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PubMed1991

[Isolation and purification of Lpm and alpha-2 M macroglobulins from mink serum].

A procedure for large-scale separation and purification of two mink serum macroglobulins, Lpm and alpha 2M, is described. Individual preparations of each of these macroglobulins were obtained in an immunologically pure state. After precipitation from the serum at 6.5-13% PEG 6000, Lpm and alpha 2M were separated by a pH stepwise gradient elution metal chelate affinity chromatography and purified by chromatographies on Biogel A 1.5 m and DEAE-Trisacryl M. Each of these macroglobulins was tested by counter-immunoelectrophoresis with the corresponding monospecific antiserum. The yields per 100 ml of the source serum were 23-44 mg of Lpm and 7-30 mg of alpha 2M which corresponded to 10-20% of their serum contents. Some of general biochemical properties of mink Lpm and alpha 2M and of all mammalian alpha-macroglobulins are discussed.

Animals↗

PubMed1986

Increased serum levels of alpha-2-macroglobulin in severe chronic airflow obstruction.

Serum levels of alpha-2-macroglobulin, the major proteinase inhibitor besides alpha-1-antitrypsin, were investigated in 20 patients with severe Chronic Airflow Obstruction (CAO), as compared to 20 age- and sex-matched controls. Alpha-2-macroglobulin was assessed by rocket immuno-electrophoresis, and alpha-1-antitrypsin by a laser-nephelometric method. All patients had spirometric values determined, including diffusing capacity. The reversibility test for isoprenalin was performed. Alpha-2-macroglobulin levels were found to be significantly elevated in patients with CAO, even when two patients with alpha-1-antitrypsin deficiency were omitted from the statistical evaluation. Except for these two patients, there was no difference in alpha-1-antitrypsin level between the patients and the control group. It is concluded that elevated levels of alpha-2-macroglobulin are associated with the development of severe CAO and emphysematous lesions, also in the absence of alpha-1-antitrypsin deficiency.

Adult↗

PubMed1987

Carbohydrate recognition systems in amphibians: primitive alpha 2-macroglobulin receptors.

Two alpha-macroglobulins were isolated from the plasma of the frog. Murine clearance studies were performed with these proteins after they were reacted with proteinase. These studies indicated that clearance behavior was more complex than observed with avian or human homologues, since it involved not only specific receptors for the complex, but also carbohydrate recognition. Recognition of one of these macroglobulins by both the alpha-macroglobulin receptor and carbohydrate receptors required conformational change in the inhibitor. Clearance studies were then performed in frogs to probe the nature of carbohydrate receptor recognition. Model glycoproteins were employed to avoid the problem of heterogeneous carbohydrate end groups in the alpha-macroglobulins. These studies demonstrated that the N-acetylglucosamine/mannose receptor is the major carbohydrate recognition system in frogs.

Animals↗

PubMed1989

Immunohistochemical localisation of alpha 2-macroglobulin in the horse.

A peroxidase antiperoxidase technique was used to identify alpha 2-macroglobulin in formalin-fixed sections of normal equine lung and liver and in tissue sections and bronchoalveolar lavage fluid from horses with various lung diseases. Equine peripheral blood leucocytes and bronchoalveolar lavage samples from clinically normal horses were negative for alpha 2-macroglobulin. It was concluded that liver and pulmonary macrophages may be potential sources of alpha 2-macroglobulin. Although alpha 2-macroglobulin may play a role in various chronic bronchointerstitial pneumonias of the horse, it is doubtful that it is of importance in equine chronic small airway disease.

Animals↗

PubMedDate not supplied

[Serum levels of alpha-2-macroglobulin, ceruloplasmin, transferrin, alpha-1-antitrypsin and complement (beta-1-C) before and following 3- and 6-day injections of D-penicillamine in man].

