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Biomedical subjects

W Pruzanski

Publications and source records attributed to W Pruzanski.

At least 91 records · Page 5Linked to original sources
PubMed1988

Pathogenesis of hypotension in septic shock: correlation of circulating phospholipase A2 levels with circulatory collapse.

Circulating phospholipase A2 (PLA2) has been recognized as a mediator of circulatory collapse in experimental endotoxic shock. To assess the role of serum PLA2 in septic shock in man, we determined serum PLA2 profiles in a prospective study in 12 patients with septic shock. During the hypotensive phase of sepsis, serum PLA2 levels were consistently elevated as high as 33,428 U/ml (normal range 115 +/- 12 [SE]; n = 101). In all 12 patients, PLA2 levels correlated directly with the magnitude and duration of circulatory collapse (p less than .001), with a progressive fall of serum PLA2 levels during convalescence. In contrast, serum PLA2 levels in patients with cardiogenic shock secondary to myocardial infarction remained low. In pancreatitis, PLA2 levels paralleled fluctuations of serum amylase and lipase, whereas in septic shock without pancreatic involvement, PLA2 changes were discordant with changes in pancreatic enzymes. As well, septic shock serum PLA2 failed to crossreact by radioimmunoassay with antiserum against human pancreatic PLA2. These data are consistent with an extrapancreatic source of intravascular PLA2 release during sepsis. Since endogenous serum PLA2 levels correlate directly with the magnitude of hypotension in both experimental endotoxic shock and clinical septic shock, and since parenteral administration of purified exogenous PLA2 reproduces hypotension in experimental models, we conclude that high levels of intravascular PLA2 may contribute similarly to the circulatory collapse in septic shock in man.

Adult↗
PubMed1988

Concordance of endogenous cortisol and phospholipase A2 levels in gram-negative septic shock: a prospective study.

Lipocortins, a group of corticosteroid-induced phospholipase-inhibitory proteins, are thought to play a prominent role in the mediation of the anti-inflammatory effects of steroids. The synthesis and release of these proteins may represent a major endogenous mechanism of regulation of extracellular phospholipase A2 (PLA2) activity. Because soluble PLA2 activity has been associated with circulatory collapse in hyperphospholipasemic conditions, such as septic shock and pancreatitis, we examined the relationship between circulating PLA2 activity and adrenocortical function. In a prospective study of 10 episodes of septic shock, serum PLA2 and cortisol levels correlated significantly in all survivors (p less than 0.0001), whereas such a correlation was absent in all nonsurvivors (p less than 0.07). No significant correlation of cortisol and adrenocorticotropic hormone (ACTH), or PLA2 and ACTH, was found in any patient, suggesting that the stimulus for cortisol release arises from outside the hypothalamic-pituitary axis. These data suggest that, in human beings, the regulation of soluble PLA2 activity may be mediated by adrenocortical hormones, perhaps through the intermediary action of lipocortins.

Adrenocorticotropic Hormone↗
PubMed1988

Phospholipase A2 activity associated with synovial fluid cells.

High activity of phospholipase A2 (PLA2) has been detected in synovial fluids (SF) in inflammatory arthritides. Since the source(s) of SF PLA2 has not been identified, we tested PLA2 content in SF cells obtained from 11 SF. Cell sonicates were prepared at 5 X 10(6) cells/ml. In the supernatants of the sonicated SF cells (n = 11), PLA2 activity ranged from 38-755 U/ml, mean 368 +/- 243 (SD) U/ml, compared to 5-64 U/ml, mean 31 +/- 15 (SD) U/ml in sonicates of normal peripheral blood PMN (n = 5) (p less than 0.0001). Spontaneous release of PLA2 from unstimulated SF cells ranged from 26-365 U/ml, mean 131 +/- 144 (SD) U/ml (n = 5), whereas spontaneous release from peripheral blood PMN was negligible. Neither 10(-8) M FMLP nor 5 X 10(-6) M dexamethasone altered extracellular PLA2 release. To assess whether PLA2 adsorbs passively to cell membranes through hydrophobic interaction, normal peripheral PMN were incubated in crude SF (n = 7) with PLA2 ranging from 4,000-24,300 U/ml, or with purified human SF PLA2 or Naja naja PLA2. We found that soluble PLA2 adsorbed to PMN membranes in a concentration dependent fashion. PLA2 activity in sonicates of PMN incubated in crude SF ranged from 185-358 U/ml compared to controls of 21-64 U/ml. Sonicates of PMN incubated with purified human SF PLA2 (5,000-30,000 U/ml) showed progressive concentration dependent increase in PLA2 from 7 +/- 4 to 212 +/- 11 (SD) U/ml (p less than 0.001). PMN incubated with Naja naja PLA2 also showed marked increase in the content of PLA2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1988

Serum phospholipase A2 correlates with disease activity in rheumatoid arthritis.

