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Biomedical subjects

I M Goldstein

Publications and source records attributed to I M Goldstein.

At least 55 records · Page 3Linked to original sources
PubMed1984

Complement and endotoxin-induced lung injury in sheep.

Intravenous infusions of endotoxin in sheep cause lung injury characterized by edema due to increased microvascular permeability. Similar increases in pulmonary microvascular permeability are seen in septic patients with the adult respiratory distress syndrome. Since endotoxin-induced lung injury may be mediated by interactions between products of complement activation and polymorphonuclear leukocytes, plasma and lung lymph from six unanesthetized sheep infused with Escherichia coli endotoxin (1.0 micrograms/kg over 30 min) were examined for complement-derived chemotactic activity. By 2-3 hr following infusion of endotoxin, all animals had the increased lung lymph fluid and protein flows characteristic of permeability edema. Preinfusion samples of plasma and lung lymph did not contain chemotactic activity for polymorphonuclear leukocytes. Following infusion of endotoxin, however, significant chemotactic activity was detected in plasma at 0.5-3.5 hr (P less than 0.05) and in lymph at 1.5-6.5 hr (P less than 0.025). The chemotactic activity was heat stable (56 degrees C for 30 min) but was abolished by treatment with antibodies to C5. These data indicate that infusions of endotoxin lead to the generation in plasma, and the appearance in lung lymph, of C5-derived peptides with chemotactic activity for polymorphonuclear leukocytes. C5-derived peptides may account for the pulmonary microvascular leukostasis and endothelial injury that lead to increased permeability edema after infusions of endotoxin.

Animals↗
PubMed1984

Complement (C5)-derived chemotactic activity accounts for accumulation of polymorphonuclear leukocytes in cerebrospinal fluid of rabbits with pneumococcal meningitis.

Experiments were performed to identify the chemoattractant for polymorphonuclear leukocytes that appears in the cerebrospinal fluid of rabbits with experimental pneumococcal meningitis. Meningitis was induced in anesthetized New Zealand white rabbits by injecting 10(4) cells of stationary-phase Streptococcus pneumoniae type III intracisternally. Before bacteria were injected, cerebrospinal fluid contained neither polymorphonuclear leukocytes nor chemotactic activity. Significant chemotactic activity for rabbit polymorphonuclear leukocytes was detected 12 h after inoculation with bacteria and was maximal after 18 to 20 h. Chemotactic activity appeared in cerebrospinal fluid while concentrations of pneumococci and total protein were increasing but before there was any accumulation of polymorphonuclear leukocytes. The chemotactic activity in cerebrospinal fluid was heat stable (56 degrees C for 30 min), eluted from Sephadex G-75 with a profile identical to that of the chemotactic activity in zymosan-activated rabbit serum, and was inhibited by treatment with antibodies to native human C5. In addition, preincubation of polymorphonuclear leukocytes with partially purified rabbit C5a selectively inhibited their subsequent chemotactic responses to cerebrospinal fluid. These data indicate that complement (C5)-derived chemotactic activity appears in cerebrospinal fluid during the course of experimental pneumococcal meningitis in rabbits and suggest that this activity accounts for the accumulation of polymorphonuclear leukocytes observed in this infection.

Animals↗
PubMed1984

Biologically active products of complement and acute lung injury in patients with the sepsis syndrome.

To determine if biologically active products of complement appear during sepsis and to establish the relationship of these components to the respiratory and hemodynamic complications of sepsis, we measured C5a des Arg and C3a des Arg (radioimmunoassay), neutrophil chemotaxis, and neutrophil-aggregating activity in plasma obtained from 40 patients at the time sepsis was suspected clinically. Levels of C3a des Arg and C5a des Arg were elevated in 35 and 38 patients, respectively, and in all 25 with positive blood cultures. Highest C5a des Arg levels occurred in patients with hypotension (less than 90 mmHg) and/or acidemia. The C5a des Arg concentrations were significantly higher in patients with than in those without neutrophil-chemotactic activity. Neutrophil-aggregating activity was less sensitive an index of complement activation, as it was positive in only 8 patients and correlated poorly with C5a des Arg and C3a des Arg values. Using a composite scoring system to quantify sepsis-related pulmonary abnormalities, we found that neither biologic nor immunologic assays of complement activation products correlated with the initial severity nor predicted the development or worsening of associated acute lung injury.

