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Biomedical subjects

H S Jacob

Publications and source records attributed to H S Jacob.

At least 109 records · Page 6Linked to original sources
PubMed1982

Therapeutic ramifications of the interaction of complement, granulocytes, and platelets in the production of acute lung injury.

Evidence is reviewed that activation of complement through its ability to cause adhesion of granulocytes to the pulmonary endothelium (margination) and aggregation and embolization of these cells to the lung microvasculature is an important cause of pulmonary injury. Agents capable of diminishing such stimulated adhesiveness might be rational therapeutic adjuncts in vascular-damaging syndromes and are being investigated. To date, corticosteroids, such as methylprednisolone (in enormous doses), and certain nonsteroidal anti-inflammatory drugs, such as ibuprofen, have been shown to diminish granulocyte stickiness in vitro and diminish complement-mediated tissue damage in vivo. Moreover, platelets amplify complement/granulocyte-induced endothelial damage by releasing serotonin, which, in turn, potentiates granulocyte adhesion to endothelium. This potentiation is abrogated by the serotonin antagonists imiprimine and methysergide. Since these diverse agents inhibit granulocyte-adhesion phenomena by different mechanisms, they might predictably be synergistic in their beneficial effect. This prediction is validated for methylprednisolone and ibuprofen, for which we report a threefold synergism in preventing complement-mediated granulocyte aggregation in vitro. Preliminary studies indicate utility of this synergism in vivo as well, in that the degree of myocardial infarction [a complement-activating phenomenon) is diminished in coronary-ligated animals in which rather small doses of the two drugs administered together.

Adrenal Cortex Hormones↗
PubMed1982

Lysozyme stimulates lymphocyte proliferation in monocyte-depleted mixed lymphocyte cultures.

Human LZM was found to enhance 3H-thy uptake and lymphoblast transformation in monocyte-depleted MLC. The effect was maximal (up to sixfold increase) in "low level" (less than 10,000 cpm) MLC. Maximal MLC enhancement was obtained with 250 micrograms/ml LZM; higher LZM concentrations appeared to be inhibitory. LZM enhancement of MLC could not be demonstrated in the presence of monocytes. LZM did not enhance lymphocyte responses to SKSD. Several observations support the possibility that LZM enhancement of MLC is due to LZM augmentation of stimulator cell antigenicity. LZM pretreatment of stimulator but not responder lymphocytes enhanced MLC. This enhancement was blocked by the LZM inhibitor tri-GlcNAc. LZM enhancement of MLC was maximum when the antigenic stimulus was minimized by either reducing the number of stimulator cells or utilizing DRw-matched donors in MLC. These data suggest that (1) LZM may enhance lymphocyte proliferative responses to allogeneic stimuli by altering stimulator cells' antigenicity and (2) monocyte-macrophage enhancement of lymphocyte proliferation in MLC may be partially mediated by LZM. (J Lab Clin Med 99:370, 1982.)

B-Lymphocytes↗
PubMed1982

Tissue damage caused by activated complement and granulocytes in shock lung, post perfusion lung, and after amniotic fluid embolism: ramifications for therapy.

The complement system evolved as a beneficial antimicrobial system. However when activated during extracorporeal perfusion, as with hemodialysis or cardiopulmonary bypass, modest pulmonary dysfunction associated with granulocyte aggregation and embolization can occur. When complement activation is more massive and prolonged as with severe sepsis, trauma and acute pancreatitis or during infusions of amniotic fluid or other lipid-rich suspensions, severe pulmonary damage which we often recognize as shock lung may occur. Therapeutic ramifications of these conclusions are evident. Thus, high doses of corticosteroids (or of non-steroidal anti-inflammatory agents, such as ibuprofen--herein not discussed) have the ability to prevent aggregation and embolization of stimulated granulocytes to patent vessels downstream and also inhibit their production of toxic oxygen radicals. These beneficial properties suggest the use of these agents may be appropriate in shock states, particularly shock lung or during suspected amniotic fluid infusion. Appropriate clinical trials to substantiate this suggestion are awaited with interest.

Adrenal Cortex Hormones↗
PubMed1982

Protein A adsorption of acute myelogenous leukemia serum induces in vitro blast lysis.