We previously demonstrated a marked elevation of the proinflammatory enzyme phospholipase A2 (PLA2) in all synovial fluids and some sera of patients with rheumatoid arthritis (RA). Since PLA2 was found to induce inflammatory changes in the skin and joints of experimental animals, we tested whether the serum level of PLA2 correlates with the clinical activity of RA. In the group of 51 patients with classical or definite RA, 13 (25%) had high serum levels of PLA2 (over 2 standard deviations above the normal mean). Comparison of clinical disease activity in patients with high levels of PLA2 with those with normal PLA2 levels showed that patients with high PLA2 levels had a significantly higher joint count, more swollen joints, much higher Landsbury index, lower functional class, lower hemoglobin, lymphopenia and higher erythrocyte sedimentation rate (ESR). To more accurately assess the relationship between the PLA2 level and disease activity in RA, we formulated 2 indices. Clinical index consisted of the Landsbury index, number of swollen joints and duration of morning stiffness. Laboratory index consisted of hemoglobin, absolute number of peripheral blood lymphocytes, platelet count and ESR. Our results showed that both indices correlated strongly with PLA2 activity (p less than 0.0001). The results support the hypothesis that PLA2 plays a pathogenetic role in RA and suggest that serum PLA2 levels may serve as an additional measure of disease activity.

Adult↗
PubMed1987

Cryptic cold agglutinin activity of monoclonal macroglobulins.

One hundred and twenty sera with monoclonal immunoglobulin M's (IgM's) were tested for cryptic cold agglutinin activity against papain- and neuraminidase-treated adult and cord red blood cells (RBC). Fifteen sera (12.5%) agglutinated papain-treated RBC. Fourteen of these 15 sera also agglutinated neuraminidase-treated RBC. Ten additional sera agglutinated neuraminidase-treated but not papain-treated cells. Three patterns were observed among agglutinators of papain-treated RBC: either predominant agglutination of adult RBC, or of cord RBC or equal reaction, thus resembling I, i and non-Ii patterns of conventional cold agglutinins. We propose to call these patterns, tentatively, Icr (cr for cryptic), icr, and non-Iicr, respectively. Purified monoclonal IgM's retained the above patterns. Eluates from enzyme-treated cells contained monoclonal IgM's. Investigation of neuraminidase-treated RBC has shown that in distinction to T-anti-T system (Thomsen-Friedenreich receptor system), the majority of sera with monoclonal IgM's agglutinated more strongly adult RBC, and some agglutinated more strongly cord RBC. There was no loss of agglutinating activity after repeat freezing and thawing of the sera. Thus, it seems that monoclonal IgM's which react with neuraminidase-treated RBC detect antigenic determinants different from the T antigen. Cryptic CA activity of IgM's should be added to the list of antibody activities of these monoclonal immunoglobulins.

Adult↗
PubMed1987

Influence of neutrophil cationic proteins on generation of superoxide by human polymorphonuclear cells during phagocytosis.

The cationic proteins from neutrophil lysosomes have been shown to modulate phagocytic activity of granulocytes. The present study reports the effects of the cationic protein fractions on the generation of O2- by human PMNs during phagocytosis. Human PMNs were reacted with different phagocytic stimuli in the presence and absence of lysosomal cationic proteins and the amount of O2- generated was determined by superoxide dismutase inhibitable reduction of cytochrome c. Total cationic protein extract from neutrophil lysosomes enhanced O2- generated by PMNs during the phagocytosis of IgG-coated latex beads and opsonized zymosan particles. The analysis of the fractions of cationic proteins obtained from a Sephadex G-75 column showed that the O2- generation-enhancing activity was associated with the proteins eluted in fractions III and IV. A protein fraction mainly eluted in void volume inhibited the cytochrome c reduction by O2- formed during phagocytosis. This was due to the presence of superoxide dismutase-like activity since O2- generated by the xanthine-xanthine oxidase system was also inhibited by this fraction. The cationic protein fractions III and IV from the Sephadex G-75 column were further subfractionated. Although the O2(-)-enhancing activity was eluted in the same fractions as chymotrypsin activity, there was no quantitative correlation between the amount of O2- generation and chymotrypsin activity. Moreover, commercial chymotrypsin did not enhance O2- generation. Electrophoretic analysis of the isolated protein fractions suggests that O2- generation enhancing protein (SGEP) is different from lysozyme or chymotrypsin and probably represents previously undescribed protein.

Antimicrobial Cationic Peptides↗
PubMed1987

Antinucleic acid autoantibody responses of normal human origin: antigen specificity and idiotypic characteristics compared to patients with systemic lupus erythematosus and patients with monoclonal IgM.