Bacterial Infections↗
PubMed1984

Prostaglandin I2 is not a major metabolite of arachidonic acid in cultured endothelial cells from human foreskin microvessels.

Prostaglandin I2 (PGI2), a potent vasodilator and inhibitor of platelet aggregation, is a major product of arachidonic acid metabolism in endothelial cells that are derived from large blood vessels (e.g., umbilical veins). We have examined whether PGI2 is also a major product of arachidonic acid metabolism in cultured endothelial cells that are derived from dermal microvessels in human newborn foreskin. Supernatants from confluent monolayers of endothelial cells that had been incubated for 20 min with [3H]arachidonic acid and the calcium ionophore A23187 (10 microM) were assayed for prostaglandin F2 alpha (PGF2 alpha), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1 alpha (PGF1 alpha) (the stable metabolite of PGI2) by using authentic standards and high performance liquid chromatography. Whereas supernates from stimulated umbilical vein endothelial cells contained 6-keto-PGF 1 alpha much greater than PGF 2 alpha much greater than PGE2, supernates from stimulated foreskin microvessel endothelial cells contained PGF 2 alpha congruent to PGE2 much greater than 6-keto-PGF 1 alpha. Similar results were obtained when supernates from stimulated, unlabeled endothelial cells were analyzed by radioimmunoassay. These data indicate that PGI2 is not a major metabolite of arachidonic acid in cultured endothelial cells from human foreskin microvessels.

Arachidonic Acid↗
PubMed1984

Production of chemotactic activity for polymorphonuclear leukocytes by cultured rat hepatocytes exposed to ethanol.

Acute alcoholic hepatitis is characterized by infiltration of the liver parenchyma with polymorphonuclear leukocytes. As a possible explanation for this phenomenon, we have found that ethanol stimulates cultured rat hepatocytes to generate potent chemotactic activity. Hepatocytes (greater than 99% pure), isolated from the livers of Sprague-Dawley rats, responded to incubation with ethanol (2.0-10 mM) by releasing chemotactic activity for human polymorphonuclear leukocytes into culture supernatants in a time- and concentration-dependent fashion. Chemotactic activity was maximal after incubation of hepatocytes with 10 mM ethanol for 6 h. It was undetectable in the absence of ethanol and was reduced in the presence of either the alcohol dehydrogenase inhibitor, 4-methylpyrazole, or the acetaldehyde dehydrogenase inhibitor, cyanamide. Ethanol failed to stimulate generation of chemotactic activity by either rat dermal fibroblasts, hepatic sinusoidal endothelial cells, or Kupffer cells. The chemotactic activity generated by ethanol-treated rat hepatocytes was recovered from culture supernatants in the lipid phase after extraction with chloroform/methanol. Thin-layer chromatography and high performance liquid chromatography of chloroform/methanol extracts demonstrated that the chemotactic factor probably is a polar lipid. This chemotactic lipid may account, in part, for the leukocytic infiltration of the liver parenchyma that is observed during the course of acute alcoholic hepatitis.

Adult↗
PubMed1984

Selective inhibition by phenytoin of chemotactic factor - stimulated neutrophil functions.

We have found that pretreatment of human neutrophils with phenytoin (0.05 to 0.8 mM) results in concentration-dependent, reversible inhibition of both superoxide anion generation and release of lysosomal enzymes (myeloperoxidase, lysozyme, beta-glucuronidase) provoked by either the synthetic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP) or the complement fragment C5a. In contrast, phenytoin did not inhibit either enzyme release or superoxide anion generation by neutrophils stimulated with phorbol myristate acetate or serum-opsonized zymosan particles. Phenytoin did not provoke leakage from neutrophils of the cytoplasmic enzyme, lactate dehydrogenase, and did not inhibit directed migration (chemotaxis) of neutrophils toward either FMLP or C5a. Specific binding of 3H-FMLP to neutrophil membrane receptors was not altered significantly by pretreatment of the cells with a wide range of concentrations of phenytoin. With flow microfluorometry and the fluorochrome, 3,3'-dipentyloxacarbocyanine, phenytoin was shown to prevent FMLP-induced changes in fluorescence intensity (i.e., apparent neutrophil membrane depolarization). These data indicate that various neutrophil functions may be regulated independently at other than the receptor level and that neutrophil chemotactic responses to FMLP and C5a do not appear to be dependent on membrane events registered by 3,3'-dipentyloxacarbocyanine.