We studied cytotoxic activity of acute myelogenous leukemia (AML) sera for AML blasts before and after immunoadsorption with Staphylococcus aureus, Cowan I (SAC), which contains protein A. We found in vitro that incubation with treated AML sera reduced viability to 42.7% of control (p less than 0.01) for autologous and 21.0% of control (p less than 0.01) for allogeneic blasts. Normal peripheral blood cells were not killed by treated AML sera. Wood 46 strain of Staphylococcus aureus, which does not contain protein A, did not significantly reduce AML blast viability (94.8%, p greater than 0.4), while Sepharose-bound protein A reduced viability to 63.8% (p less than 0.01). Cytotoxicity does not appear to be complement-mediated, byt cytotoxic activity is trypsin-sensitive and is contained in the immunoglobulin fraction. This model for study of the tumoricidal action of protein A adsorption should be useful for predicting utility of plasma adsorption as a therapeutic adjunct in the future.

Cytotoxicity, Immunologic↗
PubMed1982

Activation of plasma complement by perfluorocarbon artificial blood: probable mechanism of adverse pulmonary reactions in treated patients and rationale for corticosteroids prophylaxis.

Perfluorocarbons have shown promise as clinical blood substitutes. Although early experience in Japan with one such product--Fluosol-DA--has been uncomplicated, we observed an adverse pulmonary reaction in the first American patient to receive it and know of similar reactions in two other Americans so treated. Postulating that activation of plasma complement (C) by the perfluorocarbon emulsion might have caused the reaction, we tested the product to determine if it is an activator of complement. Incubation of Fluosol with plasma led to C3 conversion, decrement in CH50, and generation of C5a-related PMN aggregating activity; EDTA prevented such activation, while EGTA did not, suggesting that it proceeded via the alternative C pathway. Infusion of Fluosol into rabbits produced hypoxemia, neutropenia, thrombocytopenia, and pulmonary leukostasis, mimicking abnormalities previously demonstrated in rabbits receiving infusions of zymosan-activated plasma C. These deleterious responses to Fluosol were diminished by premedicating rabbits with corticosteroids (which had seemed to benefit when used empirically in our patient). In vitro and in vivo, Fluosol's effects were reproduced by Pluronic F-68, the nonionic detergent used to maintain the emulsion stability of Fluosol-DA. We conclude that adverse reactions to Fluosol are probably mediated by C activation and that steroid premedication may prevent them in susceptible patients.

Adrenal Cortex Hormones↗
PubMed1982

Fibronectin enhances in vitro monocyte-macrophage-mediated tumoricidal activity.

Control of neoplastic proliferation reflects in part monocyte/macrophage destruction of target cells--destruction that evidently requires cell-cell interaction. We herein show it to involve the natural plasma opsonin, fibronectin. With two cultured human tumor lines--Malme melanoma and CAK-I renal carcinoma cells--addition of fibronectin, purified to homogeneity, enhances macrophage-mediated cytotoxicity 2--4-fold (p less than 0.01). Both fresh human monocytes or the U-937-cultured macrophage line become more lethal to tumor cells with added fibronectin. The fibronectin-enhanced monocyte and U-937 tumoricidal activity occurred in a dose-dependent fashion. Specificity of fibronectin's action was validated by use of affinity-purified rabbit antifibronectin antibody, which completely abated its enhancement of tumoricidal activity. Enhancement of tumoricidal activity did not occur when monocytes or U-937 were exposed to fibronectin-coated plates. However, the addition of soluble fibronectin to fibronectin-coated plates was then capable of enhancing cytocidal activity. These studies demonstrate that human fibronectin is capable of increasing both fresh and cultured human monocyte tumor-directed cytotoxicity. Fibronectin appears to be a potentially important circulating molecule that may favorably influence human monocyte tumor cell cytotoxicity.

Cell Communication↗
PubMed1982

Glycogenolysis versus glucose transport in human granulocytes: differential activation in phagocytosis and chemotaxis.

