose of the present study was to investigate potential intra-articular effects of calprotectin. Calprotectin was injected into joints of healthy male Lewis rats and into joints of rats in the latency period before onset of avridine-induced arthritis. In addition, a group of animals had IgG antibodies to rat calprotectin injected into joints before onset of avridine-induced arthritis. Injection of 0.2 or 10 micrograms calprotectin into the ankles of healthy male Lewis rats resulted in histologically minor and reversible inflammatory changes, but without any circulating antibodies to calprotectin. Furthermore, animals with 40 micrograms calprotectin injected into ankles before the expected onset of avridine-induced arthritis had lower scores for cellular infiltration than were seen in control joints. This difference did not quite reach statistical significance in the two-sided test used. However, the induced arthritis increased in joints injected with IgG antibodies to calprotectin. These findings may indicate that increased local concentrations of calprotectin are partially protective against avridine-induced arthritis. In contrast, reduced local concentrations appear to exacerbate the severity of arthritis. Calprotectin may thus be involved in the regulation of inflammatory processes in joints.
Adjuvants, Immunologic↗
Calcium binding and concomitant changes in the structure and heat stability of calprotectin (L1 protein).
Aim-To obtain further data on the structure and conformation of calprotectin, a prominent leucocyte protein found in many species.Methods-The binding of Ca(2+) to calprotectin was studied by means of equilibrium dialysis using (45)Ca as tracer. The thermal stability and denaturation kinetics of calprotectin were studied by means of differential scanning calorimetry. Con-comitant alterations in optical activity resulting from different conditions were measured. A computer program calculated the parameters to fit different models of protein structure. Ultraviolet spectroscopy gave absorbtion spectra. Sedimentation velocity studies and molecular weight determinations by the low speed (sedimentation) equilibrium technique were performed.Results-A maximum of six calcium ions were bound per calprotectin molecule at 0.7 mM calcium chloride. The apparent dissociation constants were calculated. Ca(2+) ions increased the denaturation temperature by 26 degrees K. The enthalpy of denaturation was also increased by Ca(2+). Addition of Ca(2+) to the buffers caused a gradual change in the near UV circular dichroism spectrum, while only minor changes were seen at wavelengths of 210-240 nm. A gradual increase in the sedimentation coefficient was observed on addition of calcium chloride. The extinction coefficient at 279nm was determined: E(279)= 2.53.10(4) M(-1) cm(-1).Conclusions-Calprotectin can bind six calcium ions. Upon binding, the protein shows distinct conformational changes and increased thermal stability. The former may be of importance for its function, while the biological significance of the latter is unknown.
Journal Article↗
Plasma calprotectin: a new prognostic marker of survival in alcohol-induced cirrhosis.
Plasma levels of calprotectin were determined in 84 patients with alcohol-induced cirrhosis. Calprotectin is released from disintegrating neutrophils, and plasma levels seem to reflect activation and turnover of such cells. The purpose of the study was to investigate the degree of activation of neutrophils, which has been indicated to be increased and a cause of neutrophil exhaustion in these patients. Additionally, on follow-up after a median observation period of 559 days, we investigated the prognostic value of calprotectin for survival. No difference was found in calprotectin levels when comparing healthy controls with patients with compensated cirrhosis and those with decompensated cirrhosis. However, high calprotectin concentrations (> median) were a significant prognostic marker of poor survival (P = .001, log-rank test). Using a multivariate Cox proportional hazard model, the prognostic value of calprotectin seemed independent of severity of liver disease evaluated on eight clinical and biochemical variables of liver disease. Divided into groups by the median calprotectin concentration, analysis of survival was performed in the whole series of patients (n = 84) as well as in patients who were completely without signs of recent or actual infection (n = 54). In both groups, calprotectin levels (> median) showed a much higher prognostic value than albumin, prothrombin complex, bilirubin, and ascites. During follow-up, calprotectin levels (> median) were also a predictor of recurrent infection (P = .009). Thus, in patients with alcoholic cirrhosis, plasma calprotectin seems to be a new prognostic marker of survival, which seems independent of the severity of liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Reduced complement and granulocyte activation with heparin-coated cardiopulmonary bypass.
Plasma concentrations of the complement activation products C3b, iC3b, and C3c; the terminal C5b-9 complement complex; and the granulocyte proteins calprotectin, myeloperoxidase, and lactoferrin were assessed in two groups of patients undergoing aortocoronary bypass procedures. In 10 patients operated on, the bypass circuits were coated by the Carmeda Bio-Active Surface and systemic heparinization was reduced to 1.5 mg/kg; in another 10, the systems were uncoated and the dosage of systemic heparinization was 4 mg/kg. In both groups, significant complement activation was observed after the onset of cardiopulmonary bypass, but the maximum levels of C3b, iC3b, and C3c and the terminal C5b-9 complement complex were significantly lower in the heparin-coated group. In both groups, a significant increase in calprotectin, myeloperoxidase, and lactoferrin release was observed by the end of operation. The maximum myeloperoxidase levels were significantly lower in the heparin-coated group than those in the uncoated group (p = 0.03). There was a correlation of borderline significance between the formation of terminal C5b-9 complement complex and lactoferrin release, as well as between the formation of terminal C5b-9 complement complex and myeloperoxidase release (p = 0.05). The postoperative blood loss did not differ significantly between the two groups. We conclude that coating by end point-attached and functionally active heparin allows a significant reduction in the amount of systemic heparinization, and significantly reduces complement and granulocyte activation.
