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PubMed2003

Contribution of protein G-related alpha2-macroglobulin-binding protein to bacterial virulence in a mouse skin model of group A streptococcal infection.

Protein G-related alpha(2)-macroglobulin-binding (GRAB) protein is a cell wall-attached determinant of group A streptococcus (GAS) that interacts with the human protease inhibitor alpha(2)-macroglobulin (alpha(2)-M). Of 86 clinical isolates tested, 23% could bind alpha(2)-M. However, all strains tested contained the grab gene. High levels of anti-GRAB antibodies were found in the serum of convalescent GAS-infected patients, a finding that indicates that this protein is expressed during the infection process. Among the alpha(2)-M-binding strains, 80% were skin isolates, and 20% were throat isolates, findings that suggest that the skin environment is a preferential site for expression of alpha(2)-M-binding activity. To test this possibility, we determined the role of GRAB in a mouse model of GAS skin infection. The wild-type strain KTL3, which interacts with alpha(2)-M, showed high virulence. The isogenic mutant of KTL3, MR4, devoid of surface-bound GRAB, was attenuated in virulence, compared with the wild-type strain. Thus, mice infected with MR4 survived longer, developed smaller skin lesions, and exhibited lower levels of bacterial dissemination than did those infected with KTL3. These results emphasize the role of GRAB as a virulence factor of GAS.

Animals↗

PubMed1979

The response of the acute-phase plasma protein alpha2-macroglobulin to vitamin A deficiency in the rat.

Alpha2-macroglobulin (alpha2-M) was determined in the sera of vitamin A-deficient and pair-fed control rats. Alpha2-macroglobulin levels were assayed by radial immunodiffusion using a purified standard sample from sera from turpentine-stressed rats. There was no significant increase in the serum level of alpha2-M in vitamin A-deficient rats relative to pair-fed controls, indicating that there was no acute response to the stress of the deficiency. When turpentine was injected to elicit an acute response, the serum level of alpha2-M rose equally (by almost 100-fold) in both deficient and normal rats. It was concluded that the response to vitamin A deficiency of serum glycoprotein synthesis shows some specificity in that the synthesis of alpha2-M in response to stress was not affected by vitamin A, whereas we previously found that levels of alpha1-M, which is very similar to alpha2-M, decline with vitamin A deficiency.

Animals↗

PubMed1991

Alpha-macroglobulin-like plasma inactivator for Vibrio vulnificus metalloprotease.

The metalloprotease produced by Vibrio vulnificus (VVP) is known to be quickly inactivated by plasma proteins which belong to the class of alpha-macroglobulins in vitro at a molar ratio of 1:1. But the in vivo potential of the inactivators has not been studied. Macroalbumin (MA), a member of alpha-macroglobulins in guinea pig plasma, was found to inactivate VVP by means of physical entrapment in vitro. In vivo actions of VVP, permeability-enhancing and hemorrhagic actions, were greatly augmented by simultaneous injection of the antibody against MA, which had no effect on in vitro proteolytic action toward azocasein. The interstitial-tissue space in the normal guinea pig skin contains a negligible amount of MA. However, sufficient MA was present in the extravascular fluid collected after the intradermal injection of VVP. Besides, in the extravascular fluid, VVP formed a complex with MA and no inactivator other than MA was found. These results indicate that plasma MA leaked from the vascular system owing to the permeability-enhancing and hemorrhagic actions of VVP, resulting in inactivation of VVP in situ.

Animals↗

PubMed1983

Alpha-2-macroglobulin-like protease inhibitor from the egg white of cuban crocodile (Crocodylus rhombifer).