UNLABELLED: The serum levels of alpha-1-antitrypsin, ceruloplasmin, transferrin, alpha-2-macroglobulin and complement (beta-1-C) were measured by the radioimmunodiffusion method of Mancini before treatment, after three days treatment with D-penicillamine (1,00 g. i. v. daily) and after treatment for 3 days with 2 x 1,00 g i. v. D-Penicillamine. The levels of alpha-2-macroglobulin, coeruloplasmin and transferrin dropped significantly after 3 days' treatment. Doubling the dosage for 3 days induced a further drop in transferrin and ceruloplasmin. The alpha-2-macroglobulin was not further influenced. The levels of alpha-1-antitrypsin and complement were not influenced by D-Penicillamine treatment. KEYWORDS: D-penicillamine, alpha-1-Antitrypsin, alpha-2-macroglobulin, transferrin, ceruloplasmin, complement (beta-1-C).

Adult↗

PubMed1976

Platelet alpha2-macroglobulin and alpha1-antitrypsin.

Subcellular membrane and granule fractions derived from human platelets contain immunologically identifiable alpha2-macroglobulin and alpha1-antitrypsin. These platelet-derived inhibitors show a reaction of immunologic identity when compared to alpha2-macroglobulin and alpha1-antitrypsin purified from human plasma. Further, the platelet protease inhibitors possessed a similar subunit polypeptide chain structure to their plasma counterparts as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis. Studies of the binding of radiolabeled trypsin to the various solubilized platelet subcellular fractions suggest that the granule-associated alpha2-macroglobulin and alpha1-antitrypsin, as well as membrane-associated alpha2-macroglobulin were functionally active. Quantitatively, circulating platelets contain relatively small concentrations of these inhibitors as compared to platelet-associated fibrinogen and factor VIIIAGN. Platelet protease inhibitors may modulate the protease-mediated events involved in the formation of hemostatic plugs and thrombi.

Blood Platelets↗

PubMed1983

Individual levels of plasma alpha 2-antiplasmin and alpha 2-macroglobulin during the normal menstrual cycle and in women on oral contraceptives low in oestrogen.

Determinations of alpha 2-antiplasmin and alpha 2-macroglobulin were made in plasma samples collected during one normal or hormone induced cycle in 15 normal women and 11 women using oral contraceptives containing 30 micrograms ethinyl oestradiol and 150 micrograms levo-norgestrel. The immediate plasmin inhibition test for determination of alpha 2-antiplasmin was modified for application on a centrifugal analyser using the chromogenic peptide substrate Chromozym PL. alpha 2-Macroglobulin concentration was determined by radial-immunodiffusion. There were no differences between the two groups in the mean concentrations of alpha 2-antiplasmin and alpha 2-macroglobulin, but during the cycle a slight, and statistically significant fall occurred in the alpha 2-antiplasmin concentration in both groups, while the fluctuations of alpha 2-macroglobulin were small and insignificant. Distinctly individual levels of both inhibitors were found to exist. The variations in these during the periods of the cycle fluctuated within a much narrower range than the variation of the total average. The results stress the importance of determining the fluctuations in individual levels in longitudinal studies. These findings exclude variations in the concentrations of these inhibitors as possible sources of a change in the antithrombotic potential caused by oral contraceptives.

Adult↗

PubMed1984

Kinetics of association of human proteinases with human alpha 2-macroglobulin.

Association rates have been determined for the interaction of human alpha 2-macroglobulin with human neutrophil elastase, cathepsin G, and human plasma kallikrein. Both of the neutrophil enzymes are rapidly inactivated by this inhibitor; however, the inactivation of plasma kallikrein is much slower. Comparison of the rates of inactivation with those already established for other inhibitors clearly indicate that alpha 1-proteinase inhibitor is the controlling inhibitor for neutrophil elastase and alpha 1-antichymotrypsin for cathepsin G, alpha 2-macroglobulin acting only as a secondary inhibitor. The control of plasma kallikrein would appear to be rather poor since neither alpha 2-macroglobulin nor C1-inhibitor appears to react very rapidly with this proteinase. Thus, a primary role for alpha 2-macroglobulin in directly inactivating proteinases in blood, under normal physiological conditions, remains to be established.