Animals↗
PubMed1983

A novel dioxygenation product of arachidonic acid possesses potent chemotactic activity for human polymorphonuclear leukocytes.

We have found that a novel dioxygenation product of arachidonic acid, 8(S),15(S)-dihydroxy-5,11-cis-9,13-trans-eicosatetraenoic acid (8,15-diHETE), possesses chemotactic activity for human polymorphonuclear leukocytes comparable to that of leukotriene B4. Authentic 8,15-diHETE, identified by gas chromatography-mass spectrometry, was prepared by treating arachidonic acid with soybean lipoxygenase and was purified by reverse-phase high performance liquid chromatography. Using a "leading front" assay, 8,15-diHETE exhibited significant chemotactic activity at a concentration of 5.0 ng/ml. Maximum chemotactic activity was observed at a concentration of 30 ng/ml. The 8,15-diHETE generated by mixed human leukocytes after stimulation with arachidonic acid and the calcium ionophore, A23187, exhibited quantitatively similar chemotactic activity. Two synthetic all-trans conjugated isomers of 8,15-diHETE, however, were not chemotactic at concentrations up to 500 ng/ml. In contrast to its potent chemotactic activity, 8,15-diHETE (at concentrations up to 10 micrograms/ml) was relatively inactive with respect to its ability to provoke either degranulation or generation of superoxide anion radicals by cytochalasin B-treated leukocytes. Both leukotriene B4 and 8,15-diHETE may be important mediators of inflammation.

Arachidonic Acid↗
PubMed1983

Radioimmunoelectrophoresis, a sensitive method for detecting cleavage of the fifth component of human complement (C5).

A method has been developed for detecting cleavage of human C5 in serum and whole blood as a consequence of complement activation. Standard, single-dimension immunoelectrophoresis was performed using as antibody a radioiodinated IgG fraction prepared from a commercially available antiserum to human C5. Autoradiographs developed after radioimmunoelectrophoresis of either normal human serum or functionally pure human C5 revealed only one precipitin band. In contrast, when either zymosan-treated serum or trypsin-treated human C5 were examined with this technique, two additional precipitin bands were detected. One migrated more anodally than native C5 while the other remained at the origin (cathode). Radioimmunoelectrophoresis was significantly more sensitive as an indicator of complement activation in human serum than either measurements of total hemolytic complement or a standard assay for complement (C5)-derived chemotactic activity.

Complement Activation↗
PubMed1983

Infections and hypocomplementemia.

The complement system, phagocytic leukocytes, and antibodies constitute the "department of defense" in the battle against infections caused by pyogenic microorganisms. Complement components are capable of directly killing (by lysis) certain susceptible bacteria and are the source of chemotactic peptides and heat-labile opsonin, which facilitate recognition and killing of microbes by phagocytic cells. When these vital functions are compromised, as in individuals with inherited deficiencies of complement components, the result is unusual susceptibility to severe infections.

Complement Activation↗
PubMed1983

Antiinflammatory effects of endotoxin. Inhibition of rabbit polymorphonuclear leukocyte responses to complement (C5)-derived peptides in vivo and in vitro.

Although capable of provoking a variety of inflammatory effects, endotoxin (bacterial lipopolysaccharide) paradoxically has been reported to be antiinflammatory. The authors have found that single intravenous injections of Escherichia coli endotoxin, 24 hours before challenge, inhibit almost completely the vascular permeability changes and exudation of polymorphonuclear leukocytes induced in rabbit skin by reversed passive Arthus reactions. Whereas intravenous injections of endotoxin also caused modest inhibition of the vascular permeability changes induced in rabbit skin by the synthetic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), exudation of polymorphonuclear leukocytes was unaffected. Polymorphonuclear leukocytes from rabbits given single injected doses of endotoxin exhibited markedly diminished chemotactic and degranulation responses to complement (C5)-derived peptides in vitro. Responses of these cells to FMLP, however, were normal. These data suggest that selective suppression of polymorphonuclear leukocyte responses to C5-derived peptides accounts, in part, for the antiinflammatory effects of endotoxin.

