Transient changes of serum lipoprotein(a) as an acute phase protein.

Serum lipoprotein(a) (Lp(a)) was serially determined after acute attacks of myocardial infarction and after surgical operations. Acute phase proteins, such as C-reactive protein, alpha 1-acid glycoprotein, alpha 1-antitrypsin and haptoglobin, increased rapidly and markedly after the episodes. Initial values of serum Lp(a) concentrations were almost the same in both groups. Increases in serum Lp(a) levels were also observed during the first few days, with a return to the initial levels after more than 1 month. The periods for reaching maximal levels of acute phase proteins were similar in both groups of patients. On the contrary, the period required for Lp(a) to reach the maximal level in the myocardial infarction group was significantly longer than in the post-operative group. The present study suggests that Lp(a) has the characteristics of an acute phase reactant and may play an important role in recovery from tissue damage.

Estimating mortality risk in preoperative patients using immunologic, nutritional, and acute-phase response variables.

We measured the delayed type hypersensitivity (DTH) skin test response, along with additional variables of host immunocompetence in 245 preoperative patients to determine which variables are associated with septic-related deaths following operation. Of the 14 deaths (5.7%), 12 were related to sepsis and in 2 sepsis was contributory. The DTH response (p less than 0.00001), age (p less than 0.0002), serum albumin (p less than 0.003), hemoglobin (p less than 0.02), and total hemolytic complement (p less than 0.03), were significantly different between those who died and those who lived. By logistic regression analysis, only the DTH skin test response (log likelihood = 41.7, improvement X2 = 6.24, p less than 0.012) and the serum albumin (log likelihood = 44.8, improvement X2 = 17.7, p less than 0.001) were significantly and independently associated with the deaths. The resultant probability of mortality calculation equation was tested in a separate validation group of 519 patients (mortality = 5%) and yielded a good predictive capability as assessed by (1) X2 = 0.08 between observed and expected deaths, NS; (2) Goodman-Kruskall G statistic = 0.673) Receiver-Operating-Characteristic (ROC) curve analysis with an area under the ROC curve, Az = 0.79 +/- 0.05. We conclude that a reduced immune response (DTH skin test anergy) plus a nutritional deficit and/or acute-phase response change are both associated with increased septic-related deaths in elective surgical patients.

Acute-phase response to scalding: changes in serum properties and acute-phase protein concentrations.

The time course of changes in the concentrations of individual acute-phase proteins (APRs) in the plasma was examined in the model of rats exposed to a single (sublethal) and repeated (fatal) scalding. These data were interrelated with the rate of survival, plasma volume, corticosterone level, and immunosuppressive potency of the serum. The infliction of a sublethal scalding composing 20% body surface area resulted in an initial 50% reduction of the plasma volume and a severalfold increase of the corticosterone level and immunosuppressive activity of the serum. A subsequent normalisation of these deviations proceeded in parallel with an increased rate of APR synthesis. An early infliction of a second scald was fatal. It led to a 60% reduction of the plasma volume, a lack of plasma APRs, and an additional enhancement of the immunosuppressive activity of serum.

[Acute phase protein (alpha 1 AT) as a tumor marker in patients with ovarian cancer (OC)].

Serum alpha 1 AT was measured in 30 healthy women, 30 pregnant women, in 97 patients with various benign gynecologic diseases, and 38 patients with OC. The positive ratio (cut off level: 317 mg/dl) in OC patients was 78.9% (30/38), 11.3% (11/97) in patients with a benign gynecologic disease, 90% (27/30) in pregnant women, and 0% (0/30) in healthy women. Histologically 92.3% of the patients (12/13) with a serous cystadenocarcinoma, 50% (4/8) with an endometrioid carcinoma, and 77.8% (7/9) with a mucinous cystadenocarcinoma were positive, but only 5.9% of the patients with a chocolate cyst were positive. Thus it was found that alpha 1 AT is a useful tumor marker in diagnosing OC.

The acute phase nature of interleukin 6: studies in Kawasaki disease and other febrile illnesses.

Interleukin 6 (IL-6) has manifold biological functions involved in the immune or inflammatory responses of the host to various stimuli. Here we asked whether IL-6 might be responsible for manifestations of Kawasaki disease (KD), such as immunoglobulin hypersecretion, lymphocyte activation and systemic vasculitis. IL-6 activity in the serum was determined by a sensitive colorimetric assay using an IL-6-dependent murine hybridoma clone. Usually sera from healthy or afebrile donors contained only negligible levels of IL-6 activity below the detection threshold of the assay. Importantly it was found that serum IL-6 was markedly elevated in all patients with acute KD. Serum levels of IL-6 activity gradually diminished during the course of the disease and reached undetectable or lower levels at the convalescent phase. However, such elevated levels of serum IL-6 activity were also observed in the majority of other febrile diseases, such as bacterial or viral infections, indicating that the appearance of IL-6 in the serum could generally occur in febrile or inflammatory disease conditions. Serum IL-6 activity correlated with serum concentrations of some acute phase proteins (APP), such as C-reactive protein, haptoglobin and alpha 1-acid glycoprotein, implying its role for modulating induction of APP in vivo. IL-6 is well known to be secreted by a variety of cell types. Further studies, including immunohistochemical analysis using anti-IL-6 antibody, will be necessary to examine whether the source of serum IL-6 in KD might be different from that seen in other diseases.