Binding Sites↗

PubMed1984

Temperature and pH dependence of the association rate constant of elastase with alpha 2-macroglobulin.

Binding kinetics of porcine pancreatic elastase to human alpha 2-macroglobulin was monitored by measuring the enzymatic activity of alpha 2-macroglobulin-bound elastase on succinyltrialanine p-nitroanilide after inhibition of free elastase by alpha 1-proteinase inhibitor. The association of the two proteins follows second-order kinetics with a rate constant ka = 4.4 X 10(6) M-1 S-1 at pH 8.0 and 25 degrees C. The rate of association strongly increases between pH 5.0 and 8.0, suggesting that the rate-limiting step of binding is the proteolytic cleavage at the bait region of the macroglobulin. The study of the temperature dependence of ka shows that the binding of elastase to alpha 2-macroglobulin is characterized by a positive entropy of activation (delta S* = +35.3 e.u. at 25 degrees C).

Animals↗

PubMedDate not supplied

[Antiproteinase activity of alpha 2-macroglobulin].

Blood serum separation by the method of gel filtration on Sephadex G-200 with the subsequent immunochemical determination of the quantitative content of basic proteolysis inhibitors permitted isolating the alpha 2-macroglobulin fraction while alpha 1-antitrypsin and alpha 1-antichymotrypsin separation was a failure. The immunochemical analysis of the antienzymic activity of the isolated inhibitors showed that 32.3 +/- 3.5% of the introduced kallikrein, 18.7 +/- 0.6% of trypsin and 14.4 +/- 4.1% of chymotrypsin were bound in the zone of alpha 2-macroglobulin. The rest of antienzymic activity was localized in the zone of alpha 1-antitrypsin and alpha 1-antichymotrypsin. After a preliminary saturation of blood serum with trypsin in the amount equivalent to its antitryptic capacity (200 micrograms/ml) the ability of alpha 2-macroglobulin to bind kallikrein and chymotrypsin lowers considerably (by 69 and 72%, respectively). In the zone of alpha 1-antitrypsin and alpha 1-antichymotrypsin a decrease in the ability to bind kallikrein and chymotrypsin amounted to 44 and 12% respectively. Thus, alpha 2-macroglobulin being bound with trypsin looses considerably its ability to bind other enzymes.

Chromatography, Gel↗

PubMed1977

[Immunochemical identification of human kidney-specific alpha2-macroglobulin].

Renospecific alpha2-macroglobulin (RS) with molecular weight 2 000 000 was identified by methods of immunochemical analysis. The revealed antigen was not identical to alpha2H-globulin (ferritin), to reno-pancreatic alpha2-globulin, uromucoid and alpha 2-macroglobulin of blood serum. The RS alpha2-macroglobulin content in the tumour tissue of the kidney decreased as compared to that in the normal kidney, in 16 of 23 tumors it was not revealed. On the sensitivity level of the monospecific RS alpha2-macroglobulin test-system it was not demonstrated in the blood of healthy persons and in the blood and urine of nephrologic patients.

Adult↗

PubMed1993

Differences in elastase-binding activity of alpha 1-protease inhibitor and alpha 2-macroglobulin for asthma patients and control subjects with various alpha 1-protease inhibitor phenotypes.