Animals↗
PubMed1983

Generation of biologically active, complement-(C5) derived peptides by cathepsin H.

The thiol proteinase cathepsin H, isolated and purified from rat liver lysosomes, provokes acute inflammation characterized by the accumulation of polymorphonuclear leukocytes (PMN) when injected intracutaneously into newborn rats. We have examined the possibility that the accumulation of PMN at skin sites injected with cathepsin H is due, in part, to generation locally of C-derived chemotactic factors. We have found that cathepsin H acts in a concentration- and time-dependent fashion in whole human (and rat) EDTA-plasma to generate C5-derived peptides with chemotactic activity for PMN. Chemotactic activity was not generated in EDTA-plasma by either heat-inactivated cathepsin H or by a combination of active enzyme and a thiol proteinase inhibitor isolated from rat epidermis. Cathepsin H also acted in a concentration- and time-dependent fashion on isolated (functionally pure) human C5 to yield chemotactic activity for PMN as well as PMN lysosomal enzyme-releasing activity. Whereas 10 ng/ml cathepsin H generated significant chemotactic activity from isolated C5 (1000 CH50 U/ml), 7 to 10 micrograms/ml were required to generate chemotactic activity in whole EDTA-plasma. Cathepsin H not only was capable of generating biologically active, C5-derived peptides, but also was capable of degrading these peptides. Incubation of either whole EDTA-plasma or isolated C5 with high concentrations of cathepsin H (e.g., 25 micrograms/ml and 100 ng/ml, respectively) caused the rapid appearance of chemotactic activity followed by an equally rapid disappearance. PMN accumulated more rapidly in the skin of newborn rats injected with cathepsin H-treated C5 than in the skin of animals injected with cathepsin H alone. These data suggest that generation by cathepsin H of C-derived chemotactic activity contributes to the ability of this enzyme to induce dermal inflammation.

Animals↗
PubMed1983

Status Asthmaticus: use of acetylcysteine during bronchoscopy and lavage to remove mucous plugs.

Three patients suffering from severe, chronic, bronchial asthma underwent bronchoscopy and lavage, using in the irrigant fluid acetylcysteine, isoetharine and Solu-Medrol. All patients had a large amount of thick mucus in the tracheobronchial tree which was removed during the lavage. Following the lavage, all three patients were easily treated with conventional allergic measures and were able to lead normal lives, which they could not do before. A discussion of the precautions to be taken by the medical-surgical team in charge of a patient undergoing bronchoscopy and lavage is made. These conclusions were based on the results of two previous reports by the authors in addition to the present communication.

Acetylcysteine↗
PubMed1983

Complement (C5)-derived chemotactic activity in serum from patients with pancreatitis.

Samples of serum and plasma obtained from eight patients with acute pancreatitis were examined for the presence of complement-derived chemotactic activity for human PMN. Significant chemotactic activity was found in acute phase serum and plasma samples from five patients. The presence of chemotactic activity was associated with reduced levels of CH50 as well as degradation products of C5 (detected by a new method, i.e., radioimmunoelectrophoresis). The chemotactic activity was heat-stable (56 degrees C for 30 min), inhibitable by treatment with antibodies to human C5, and exhibited an apparent molecular weight of 16,000 (determined by chromatography on Sephadex G-75). These properties are identical with those of chemotactic C5-derived peptides (C5a and/or C5a des Arg). Recently, C5-derived peptides have been implicated as being mediators of acute lung injury (i.e., "shock lung") in some clinical situations. It is intriguing to speculate, therefore, that circulating C5-derived chemotactic peptides may play a role in the pathogenesis of the lung injury observed in some patients during the course of acute pancreatitis.

Chemotaxis, Leukocyte↗
PubMed1982

Ceruloplasmin: an acute phase reactant that scavenges oxygen-derived free radicals.