Concentrations of tumor-associated trypsin inhibitor and C-reactive protein in serum in acute pelvic inflammatory disease.

We measured tumor-associated trypsin inhibitor (TATI) and C-reactive protein (CRP) in serum of 29 patients with proven pelvic inflammatory disease (PID). TATI values were increased in seven (24%), paralleling increases in CRP. TATI was increased by about 3.5-fold in seven of eight patients with CRP concentrations greater than 90 mg/L, but in none of 21 patients with CRP concentrations less than 90 mg/L. TATI concentration and severity of PID as determined by laparoscopy or endometrial biopsy were not correlated. These results suggest that, in severe infections, regulation of TATI synthesis resembles that of acute-phase proteins.

Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute-phase response.

Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of fibrinolysis. It circulates in blood both in free active form and in inactive form complexed with tissue type plasminogen activator (t-PA). Control mechanisms for its synthesis and release from hepatocytes and endothelial cells are important in the pathogenesis of thrombosis. Possible risk factors for myocardial infarction include high insulin and PAI-1 levels, which correlate with one another in healthy subjects, and fibrinogen, which together with PAI-1, is an acute-phase reactant. We therefore studied the interrelationships between PAI-1, plasma insulin, and acute-phase proteins in 67 patients with angina pectoris. Plasma insulin correlated strongly (r = 0.59, p less than 0.001) with PAI activity, free PAI-1 antigen (r = 0.60, p less than 0.001), and total PAI-1 antigen (r = 0.58, p less than 0.001). The acute-phase proteins, fibrinogen and C-reactive protein, correlated significantly with t-PA antigen, total PAI-1 antigen, and PAI-1/t-PA complexes but not with PAI activity or free PAI-1. The results suggest that insulin stimulates synthesis and release of free PAI-1 (probably via hepatocytes as previously shown with cell culture) and that endothelial cell synthesis and release of t-PA, together with PAI-1, reflects a nonspecific acute-phase response to chronic vascular disease. Hyperinsulinemia found in patients with angina pectoris could play a role in the development of myocardial infarction via the induction of high plasma PAI-1 activity.

Human hepatocyte-stimulating factor-III and interleukin-6 are structurally and immunologically distinct but regulate the production of the same acute phase plasma proteins.

Human squamous carcinoma (COLO-16) cells synthesize and secrete hepatocyte-stimulating factor-III (HSF-III), a glycoprotein with Mr = 39,000, which stimulates the synthesis of several acute phase plasma proteins in human hepatoma (HepG2) cells. The qualitative response of HepG2 cells to HSF-III is essentially the same as that elicited by human recombinant interleukin-6 (IL-6). Although similar in hepatocyte-stimulating activity, HSF-III and IL-6 are distinct molecules which differ not only in size and charge but also in immunologic properties: no cross-recognition of HSF-III and IL-6 occurs using neutralizing antibodies against IL-6 and HSF-III, respectively. In addition, Northern blot hybridization of IL-6 cDNA to mRNA from COLO-16 cells revealed no detectable IL-6 message. HSF-III does not compete for binding to the IL-6 receptors suggesting that HepG2 cells carry receptors specific for each hormone. Both receptor types may trigger similar intracellular processes explaining the identical regulation of acute phase protein expression.

Automated quantification of rat plasma acute phase reactants in experimental inflammation.

Methods are described for the quantification of certain acute phase reactants (albumin, iron, fibrinogen, seromucoid, haptoglobin, and ceruloplasmin) in small amounts of plasma using the COBAS-BIO centrifugal analyzer. These methods have been applied to determine the concentrations of these acute-phase reactants (APRs) in rat plasma during the first 5 days of adjuvant-induced arthritis. The levels of the APRs alter with the degree of inflammation in a dose-related manner. Administration of the antiinflammatory and antirheumatic drugs (indomethacin, dexamethasone, and clobuzarit [CLOZIC]) during the course of the adjuvant-induced arthritis reduced the inflammatory response as judged by the measurement of oedema. These compounds, however, show differential effects on the profile of APRs as systemic measurements of the inflammatory disease. The present study shows that specific classes of drug have defined effects on acute-phase protein concentration. We believe that the multiple analysis of APR levels during the course of inflammation may help to distinguish between and elucidate the mechanisms of action, of antiinflammatory and antirheumatic drugs.