Aged↗
Effects of human calprotectin (L1) on in vitro immunoglobulin synthesis.
Calprotectin (L1) is a major cytoplasmic protein of neutrophilic granulocytes and monocytes/macrophages which is released from leucocytes during activation or cell death. Apart from in vitro antimicrobial and antiproliferative activity little is known about the biological function of the protein. Since previous investigations have shown that calprotectin plasma levels are elevated in various inflammatory rheumatic diseases, we wanted to investigate if calprotectin has an effect on immune cell functions. Peripheral blood mononuclear cells, either unstimulated or polyclonally stimulated with mitogen, were incubated with calprotectin and effects were assessed by enumeration of immunoglobulin secreting cells (ELISPOT). The results indicate that incubation with high concentrations of calprotectin (> 64 micrograms/ml) inhibit the production of the three classes of immunoglobulins investigated (IgG, IgM and IgA), both for mitogen stimulated and unstimulated lymphocytes. Except for the highest concentration of calprotectin (500 micrograms/ml), it seems plausible that the observed inhibitory effect of calprotectin on Ig production is not a result of a direct toxic effect of calprotection on B lymphocytes. Altogether, these effects of high calprotectin levels might be of importance in the immunoregulation of inflammatory conditions.
Adult↗
Roller and centrifugal pumps compared in vitro with regard to haemolysis, granulocyte and complement activation.
A Biomedicus centrifugal pump and a Polystan roller pump were compared in vitro with regard to differences in haemolysis, granulocyte and complement activation. Six circuits of tubing and oxygenators were connected to each pump. Heparinized fresh human blood was circulated for 72 hours in the systems. Blood samples were drawn at defined intervals. Haemolysis was assessed by determination of lactate dehydrogenase (LD) and potassium, and granulocyte activation by quantification of the granulocyte proteins calprotectin, lactoferrin and myeloperoxidase. Complement activation was assessed by measuring C3 activation products (C3b, iC3b and C3c), and the terminal C5b-9 complement complex (TCC). The results indicate more haemolysis and complement activation in the roller pump group, revealed by significantly higher concentrations of LD, potassium, C3 activation products and TCC. Calprotectin, lactoferrin and myeloperoxidase were all significantly increased in both groups, but the rise appeared earlier in the roller pump group. The concentrations of LD and potassium both correlated significantly with C3 activation products, indicating that complement activation may at least partly be responsible for the haemolysis.
Cell Adhesion Molecules, Neuronal↗
Biocompatibility of heparin-coated circuits used in cardiopulmonary bypass.
The combined effect of heparin coating of cardiopulmonary bypass (CPB) circuits and reduced dose of systemic heparin on activation of the complement system and blood leukocytes was investigated in 19 patients undergoing coronary bypass surgery and randomly allocated to two groups. A heparin-coated CPB circuit together with a 50% reduction of the standard heparin dose were used for ten patients (HC group), and a standard CPB circuit with a standard heparin dose (300 IU/kg) for nine (C group). Significant rise in the levels of neutrophil-derived myeloperoxidase, lactoferrin and calprotectin were observed during CPB in both groups, but the total accumulated levels were significantly lower in the HC than in the C group (p < 0.05). Complement activation, assessed from levels of C3a and terminal complement complexes was similar in both groups. The lower levels of myeloperoxidase, lactoferrin and calprotectin during CPB in the HC group indicate that surface modification with end-point attached heparin enhances the biocompatibility of CPB.
Biocompatible Materials↗
Elevated serum calprotectin levels in HIV-infected patients: the calprotectin response during ZDV treatment is associated with clinical events.
The calcium-binding myelomonocytic protein calprotectin (L1 protein) was quantified in serum from 51 patients with HIV infection and in 20 HIV-seronegative blood donors. Significantly elevated levels were found both in asymptomatic patients and in people with AIDS compared with controls. The calprotectin level was not related to ongoing or recent opportunistic infections. For patients with CD4+ counts above 50 x 10(6)/L, a significant negative correlation was found between serum calprotectin levels and the CD4+ counts. Serial samples from 24 patients during their first year of zidovudine (ZDV) treatment showed a further elevation of serum calprotectin during the first months of ZDV treatment, with a subsequent decline to pretreatment levels. A low calprotectin response during the first 6 months, determined as area under the curve, was associated with the occurrence of at least one AIDS-defining infection during the first year of antiviral treatment. Also, a low calprotectin maximal response during ZDV therapy was associated with short survival. Similar associations were not found for neopterin, beta 2-microglobulin, HIV p24 antigen, or CD4+ or CD8+ lymphocytes in blood. Our findings in a limited number of patients suggest that calprotectin levels may reflect immune activation and other immune mechanisms correlated with enhanced antimicrobial defense induced at least transiently by antiviral treatment.