Granulocytes depend primarily on anaerobic glycolysis to supply the necessary energy for locomotion and chemotaxis. Either transmembrane transport of extracellular glucose or catabolism of intracellular glucose can supply glycolytic substrate. In this report, using enzymatic analysis of granulocyte glycogen, we describe conditional requirements for glycogenolysis, namely phagocytosis. With abundant extracellular glucose, granulocyte glycogen content (12.2 +/- 1.6 micrograms/10(6) cells) is not depleted whether or not incubations include various soluble chemotaxins (e.g., FMLP, C5ades arg, arachidonic acid). These chemotaxins accelerate transmembrane glucose uptake. With near complete absence (less than 6 mg/dl) of extracellular glucose, both resting and chemotaxin (FMLP, C5ades arg, arachidonic acid) stimulated granulocytes catabolize significant endogenous glycogen. Phagocytosis, however, fails to enhance glucose uptake and promotes glycogen consumption even with abundant extracellular glucose. Simple particle-phagocyte attachment without internalization (produced by cytochalasin-B) also promoted glycogen consumption, suggesting that this membrane deformation alone is a sufficient trigger for glycogenolysis. Resting or chemotactic granulocytes, therefore, can adapt their energy source pending extracellular glucose availability--often compromised at inflammatory sites-while phagocytic cells depend primarily, if not exclusively, on endogenous glycogen stores. This differential metabolic activation defends the granulocytes energy supply and may be critical in supporting antimicrobial activity in acute inflammation.

Arachidonic Acids↗
PubMed1982

Leukoembolization in ocular vascular occlusion.

The occurrence of complement-induced white blood cell aggregation and embolization has previously been little suspected. This may be a mechanism which underlies certain occlusive vascular diseases. It is possible that the fundus picture which has been described as Purtscher's Retinopathy following severe trauma and acute pancreatitis may be explained by this mechanism. A further case of Purtscher's type Retinopathy associated with acute pancreatitis is reported.

Acute Disease↗
PubMed1982

Tumor-induced eosinophilia and endocardial fibrosis: evidence for ectopic eosinophilopoietin production and toxic O2 metabolite-mediated endothelial damage.

We have described a patient with the clinical triad of anaplastic pulmonary carcinoma, extreme eosinophilia, and endocardial damage, with resulting fibrosis and mural "thrombosis." Since the "thrombi" consisted mainly of masses of aggregated eosinophils in close approximation to areas of fibrotic cardiac endothelium, it was hypothesized that eosinophils might provoke endothelial damage. Indeed, eosinophils generated large amounts of toxic oxygen species and were highly toxic to cultured endothelial cells in vitro; moreover, high concentrations of corticosteroids inhibited in tandem these phenomena. In addition, from the patient's tumor a 45,000-dalton "eosinophilopoietin" was extracted which stimulated eosinophil colonies without help from T-lymphocytes. We believe our results help explain both the hypereosinophilia which accompanies certain anaplastic carcinomas and the endocardial damage with thrombosis and embolization which may occur in any patient with excessive eosinophils. In this latter regard, our studies suggest that very high doses of corticosteroids--since they decrease generation of toxic oxygen products by, and the numbers of, eosinophils--may be rational therapy in hypereosinophilic syndromes.

Aged↗
PubMed1981

Deleterious effects of endotoxin on cultured endothelial cells: an in vitro model of vascular injury.

The effects of endotoxin-triggered granulocytes on the viability of endothelial cells in vitro was investigated. Endotoxin or its lipid A component caused granulocytes to adhere to and significantly damage cultured endothelial cells. Fresh serum is not necessary but does amplify both adherence and endothelial injury. Much of the endothelial injury was inhibited by free-radical scavengers or by blocking granulocyte adhesion to endothelial cells and appears to result from free radical production by the stimulated granulocyte. Studies in this model suggest a pathogenic role for the endotoxin-triggered granulocyte in the Shwartzman reaction and perhaps related clinical disorders.

Bacterial Toxins↗
PubMed1981

Cholesterol and atheroma lipids activate complement and stimulate granulocytes. A possible mechanism for amplification of ischemic injury in atherosclerotic states.