One idiotype family 4.6.3 derived from a human hybridoma IgML monoclonal anti-DNA antibody of normal origin is commonly expressed (approximately 85%) in the serum of patients with systemic lupus erythematosus but not in normal controls, where its level appears to fluctuate with clinical disease activity. In contrast, the IgM released by normal cultured lymphocytes in vitro expresses this idiotype family but does not bind DNA. Both idiotype 4.6.3 and anti-DNA antibodies are frequently detectable in the serum of patients with monoclonal IgM but not IgG. Therefore, it is likely that idiotype 4.6.3 reflects the expression of a common germ line immunoglobulin gene family. Some of the IgM molecules encoded by these germ line immunoglobulin genes also bind DNA.

Antibodies, Antinuclear↗
PubMed1986

Suppression of chemotactic activity of human polymorphonuclears by monoclonal IgMs with and without biological activity.

The influence of monoclonal IgMs on migration of human polymorphonuclears was studied at various temperatures by the use of 19 sera with monoclonal IgMs from patients with macroglobulinemia of Waldenstrom (MW) without obvious biological activity, 29 sera with monoclonal IgM cold agglutinins (18 with anti-I and 11 with anti-i IgMs) and 3 sera with monoclonal IgM rheumatoid factor (RF). Under-agarose migration method and modified Boyden chamber method with double filters and 51Cr-PMNs were used. In under-agarose method, chemotactic differentials for controls, MW, anti-I, and anti-i groups were, respectively, 57 +/- 8 mm, 39 +/- 9 mm, 44 +/- 14 mm, and 32 +/- 16 mm at 37 degrees C and 47 +/- 18 mm, 22 +/- 11 mm, 17 +/- 9 mm, and 15 +/- 12 mm at 24 degrees C. All three sera with IgM RF inhibited chemotaxis. The differences between all groups and controls were significant at p less than 0.01. Random migration was inhibited at 24 degrees C (p less than 0.01) but not at 37 degrees C. Inhibitory concentrations of IgM in the sera tested were equal or less than 0.5 mg/ml. Thirteen sera were tested by the modified Boyden chamber method. At 37 degrees C 8 of 13 sera and at 24 degrees C 11 of 13 sera inhibited significantly chemotaxis at a concentration of IgM of 1 mg/ml. The lowest inhibitory concentration of IgM was 25 micrograms/ml. Eleven chromatographically pure IgMs were tested in the under-agarose assay. At concentrations of 0.4-3.7 mg/ml, eight IgMs inhibited chemotactic differential at 37 degrees C and nine inhibited it at 24 degrees C. At concentrations of 0.6-2.0 mg/ml, all seven pure IgMs tested by the Boyden chamber method significantly inhibited chemotaxis at 24 degrees C and 37 degrees C. Some IgMs inhibited chemotaxis at concentrations as low as 25 micrograms/ml. Ten IgM CA were eluted from the red blood cells. Eluates inhibited strongly chemotaxis at 24 degrees C and 37 degrees C. Heat inactivation did not alter inhibitory activity of IgM, however pepsin digestion or reduction and alkylation of purified IgMs did abolish their inhibitory activity. Inhibition of chemotaxis was not related to the light chain type, the titre, or the thermoamplitude of cold agglutination. However, monoclonal IgMs with anti-i cold agglutinin activity were stronger inhibitors than anti-I. Since 75% of IgMs tested inhibited chemotaxis at 37 degrees C, it is possible that monoclonal IgMs, especially those with anti-i cold agglutinin activity, inhibit PMN migration in vivo.

Agglutinins↗
PubMed1986

Influence of plasma proteins on activity of proinflammatory enzyme phospholipase A2.

The influence of plasma proteins on quantitation of the proinflammatory enzyme phospholipase A2 (PLA2) from rheumatoid synovial fluid was studied using two different assays. Human and bovine serum albumins increased the rate of PLA2 hydrolysis of membrane-associated phospholipid substrates. In contrast, albumin profoundly inhibited the PLA2 hydrolysis of synthetic phospholipids in micellar dispersion. Other plasma proteins (alpha, beta and gamma-globulins) had minimal effect on PLA2 activity in either assay system. Since the presence of albumin may compromise estimation of PLA2 and of phospholipase-inhibitory proteins, the appropriate selection of assay conditions is obligatory for the accurate quantitation of their respective activities.

Arthritis, Rheumatoid↗
PubMed1986

Potential therapeutic efficacy of inhibitors of human phospholipase A2 in septic shock.