Forty-two adult patients with asthma and 30 control subjects were investigated for elastase-binding capacities of alpha 1-protease inhibitor and alpha 2-macroglobulin in plasma. The binding activities of alpha 1-protease inhibitor and alpha 2-macroglobulin in asthmatic patients with the M phenotype for the alpha 1-protease inhibitor differed in their relationship to the values in control subjects with the same phenotype [less alpha 1-protease inhibitor for asthmatics (35.1 +/- 1.8) than for controls (42.9 +/- 2.0 kU/L) (P < 0.001); more alpha 2-macroglobulin for asthmatics (6.9 +/- 0.3) than for control subjects (5.9 +/- 0.4 kU/L) (P < 0.03)]. In contrast, the patients with a deficiency allele (S, V, or Z) for alpha 1-protease inhibitor had lower activities of both alpha 1-protease inhibitor [22.1 +/- 0.1 vs 42.9 +/- 2.0 kU/L (P < 0.001)] and alpha 2-macroglobulin [4.6 +/- 0.6 vs 5.9 +/- 0.4 kU/L (P < 0.001)] than did the control subjects with the M phenotypes. The relevance of the results to the pathogenesis of asthma is discussed.

Adult↗

PubMedDate not supplied

[Uniform method for determining the alpha 1-antitrypsin and alpha 2-macroglobulin activity in human blood serum (plasma)].

A modified spectrophotometric method is developed for simultaneous estimation of alpha 1-antitrypsin and alpha 2-macroglobulin in human blood serum (plasma); the method is based on dissimilar interaction of these inhibitors with trypsin in the systems with a low molecular substrate N-alpha-benzoyl-l-arginine ethyl ester. alpha 1-Antitrypsin was estimated by inhibition of the arginine esterase activity of trypsin in a mixture containing human blood serum diluted 50-fold. alpha 2-Macroglobulin was estimated by maintained arginine esterase activity of the trypsin-alpha 2-macroglobulin complex, formed after interaction of an excess of trypsin with blood serum, diluted 10-fold and after subsequent inactivation of free, unbound with alpha 2-macroglobulin, trypsin by treatment with the soy bean inhibitor of trypsin. alpha 1-Antitrypsin and alpha 2-macrog-obulin were estimated by means of the method described in blood serum of healthy persons and in patients with burns or with carcinoma of pancreas. The method enables to estimate two main inhibitors of blood plasma proteinases in a small volume of blood serum (0.1 ml) very rapidly and specifically using commercially available substrate; the method might be recommended for routine clinical analysis.

Burns↗

PubMed1996

Immunoregulatory Properties of alpha(2)-Macroglobulin.

Native and modified with ammonium ions alpha(2)-macroglobulin forms exhibit similar abilities to influence proliferative activity and secretion of immunoglobulins in cultures of human blood mononuclear cells in vitro. Effects of modified with ammonium ions alpha(2)-macroglobulin were more significant than those of native alpha(2)-macroglobulin. Revealed properties of native alpha(2)-macroglobulin could be conditioned by a partial modification of its structure with endogenous proteinases or cytokines, some of which were shown to be common affinants for both forms.

Journal Article↗

PubMed1989

Inhibition of inflammatory proteinase, medullasin, by alpha 2-macroglobulin and ovomacroglobulin.

The in vitro activity of inflammatory proteinase, medullasin, was stoichiometrically inhibited by a serum proteinase inhibitor, alpha 2-macroglobulin, and its homolog, chicken ovomacroglobulin. The two inhibitors were cleaved by medullasin only in the bait region. The effectiveness of alpha 2-macroglobulin to inhibit medullasin in competition with alpha -1-proteinase inhibitor was measured under a simulated in vivo condition and an estimation was made that about 60-70% medullasin is inhibited by alpha-1-inhibitor and 30-40% by alpha 2-macroglobulin.

Binding, Competitive↗

PubMed1985

DNA replication and differentiation in rat myoblasts studied with monoclonal antibodies against 5-bromodeoxyuridine, actin, and alpha 2-macroglobulin.