A high molecular weight protease inhibitor was purified from the egg white of Cuban crocodile (Crocodylus rhombifer). It inhibited the casein hydrolyzing activity of trypsin, subtilisin and papain. Its native molecular weight was 730,000 and it consisted of four subunits of equal molecular weight, each pair of which were disulfide bonded. The amino acid composition, circular dichroic spectrum and electron micrographs of this protein are also presented. Upon incubation with trypsin this protein yielded a fragment of Mr = 80,000, similar in size to the one known to originate from alpha 2-macroglobulin under the same conditions. The molecular parameters of this protein and the broad inhibitory activity towards thiol and serine proteases with different substrate specificities suggest that it is a protein closely related to alpha 2-macroglobulin in mammalian serum. From its native molecular weight and amino acid composition we believe that this protein is also a reptilian counterpart of the avian ovomacroglobulin described by Miller and Feeney (3).

Alligators and Crocodiles↗

PubMed1987

Paired serum and synovial fluid values of alpha 2-macroglobulin and TIMP in rheumatoid arthritis.

The levels of alpha 2-macroglobulin and tissue inhibitor of metalloproteinases (TIMP) were determined in paired serum and synovial fluid samples from rheumatoid arthritis patients. Serum levels of alpha 2-macroglobulin (mean 1580 +/- 340 mg/l) were always higher than the corresponding synovial fluid although the spread of synovial fluid levels was broad (mean 520 +/- 340 mg/l). Tissue inhibitor of metalloproteinases was always higher in synovial fluid (mean 4.59 +/- 1.8 mg/l) than serum (mean 1.3 +/- 0.39 mg/l) indicating that local synthesis occurred within the joint.

Arthritis, Rheumatoid↗

PubMed1992

Uterine uptake of alpha 2-macroglobulin and alpha 1-proteinase inhibitor from the blood during early implantation in the mouse.

The objective of this study was to investigate the uterine uptake of plasma alpha 1-proteinase inhibitor (53,000 Da) and alpha 2-macroglobulin (725,000 Da) from the blood during implantation in the mouse using isotopic methods. The uterine uptake of albumin (67,000 Da) and immunoglobulin G (150,000 Da) were also measured for comparison. Rates of uptake were assessed from permeability-surface area products estimated from the rate at which the tissue volume of distribution approaches its steady-state value. The permeability-surface area product estimates at implantation sites were 13.3 and 54.8 ml/100 g.h for alpha 2-macroglobulin and alpha 1-proteinase inhibitor, respectively. Given the circulating levels of these proteins in mice, these results demonstrate that considerable amounts of plasma proteinase inhibitors are extravasated into the interstitium in the vicinity of the implanting blastocyst. The permeability-surface area products of all the proteins studied, except immunoglobulin G, were greater at implantation compared to non-implantation sites, confirming greater vascular permeability to plasma proteins at implantation sites compared to non-implantation sites. Estimates of the permeability-surface area products of the studied proteins showed that the uterine vasculature was generally more permeable to proteins with a small than with a large molecular size. Nevertheless, the ratio of the permeability-surface area product between implantation and non-implantation sites for the proteins ranged from 1.1 to 2.9 with no obvious relationship to molecular size.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Clearance mechanism of prostate specific antigen and its complexes with alpha2-macroglobulin and alpha1-antichymotrypsin.

PURPOSE: To investigate the rate of elimination of prostate specific antigen (PSA) and its complexes with human alpha2-macroglobulin (alpha2-M) and alpha1-antichymotrypsin (ACT) and to elucidate the role of the alpha2-macroglobulin-receptor/low density lipoprotein receptor-related protein (alpha2-M-R/LRP) in the clearance mechanism. MATERIALS AND METHODS: PSA and complexes of PSA with alpha2-M and ACT were prepared and radiolabeled with [125I]Na (Amersham, Braunschweig, Germany). Radiolabeled proteins were injected into rats and the elimination of radioactivity from circulation was measured by gamma-counting of 20 microL aliquots over time. After 30 minutes different organs were removed and the total radioactivity was counted. The elimination rate and distribution of PSA and PSA-complexes was studied in the absence and presence of an excess of transformed alpha2-M. RESULTS: Radiolabeled PSA is rapidly eliminated from circulation with an initial half-life of 6.4+/-2.1 minutes mainly due to extraction by the liver and kidney. The clearance is slightly inhibited by transformed alpha2-M. PSA-alpha2-M is solely eliminated by the liver with a half-life of 6.7+/-1 minutes. Uptake by the liver is competitively inhibited by transformed alpha2-M. PSA-ACT is eliminated by the liver and kidney with an initial half-life of 3.51+/-1.1 minutes. Transformed alpha2-M failed to inhibit the clearance of PSA-ACT. CONCLUSIONS: Free PSA and PSA-inhibitor complexes are removed from the circulation by different clearance mechanisms. The sites of metabolism of the different forms of PSA are different but include liver and kidney as main organs for uptake. There are indications that alpha2-M-R/LRP is involved in PSA elimination. Thus, factors which modulate the receptor function and expression as well as the concentration of its natural ligands may interfere with the steady state concentrations of different PSA forms in blood.