Previous studies in experimental myocardial infarction have suggested that PMNs and plasma C might interact to intensify ischemic injury. From the finding of large amounts of activated C (specifically C5a) in the plasma of a patient with severe, ulcerating atherosclerosis and the cholesterol embolization syndrome, we postulated that crystalline cholesterol might activate C and thereby amplify infarctive tissue damage. On simple incubation, crystalline cholesterol--as well as lipids from atheromata--activated plasma C; such plasma then potently aggregated normal PMNs and provoked them to damage cultured endothelial cells in vitro. The active principle in cholesterol-incubated plasma was of molecular weight and antigenicity consistent with C5a (or C5a[desarginine]). Optimal activation required the presence of Ig and an intact classical C pathway. Exposure of plasma to crystalline cholesterol by ulceration of, or hemorrhage into, atherosclerotic plaques might therefore activate C in vivo, promoting further ischemic damage by causing leukostatic-leukoembolic compromise of small vessels downstream from the site of activation.

Arteriosclerosis↗
PubMed1981

Abnormal erythrocyte calcium homeostasis in oxidant-induced hemolytic disease.

The processes leading to red cell destruction in oxidant-induced hemolytic disease are not yet fully known. Oxidant damage to hemoglobin per se may be insufficient to explain the process, and the involvement of membrane damage has been suggested. We now report that at least one crucial membrane function-exclusion of calcium-is disrupted by the potent oxidant phenylhydrazine. Phenylhydrazine, both in vitro and when administered to mice in hemolytic doses, causes profound inhibition of red cell calcium ATPase. Coincident with this, red cell calcium content increases very rapidly in mice given phenylhydrazine. These observations suggest that disordered red cell calcium homeostasis may be an important element in oxidant-induced red cell destruction.

Adenosine Triphosphatases↗
PubMed1981

Complement activation and neutropenia occurring during cardiopulmonary bypass.

Complement activation and pulmonary leukostasis with neutropenia occur in hemodialysis and filtration leukapheresis, with attendant pulmonary dysfunction. Wondering whether similar phenomena might attend cardiopulmonary bypass (CPB), we studied 34 patients undergoing coronary artery bypass operations. As in the other extracorporeal circulation systems, neutropenia (mean 44.7% +/- 4.3% SEM of prebypass PMN count) occurred during the first half hour of bypass and then a rebound neutrophilia followed. CH50 and C3H50 fell 22% to 25% (p for CH50 less than 0.01) during bypass, but C3 conversion and C5a were not demonstrable in patient plasmas. Nonetheless, polymorphonuclear neutrophils (PMNs) harvested late in bypass showed low adherence to nylon and selective chemotactic and aggregative insensitivity to C5a--functional aberrations which are seen after exposure to activated complement. Furthermore, smaller infusions of activated complement into animals produced neutropenia than were required to achieve a detectable [C5a] in the plasma. We conclude that neutropenia during CPB probably results from complement activation below the threshold of detection; complement-stimulated PMNs deserve study as possible mediators of tissue injury occurring during CPB.

Agranulocytosis↗
PubMed1981

Lysozyme enhances monocyte-mediated tumoricidal activity: a potential amplifying mechanism of tumor killing.

The mononuclear phagocyte is well established as an in vitro cytotoxic effector cell for certain human tumors. The mechanism(s) for this action remains unclear. Increased levels of lysozyme, a cationic enzyme synthesized in large amounts by mononuclear phagocytes, are associated with increased resistance to transplantable animal tumors. In this study, we provide evidence that human lysozyme, isolated from the urine of leukemic patients, has marked potentiating effects on human monocyte-tumor-cell cytocidal activity. In addition, lysozyme-exposed monocytes incorporate increased quantities of leucine, suggesting that monocytes are capable of amplifying their own metabolic activation by secreting an endogenous constituent. Tri-N-acetyl-glucosamine, a competitive inhibitor for the active site of lysozyme, inhibits cytocidal activity. Conversely, protamine, an extraneous albeit similarly positively charged molecule, increases monocyte-mediated tumor cytotoxicity; this protamine effect is negated by heparin. We conclude that lysozyme, at least partially by its positive charge, is capable of enhancing in vitro monocyte tumor cell cytotoxicity; its in vivo secretion may potentiate monocyte-tumor-cell interaction.

Acetylglucosamine↗