During the differentiation of skeletal muscle, mononucleate myoblasts proliferate, then stop replicating, spontaneously fuse, and express a large number of genes which encode the muscle phenotype. We have used monoclonal antibodies specific for 5-bromodeoxyuridine, myoactin, and equine alpha 2-macroglobulin to follow and establish the sequence of events that surround the transition from a replicating to a differentiating population. Triple-label immunofluorescence microscopy was used to visualize the changes in DNA synthesis, formation of myoactin fibers, and the cessation of endocytosis of alpha 2-macroglobulin that accompany myogenesis. Our results indicate that myoblasts cease actively endocytosing alpha 2-macroglobulin after stopping DNA synthesis but prior to fusion. Formation of myoactin fibers rarely occurs in mononucleate myoblasts and only in post-mitotic cells, but they are common in multinucleate myotubes. We suggest that the regulation of DNA synthesis is critical to normal myogenesis and that detection of incorporated BrdUrd by immunofluorescence, in conjunction with other antibodies and nucleic acid probes, is a convenient method with which to study and sequence the molecular events in single cells as they relate to the transition in DNA synthesis that accompanies differentiation.

Actins↗

PubMed1991

Dexamethasone modulates alpha 2-macroglobulin and apolipoprotein E gene expression in cultured rat liver fat-storing (Ito) cells.

Fat-storing (Ito) cells are perisinusoidal liver cells thought to play a central role in vitamin A metabolism and fibrongenesis. Glucocorticoids have been shown to be beneficial in the treatment of certain types of liver diseases by delaying the development of cirrhosis. To study the regulatory effects of dexamethasone on Ito cell gene expression, Ito cells were isolated from normal rat liver and primary cultures were established. The effect of dexamethasone on the synthesis of alpha 2-macroglobulin, apolipoprotein E, fibronectin and actin was examined. Protein synthesis was studied both at the protein level and at the RNA level by means of biosynthetic labeling, immunoprecipitation followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by Northern blot analysis of total RNA. After exposure to dexamethasone for 20 hr, alpha 2-macroglobulin protein synthesis was increased threefold, whereas apolipoprotein E expression was decreased 80%. Biosynthesis of fibronectin remained unaffected by hormone treatment. The dexamethasone effect became detectable 5 hr after beginning the exposure. Deinduction kinetic experiments showed that the glucocorticoid effect was detectable more than 12 hr after the replacement of the dexamethasone-containing culture medium by medium without the hormone. Corresponding to the data obtained at the protein level, dexamethasone increased the steady-state levels of alpha 2-macroglobulin-specific messenger RNA and reduced apolipoprotein E-specific transcripts, whereas fibronectin and actin messenger mRNA remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗

PubMed1979

Interaction of alpha 2-macroglobulin with L-asparaginase.

Obvious protection of the catalytic activity of Esch. coli L-asparaginase by alpha 2-macroglobulin (alpha 2M) was observed under conditions otherwise propitious to the dissociation of the tetrameric molecule into inactive subunits, i.e. very diluted enzyme solutions or the presence of either SDS or urea. The degree of protection depended on enzyme and alpha 2M concentrations respectively, and on the preincubation time of the alpha 2M-enzyme mixture prior to substrate addition. The formation of a catalytically active complex between alpha 2M and L-asparaginase was confirmed by gel filtration on a Sephadex-G column and by polyacrylamide gel electrophoresis. The fact that the migration distance of the active complex corresponded to the migration of alpha 2M and the absence in that case of a migration band corresponding to the intact molecule suggest that complexing of the enzyme with alpha 2M prevented its dissociation into subunits and thus its inactivation. Addition of alpha 2M to the already dissociated enzyme molecule did not restore its catalytic activity. Alpha2-macroglobulin was shown to have an inhibiting effect on the proteolytic activity of almost all proteases and no effect on their esterolytic activity. Furthermore, it prevents the inhibition of esterolytic activity by some natural compounds. The effect of alpha 2M on other types of catalytic activity has not been investigated enough to afford a generalization of the possible role of this macroglobulin in the control of enzyme activity in the body. This paper reports the results of an in vitro study of the effect of alpha 2M on the catalytic activity of an important amidase, i.e. L-asparaginase (L-asparagine amidohydrolase 3.5.1.1), which in recent years has been used in the treatment of acute lymphocytic leukemia in children.

Asparaginase↗