Coagulation inhibitor levels in pneumonia and stroke: changes due to consumption and acute phase reaction.

The well-known coagulation inhibitors antithrombin and protein C, and the more recently described inhibitors, heparin cofactor II and extrinsic pathway inhibitor, were measured in plasma during a 7-day observation period, from patients with pneumonia (n = 13), and in stroke patients with infarction (n = 9) and haemorrhage (n = 9). In patients with pneumonia, elevated fibrinopeptide A levels and subnormal antithrombin and protein C levels suggested some degree of consumption of the inhibitors. Later, an increase was observed for all the inhibitors, but was most conspicuous for heparin cofactor II which reached high normal values. C-reactive protein, initially markedly elevated, decreased rapidly. This finding suggests that heparin cofactor II might act as a delayed acute phase reactant. In stroke patients only small, not statistically significant, changes occurred during the observation period, except for heparin cofactor II which increased in patients with haemorrhagic stroke.

Clinical and laboratory studies of arthritis in leprosy.

Arthritis associated with leprosy is underreported. In Egypt 66 patients from a leprosy colony were studied, 20 of whom had arthropathy. This was characterised by an inflammatory symmetrical peripheral polyarthritis. The wrist, metacarpal and proximal interphalangeal joints of the hands, the knees, and the metatarsophalangeal joints of the feet were affected with associated morning stiffness. The arthritis was erosive in 11 out of 20 patients, had no features of the arthritis associated with erythema nodosum leprosum reactions, but symptomatically responded to antileprosy treatment. This arthritis would seem to be a previously unrecognised feature of leprosy.

[Detection of the degree of activity of ulcerative colitis. Behavior of serum alpha 1-proteinase inhibitor and alpha 2-macroglobulin]. / Detección del grado de actividad de la colitis ulcerosa. Comportamiento de alfa 1-proteinasa inhibidor y alfa 2-macroglobulina séricas.

The study of two proteins, acute phase reactants, alpha 1-proteinase inhibitor and alpha 2-macroglobulin, has demonstrated their utility in the diagnosis of the activity of ulcerative colitis. Alpha 1-proteinase inhibitor presented serum increases parallel to the degree of activity, permitting differentiation of asymptomatic, mild, moderate and severe phases of the disease. Increases in alpha 2-macroglobulin coincided with less-intense phases of the disease. The possible biological basis of this different behavior is discussed, as well as its potential inclusion among the biological tests currently used in clinical practice.

Inflammatory competence of fetal rat: acute-phase plasma protein response of the fetus treated by turpentine in utero.

Using crossed immunoelectrophoresis, immunoelectrodiffusion, autoradiography, and equilibrium binding techniques, we demonstrate that the rat fetus, directly challenged in utero at 18 days by a single subcutaneous turpentine injection, presents a complex acute-phase plasma inflammatory response. A number of fetal serum proteins, 48 h after the injection, increase in concentration by factors of about 2-5. These positive acute-phase reactants (APR) are alpha 1-acute-phase globulin (alpha 1-AP), alpha 2-macroglobulin (alpha 2-M), alpha 1-acid glycoprotein (alpha 1-AG), haptoglobin (Hp), and hemopexin (Hpx). A number of proteins decrease, behaving like negative APRs. These are albumin, alpha 1-fetoprotein (AFP), transferrin, GHR-P63, thyroxine-binding prealbumin (TBPA), and transcortin (CBG). The marked fall in concentration of two of the high-affinity hormone-binding proteins of the fetal rat, i.e., the estrophilic AFP and TBPA, induce significant decreases (by 25-40%) of the estrogen- and thyroxine-binding abilities of the fetal serum. While the plasma inflammatory response of the fetus is qualitatively similar to that of the adult, the fetal reactions are, as a rule, quantitatively weaker. The characteristics of the plasma inflammatory response of the fetus are discussed in relation to the highly dynamic state of its development.

IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo.

Human rIL-6, produced either in COS cells or Escherichia coli, similarly stimulates the production of acute phase plasma proteins in cultured human and rat hepatoma cells. This anabolic effect in hepatoma cells suggested a potential in vivo role of the cytokine in mediating the hepatic response to inflammation. Injection of IL-6 into adult male rats elicited a cytokine-specific change in the liver expression of acute phase proteins. As predicted from in vitro studies, glucocorticoids were needed to achieve a maximal IL-6 response in vivo. Optimal conditions were found to be two i.p. injections of 35 to 120 micrograms IL-6 and 65 micrograms dexamethasone per kg body weight administered at 12-h intervals. Within 24 h, the plasma concentrations for alpha 2-macroglobulin, fibrinogen, thiostatin, and hemopexin were increased to levels approximating those observed in acute phase animals. These results support the notion that direct interaction of IL-6 with the liver is an essential part in initiating the hepatic acute phase reaction.