Superoxide anion radicals have been implicated recently as mediators of inflammation and tissue injury. Protection from superoxide anion radicals is provided primarily by a copper-containing, intracellular enzyme (superoxide dismutase) (SOD) that catalyzes the dismutation of superoxide to hydrogen peroxide and oxygen. We have found that the action of cytoplasmic SOD to scavenge superoxide and thereby to inhibit superoxide-mediated reactions can be mimicked by the copper-containing plasma protein and acute-phase reactant, ceruloplasmin. Ceruloplasmin, at concentrations present in normal plasma, inhibited reduction of both cytochrome c and nitroblue tetrazolium (NBT) mediated by the aerobic action of xanthine oxidase on hypoxanthine (a superoxide-generating system). Ceruloplasmin neither inhibited formation of uric acid by xanthine oxidase nor accelerated autooxidation of cytochrome c. Furthermore, in an experimental system in which contact between ceruloplasmin and indicator was prevented by a relatively impermeable lipid membrane barrier, ceruloplasmin inhibited reduction of NBT trapped within liposomes exposed to xanthine oxidase and hypoxanthine. Ceruloplasmin also inhibited reduction of cytochrome c and NBT mediated by the aerobic action of xanthine oxidase on acetaldehyde (another superoxide-generating system) and mimicked the activity of purified human erythrocyte SOD by inhibiting photoreduction of NBT and by accelerating aerobic photooxidation of dianisidine. Ceruloplasmin could be separated from purified human erythrocyte SOD by electrophoresis on alkaline 12% polyacrylamide gels and identified by its superoxide-scavenging activity. These results suggest that ceruloplasmin may function as a circulating scavenger of oxygen-derived free radicals.

Acute Disease↗
PubMed1982

Wheat germ agglutinin specifically inhibits formyl peptide-induced polymorphonuclear leukocyte chemotaxis.

Evidence that surface membrane glycoproteins of polymorphonuclear leukocytes (PMN) are involved in stimulus-response coupling prompted us to examine effects on these cells of various plant lectins. We have found that wheat germ agglutinin (WGA) (1.0 microgram/ml) completely, specifically, and irreversibly inhibits directed migration (chemotaxis) of human PMN toward the synthetic peptide, N-formylmethionyl-leucyl-phenylalanine (FMLP) (0.1 to 100 nM). This effect of WGA was not shared by subagglutinating concentrations of either concanavalin A or Bandeirea simplicifolia lectin. In contrast to its effects on FMLP-induced chemotaxis, WGA did not influence other FMLP-induced PMN responses (i.e., selective discharge of lysosomal enzymes from cytochalasin B-treated cells, generation of superoxide anion radical(s). WGA also did not influence PMN chemotactic responses to either the complement-derived peptide, C5a, or the lipoxygenase product, leukotriene B4. Inhibition of FMLP-induced chemotaxis by WGA was not reversed by washing WGA-treated cells, but was reversed (and prevented) by N-acetyl-D-glucosamine (not by N-acetyl-D-galactosamine or mannosamine). WGA did not affect either orientation or stimulated random motility of PMN, and did not interfere with specific binding to PMN of (3H)-FMLP. A derivative of WGA with 10-fold less agglutinating activity for human erythrocytes was prepared by treating the native lectin with cyanogen bromide and formic acid. The derivative also inhibited FMLP-induced PMN chemotaxis specifically and selectively. These data suggest that WGA specifically inhibits FMLP-induced PMN chemotaxis by attaching to N-acetyl-D-glucosamine residues at a locus on the PMN plasma membrane that is distinct from the binding site of the FMLP receptor.

Chemotaxis, Leukocyte↗
PubMed1982

Complement activation by nylon- and polypropylene-looped prosthetic intraocular lenses.

Uncomplicated placement of an intraocular lens at the time of routine cataract extraction is associated with a greater inflammatory response than simple lens extraction. We have shown that certain components of prosthetic intraocular lenses are capable of activating the complement system in human serum in such a fashion as to generate peptides capable of mediating acute inflammatory reactions. Normal human serum was incubated with intraocular lenses in vitro and then examined for cleavage products of C3 and C5 and for C5-derived chemotactic activity for human polymorphonuclear leukocytes. Polymethylmethacrylate lenses with nylon and polypropylene loops were found to be capable of causing cleavage of C3 (detected by crossed immunoelectrophoresis) and C5 (detected by single-dimension radioimmunoelectrophoresis) as well as generation of C5-derived chemotactic activity in human serum. Serum incubated with polymethylmethacrylate lenses without loop supports exhibited no such activity. Results of our studies indicate that certain nylon- and polypropylene-looped intraocular lenses are not "inert" biologically and may elicit acute inflammatory reactions.

Autoradiography↗