Animals↗

PubMed1988

Synthesis and secretion of alpha 2-macroglobulin by human hepatocytes in culture.

Hepatocytes were isolated by application of the two-step collagenase perfusion technique to pieces of human liver. The cells were incubated in serum-free medium or 10% FCS-medium supplemented with insulin, glucagon and dexamethasone, and kept in culture for more than 2 weeks. Seventy-five per cent of the medium was changed regularly and assayed for alpha 2-macroglobulin (alpha 2-M), pregnancy zone protein, alpha 1-antitrypsin and albumin by means of ELISA. Significant amounts of alpha 2-macroglobulin were present in all cultures. During incubation, alpha 2-M accumulated in the medium and the quantity of alpha 2-M released from the cells by far exceeded protein associated with hepatocytes prior to incubation. In 24 h 10(6) hepatocytes secreted 160.5 +/- 82.2 ng of alpha 2-M (mean +/- SD, n = 5). Cell-associated, as well as secreted alpha 2-M appeared to be on native form, as determined by immunoisolates from lysed cells and culture supernatants. Pregnancy zone protein was only detected in about 50% of the cultures and its rate of secretion was less than 2 ng 24 h-1 per 10(6) cells. In contrast, culture medium contained considerable quantities of alpha 1-antitrypsin and albumin. In 24 h, 10(6) hepatocytes released greater than 2 micrograms alpha 1-antitrypsin and greater than 5 micrograms albumin. The present study suggests the hepatocyte to be of major importance for the synthesis of intravascular alpha 2-M.

Adult↗

PubMed1987

Alpha 2-macroglobulin in the sera of patients with periodontal disease.

The concentration of alpha 2-macroglobulin (alpha 2-M) in the sera of 86 blood donors was measured by laser nephelometry. Plaque index (PII), gingival index (GI) and probing depth were recorded around all existing teeth. All measured clinical parameters correlated positively with the concentration of alpha 2-M in the sera of the examined persons, but statistically significant positive correlation was found only in with the following: average gingival index and alpha 2-M concentration in the sera of females and average probing depth and alpha 2-M concentration in the sera of all examined females and males. This study supports the hypothesis that in long-standing chronic periodontal disease, the increased levels of proteinases might trigger the synthesis of alpha 2-macroglobulin in the host. The role of alpha 2-M as a proteinase scavenger and immunosuppressive agent is discussed briefly.

Adult↗

PubMed1996

Transformed alpha 2-macroglobulin as a low-affinity growth hormone-binding protein.

Human growth hormone (GH) forms complexes with the purified proteinase inhibitor, alpha 2-macroglobulin (alpha 2-M). This inhibitor occurs in two different forms in serum, known as native and transformed alpha 2-M. It has been clearly demonstrated, using chromatography and electrophoresis combined with autoradiography, that human GH binds specifically to the transformed inhibitor and not to the native protein. The binding was characterized as being mainly non-covalent and involved specific binding sites present only in the transformed inhibitor molecule. Binding analysis, using an immunoprecipitation technique, revealed that GH possesses two different types of binding sites, with dissociation constants of 0.49 +/- 0.12 mumol/l and 61 +/- 8 mumol/l for the high- and low-affinity binding site, respectively. Distribution analysis of 125I-labelled GH in whole plasma suggests that the hormone is bound to two different proteins: first, to the high-affinity GH-binding protein (GHBP) and, second, to the low-affinity GHBP, identified as transformed alpha 2-macroglobulin.