AIDS-Related Opportunistic Infections↗
Calprotectin and complement activation during major operations with or without cardiopulmonary bypass.
Plasma concentrations of the granulocyte cell marker calprotectin were assessed during operation and 24 hours postoperatively in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass, abdominal aneurysmectomy with implantation of an aortic graft, or thoracotomy without implantation of synthetic material. The concentration of calprotectin increased significantly (p < 0.01) in all three groups. Ten of the 30 patients in the group undergoing cardiopulmonary bypass received methylprednisolone at the start of the operation. No difference in calprotectin concentration was seen between the two subgroups (p > 0.05). Plasma concentration of calprotectin was shown to increase rapidly in patients undergoing cardiopulmonary bypass and aneurysmectomy, in whom complement activation also took place. However, the calprotectin concentration increased slowly during the operation and the postoperative period in patients undergoing a thoracotomy, in whom complement was not activated. At wound closure the calprotectin concentration was significantly elevated in the cardiopulmonary bypass and aneurysmectomy groups compared with the thoracotomy group (p < 0.05). The calprotectin concentration remained elevated during the postoperative period in all three groups. Our results indicate that calprotectin may serve as a suitable cellular marker when the biocompatibility of artificial surfaces is studied.
Adult↗
Oral candidiasis is associated with low levels of parotid calprotectin in individuals with infection due to human immunodeficiency virus.
The level of the antifungal leukocyte protein calprotectin was determined in parotid saliva from 44 individuals with infection due to human immunodeficiency virus (HIV) and 19 healthy HIV-seronegative controls. Nine of the HIV-infected subjects suffered from oral candidiasis. Similar calprotectin levels were found in subjects with HIV infection as a whole group and in controls. When HIV-infected individuals with or without oral candidiasis were compared, the calprotectin level was significantly lower in the former group (67 micrograms/L vs. 216 micrograms/L). We suggest that calprotectin may play a role in the defense against oral candidal infections in HIV-infected patients, although several other antimicrobial factors also are probably operative.
AIDS-Related Opportunistic Infections↗
Sixteen years of plasma exchange in a homozygote for familial hypercholesterolaemia.
This report describes 16 years of plasma exchange in a female familial hypercholesterolaemia homozygote. During childhood she had values for total serum cholesterol of 25-30 mmol l-1. She developed tendon and skin xanthomas before the age of 12 months. Because her total serum cholesterol level was not satisfactorily changed by lipid lowering drugs, plasma exchange was started in 1976. Since then she has had plasma exchange every 3 weeks. She has now reached the age of 42. Her pre-exchange values for serum cholesterol have been 11.1 mmol l-1 (6.79-28.8), while her post-exchange values have been 4.17 mmol l-1 (1.65-10.47). There has been a considerable regression of her xanthomas, and her xanthelasmas have disappeared. No side-effects have been observed during the 16 years of plasma exchange.
Adult↗
Faecal calprotectin: a novel test for the diagnosis of colorectal cancer?
Calprotectin, a prominent cytosol protein in neutrophil granulocytes, was present in increased concentrations in stools from 50 of 53 patients with colorectal cancer, 32 of 40 patients with colorectal polyps, and all of 18 patients with gastric cancer. After radical surgery, faecal calprotectin levels reverted to the normal range in all but one patient with colorectal cancer. Calprotectin determinations are simplified by the stability of this protein in stools. Reliable estimates can be obtained in samples of only 5 g. On the basis of data from the literature, the test for calprotectin seems better than that for occult blood for the detection of gastrointestinal neoplasms.
Aged↗
Levels of calprotectin (leukocyte L1 protein) during apheresis.
The plasma concentration of calprotectin was measured before, during and after apheresis in patients with Guillain-Barré Syndrome (GBS), Waldenstrøm's syndrome or hypercholesterolaemia and in healthy donors of platelets. Increased calprotectin levels were found after plasma exchange in the Waldenstrøm's syndrome patients, probably caused by release of the protein from activated leukocytes. The decreased calprotectin values observed in the other patients, may be due to plasma dilution. Unexpectedly, the GBS patients were found to have high initial calprotectin levels in plasma but not in cerebrospinal fluid. In donors, normal and unchanged calprotectin concentrations were found throughout.
Blood Component Removal↗