Serum IgA, acute phase proteins, and glycosylation of alpha 1-acid glycoprotein in ankylosing spondylitis.

Several investigators have suggested that gastrointestinal inflammation has a role in the pathogenesis of ankylosing spondylitis. To test this hypothesis markers of gastrointestinal immunostimulation, as manifested by serum IgA concentrations, were compared with serum markers of inflammation, as manifested by acute phase proteins. Serum samples from 45 unrelated Caucasian patients with ankylosing spondylitis (AS) were tested for correlation of serum IgA and six acute phase proteins: C reactive protein (CRP), alpha 1-antitrypsin, alpha 1-antichymotrypsin, caeruloplasmin, alpha 1-acid glycoprotein (AGP), and haptoglobin. Serum IgA was shown to be significantly positively correlated with four of these six acute phase proteins: CRP (r = 0.58, p less than 0.001), alpha 1-antitrypsin (r = 0.29, p less than 0.05), AGP (r = 0.61, p less than 0.01), and haptoglobin (r = 0.58, p less than 0.001), suggesting that gastrointestinal immunostimulation does have a role in the pathogenesis of inflammation in AS. In addition, the microheterogeneity of the pattern of glycosylation of AGP, expressed as reactivity coefficients, was examined. The AGP reactivity coefficient has been shown to increase in infection, remain the same in systemic lupus erythematosus, and decrease in rheumatoid arthritis. It was found that the AGP reactivity coefficient was significantly decreased in patients with AS as compared with healthy controls (p less than 0.006). As recent studies have indicated that patterns of glycosylation reflect intrahepatocellular biosynthetic processes induced by cytokines our data suggest that cytokine-hepatocellular mechanisms in AS may be similar to those occurring in rheumatoid arthritis, but different from those in systemic lupus erythematosus or infection.

Immunopathological analysis of acute phase reactant (APR) proteins in glomeruli from patients with diabetic nephropathy.

The levels of immunoglobulins, complement components and APR proteins including alpha 1-antitrypsin (alpha 1-AT), alpha 1-acid glycoprotein (alpha 1-AG), alpha 2-macroglobulin (alpha 2-MG) and haptoglobin (Hpt) in the sera, as well as glycosylated or nonglycosylated protein fractions of these proteins in the sera, were examined by laser nephelometry in 49 patients with diabetes mellitus. Immunofluorescence studies of immunoglobulins, beta-lipoprotein (beta-Lp), complement components and APR proteins in the kidney and skin tissues of patients with diabetic nephropathy were performed to elucidate whether such factors might play a role in the development of the vascular changes in this disease. The levels of alpha 1-AT and alpha 2-MG in the sera as well as glycosylated or nonglycosylated protein fractions of these proteins in the sera from patients with diabetic nephropathy, were significantly greater than those in healthy adults. Marked linear deposition of these proteins in the glomerular or dermal vascular walls was observed in the same patients. In particular, IgG and alpha 1-AT were accumulated in the glomeruli of patients with the nodular type of this disease. The intensity of alpha 1-AT or IgG deposition in glomerular capillary walls treated with a high concentration (4 mol) of NaCl was markedly decreased in such patients. It appeared that serum APR proteins with or without glycosylation underwent exudation into the glomerular and dermal vascular walls, and then accumulated in these walls in patients with diabetic nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum amyloid A: an extremely sensitive marker for intensity of tissue damage in trauma patients and indicator of acute response in various diseases.

Acute response after traumatic events was studied in serial serum samples of 21 patients over a period of 13 days. Among the various biochemical and hematologic parameters, serum amyloid A (SAA) exhibited the most striking changes, with a pattern similar to that of the tissue marker creatine-P kinase (CPK). Maximal SAA level was detected 3-4 days after onset of the event, and reached 216 +/- 41 SEM gm/ml (normal range less than 2 gm/ml), while maximal CPK level was detected on the same day and reached 530 +/- 242 SEM IU/L (normal range 24-195 IU/L). Fibrinogen, leucocytes, platelets, albumin, alkaline phosphatase (AP), and calcium (Ca) each showed its own typical pattern of change. Fever did not develop. Comparison of SAA levels after various acute events suggests that damage to the myocardium is the most powerful stimulus for SAA induction, followed by traumatic events, arthritis, viral infections, and malignant diseases. It seems therefore that although acute response is considered a generalized reaction, it is not completely independent of the localized events which induce it. Among the known parameters, SAA is the most sensitive marker for monitoring the intensity of events.