Carrier Proteins↗

PubMed1983

Occurrence of reduced alpha 2-macroglobulin and lowered protease inhibiting capacity in plasma of amyotrophic lateral sclerosis patients.

Lowered levels of plasma alpha 2-macroglobulin were found in 13 patients with amyotrophic lateral sclerosis using anti-alpha 2-macroglobulin-embedded agar plates. Levels of this major protease inhibitor in ALS patients were contrasted with those in disease controls, consisting of patients with a variety of neurologic disorders, as well as with those in normal individuals. The patients' levels, in milligrams per deciliter, were 191 +/- 39 (SD). The disease controls had levels of 269 +/- 33. Local normal values compared with the reported normal values in the literature (260 +/- 70). A correlation was not made for either the form of motor neuron disease, disease severity, or age. As a measure of functional protease inhibition, trypsin inhibitory capacity of sera was estimated using a radioactive fibrinolytic assay. An increase in the half-maximal inhibitory concentration of sera was found in the amyotrophic lateral sclerosis group. These findings likely relate to the known increases in proteolytic activity in denervated muscle and collagenolytic activity in skin of patients with amyotrophic lateral sclerosis. The determination of whether altered protease inhibitory potential in such patients is primary or secondary may help in understanding the pathogenesis of this enigmatic disorder and provide suggestions for future approaches to intervention.

Adult↗

PubMed1964

MACROGLOBULIN FROM HUMAN PLASMA WHICH FORMS AN ENZYMATICALLY ACTIVE COMPOUND WITH TRYPSIN.

The protein from human plasma which forms an enzymatically active complex with trypsin and is able to protect trypsin from inhibition by soybean trypsin inhibitor has been shown to be an alpha(2)-macroglobulin. It was obtained from the lipid-poor euglobulin of Cohn Fraction III-0, and appears to be closely related to the 19S-glycoprotein or alpha(2)macroglobulin

Alpha-Globulins↗

PubMed1980

Serum alpha 2-macroglobulin levels in diabetes.

Serum alpha 2-macroglobulin levels have been determined in diabetic patients by quantitative radial immunodiffusion and compared with those observed in age- and sex-matched controls. In addition, the results in diabetics have been analysed with respect to such variables as the age and sex of the patient, the duration of disease, treatment, control, and the occurrence of retinopathy or nephropathy. The alpha 2-macroglobulin levels in diabetic patients were found to be significantly higher than in age- and sex-matched controls, thus confirming previous observations. However, these differences were most apparent in the more extreme age groups. Multiple regression analysis also revealed that the only variables contributing significantly to the regression apart from age and sex were control and retinopathy.

Adolescent↗

PubMed1984

Albumin bound and alpha 2-macroglobulin bound zinc concentrations in the sera of healthy adults.

Reference ranges for albumin bound and alpha 2-macroglobulin bound zinc concentrations have been determined in a study of sera obtained from 134 healthy adults. The concentrations of zinc bound to alpha 2-macroglobulin were remarkably constant with a mean (+/-SD) of 2.4 +/- 0.6 mumol/l; the variations in total serum zinc concentrations were almost entirely accounted for by variations in the zinc associated with albumin. There were no sex related differences in the transport of zinc in serum; neither was this sensitive to the use of oral contraceptives. These data provide a baseline for further investigations into the effects of zinc deficiency on the serum transport of the metal.

Adolescent↗

PubMed1989

Synthesis of alpha 2-macroglobulin by bovine adrenal cortical cell cultures.