Soluble phospholipase A2 has been implicated in the pathogenesis of local and systemic inflammatory reactions. Elevated levels of circulating phospholipase A2 (PLA2) correlate with the severity of circulatory collapse and pulmonary dysfunction in gram-negative septic shock. Characterization of septic shock serum PLA2 revealed a calcium-dependent enzyme with absolute 2-acyl specificity with a pH optimum of 7.5. We tested a number of therapeutic agents for their ability to inhibit PLA2 from human septic shock serum. Chloroquine, chlorpromazine, dexamethasone base, dexamethasone sodium phosphate, indomethacin, lidocaine, oleic acid, palmitic acid, promethazine, trans-retinoic acid, rutin and dl-alpha-tocopherol were all studied over the range of 10(-2) to 10(-7) M. All agents, with the sole exception of dexamethasone base, inhibited PLA2 activity at concentrations greater than 10(-3) M. PLA2 inhibition by dexamethasone sodium phosphate was factitious, due to the formation of calcium-phosphate complexes. Of the 11 agents studied, chlorpromazine was the most effective, with an IC50 of 7.5 X 10(-5) M, a membrane concentration achievable within its therapeutic range. Inhibition was non-competitive with an apparent Ki of 5 nM. Since serum PLA2 levels correlate with mortality in both experimental endotoxemia and clinical gram-negative septic shock, and chlorpromazine was previously shown to improve survival in these conditions, we postulate that its therapeutic efficacy resides at least in part in its PLA2-inhibitory activity.

Dexamethasone↗
PubMed1986

Purification of a soluble phospholipase A2 from synovial fluid in rheumatoid arthritis.

A soluble phospholipase A2 (PLA2) was purified 4,500-fold from human rheumatoid synovial fluid. Preparative sodium dodecyl sulfate polyacrylamide gel electrophoresis yielded two bands of PLA2 activity of molecular weights 15,000 and 17,000 and pl 4.2-5.0. Purified PLA2 had absolute 2-acyl specificity, and hydrolyzed phosphatidylcholine with optimal activity at pH 7.5-8.0 and phosphatidylethanolamine with optimal activity at pH 7.0. Human synovial fluid PLA2 did not cross-react with anti-human pancreatic PLA2, as tested by radioimmunoassay.

Arthritis, Rheumatoid↗
PubMed1986

Inflammatory effect of intradermal administration of soluble phospholipase A2 in rabbits.

Extracellular phospholipase A2 (PLA2) has been found in association with inflamed sites in experimental animals and in humans. The tissue effects of soluble PLA2 have not been defined. We studied the development of inflammatory changes in rabbit skin subsequent to intradermal injection of active and inactivated venom and pancreatic PLA2, over a broad concentration range. PLA2, at concentrations encountered in human disease, caused acute inflammatory changes characterized grossly by erythema and induration, and histologically by inflammatory cell infiltration, vascular and tissue damage, and abscess formation. Extracellular PLA2 may be considered as one of the pathogenic factors in inflammatory reaction.

Acute Disease↗
PubMed1986

Persistent cold agglutinins in AIDS and related disorders.

Eighty-one homosexual patients positive for HTLV-III antibody, including 19 with AIDS, 20 with chronic lymphadenopathy syndrome, 10 with AIDS-related complex (ARC) and 32 symptom-free individuals were assessed for the presence of cold agglutinins (CA). In 12 cases, CA were found; 4, 4, 2 and 2, respectively, in each of the above mentioned groups. Seven anti-I, 4 anti-i and 1 anti-Gd CA were identified. In 11 of 12 patients, CA were persistent. There were no differences between CA-negative and CA-positive patients with regard to the presence of other antibodies, anemia, frequency of intercurrent infections or development of lymphoproliferative neoplasia. It can be concluded that persistent synthesis of CA may be associated with the HTLV-III infection.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Lymphocytotoxins in vasculitis. Correlation with clinical manifestations and laboratory variables.

Twenty-eight of 53 patients with various types of vasculitis were found to have cold reacting lymphocytotoxins (LCT). LCT were cytotoxic to both peripheral blood B and T cells as well as to OKT4 and OKT8 subpopulations. The interaction with the B cells was more pronounced than with the T cells as shown by reactivity with the former at higher serum dilutions than with the latter. Similar results were obtained with eluates from the unseparated lymphocytes and from B or from T cells. Partial purification of LCT demonstrated that they belong to the IgM class. LCT correlated with the level of circulating immune complexes as determined by the fluid phase C1q binding assay, but they did not correlate with the level of immunoglobulins, complement or antinuclear factors. The presence of LCT correlated significantly with the activity but not with the disease duration or the number of involved organs. Correlation of LCT with the activity of vasculitis implies that these cytotoxins may have a pathogenetic role and perhaps may serve as a marker for disease activity.

Antigen-Antibody Complex↗