Primary cultures of bovine adrenal medullary cells synthesize and secrete a high-molecular-weight protein into the culture medium. The protein was purified from the serum-free medium of cultured cells and was identified as alpha 2-macroglobulin by gel electrophoresis, sedimentation velocity, electron microscopy, immunoprecipitation, immunodiffusion, and autoradiography. Antisera directed against the protein were prepared and used to determine the cell types that synthesize the protein. Immunohistofluorescence studies show that adrenal cortical cells present in the adrenal medullary cell cultures reacted with the antisera to the protein purified from the medium, but adrenal medullary chromaffin cells did not. Cell cultures prepared from bovine adrenal cortex also synthesize and secrete alpha 2-macroglobulin and react with the antisera.

Adrenal Cortex↗

PubMed1983

Distribution of acute-phase alpha 2-macroglobulin in rat fetomaternal compartments.

Rat acute-phase alpha 2-macroglobulin (AP alpha 2M) concentration was measured by radioimmunoassay in maternal serum, fetal plasma, maternal liver, fetal liver, and amniotic fluid as a function of gestational and neonatal age. The concentration profiles of AP alpha 2M in maternal serum and fetal plasma displayed two peaks, one in early gestation and another during late gestation. Synthesis of AP alpha 2M was confirmed by the immunoprecipitation of [35S]methionine incorporated into cultures of selected tissues. The following observations were made. 1) Maternal serum concentrations of AP alpha 2M were higher than those observed in fetal plasma in early gestation. This was attributable to a high level of maternal AP alpha 2M synthesis in metrial gland which was absent in liver and moderate in yolk sac. 2) In late gestation fetal plasma concentrations of AP alpha 2M greatly exceeded those observed in maternal serum. This could be explained by the pronounced synthesis of AP alpha 2M in fetal liver that was not apparent in maternal liver or yolk sac. 3) During labor, a transient increase in AP alpha 2M concentration was observed in maternal serum and fetal plasma. 4) During lactation a moderately elevated maternal serum concentration of AP alpha 2M was maintained. 5) Amniotic fluid concentration of AP alpha 2M was very low throughout gestation, which indicated that the fetal glomerulus was relatively impermeable to this large protein. It is concluded that in early gestation a principal maternal source of AP alpha 2M appears to be the metrial gland, whereas in late gestation fetal liver is a major source of AP alpha 2M appearing in fetal plasma from where some of this macroglobulin is speculated to be transported to the maternal circulation.

Aging↗

PubMed1998

Expression of alpha2-macroglobulin by the interaction between hepatocytes and endothelial cells in coculture.

The interaction between distinct cell types within the liver seems to be important in regulating hepatic function. However, these interactions have not been well characterized because of difficulty in reproducing the hepatic environment in an ex vivo model. In the present study a coculture system of hepatocytes and endothelial cells was established to investigate the communication between parenchymal and nonparenchymal cells. Freshly isolated rat hepatocytes were placed onto a monolayer of primary aortic rat endothelial cells. Analysis of the proteins secreted into the extracellular medium after pulse labeling with radioactive amino acids revealed the presence of a 180,000-apparent molecular weight glycoprotein, BBB-180, which was not detected in the extracellular medium of hepatocytes or endothelial cells when they were cultured separately. This glycoprotein was identified as alpha2-macroglobulin after sequencing of the proteolytic peptides derived from the purified protein. This finding was confirmed by Northern and Western blotting, immunoprecipitation, and RT-PCR. The expression of alpha2-macroglobulin required direct contact between hepatocytes and viable endothelial cells. These findings suggest that endothelial cells modulate hepatocyte gene expression by direct cellular interactions.

Amino Acid Sequence↗

PubMed1977

Amidolytic assay of thrombin bound to alpha2-macroglobulin in plasma.

A method for the determination in plasma of alpha2-macroglogulin-bound thrombin is described. Alpha2-Macroglobulin-bound thrombin is precipitated from plasma by 13% polyethyleneglycol, and its amidolytic activity is assayed by using the chromogenic substrate benzoyl-Phe-Val-Arg-p-nitroanilide (S 2160). After thrombin addition to plasma, only about 1.7% of the added thrombin activity was recovered in the alpha2-macro-globulin precipitate. It is suggested that the contribution of alpha2-macroglobulin to anti-thrombin activity of normal plasma is of little relevance.

Aniline Compounds↗