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Biomedical subjects

H S Jacob

Publications and source records attributed to H S Jacob.

At least 19 recordsLinked to original sources
PubMed1992

Prothrombotic phenotype diversity of human aortic endothelial cells in culture.

We have previously demonstrated that human aortic endothelium exhibits morphologic heterogeneity in situ, and this heterogeneity can be reproduced in culture. In this study, we have compared prothrombotic properties of cultured endothelial cells (EC) from areas of human aorta at high risk for atherosclerosis (HP-EC) with EC from areas at low risk (LP-EC). Using paired cultures from the same donors, we have found that the expression of cell surface thrombomodulin (TM)--as measured by the ability to generate activated protein C (APC) from protein C in the presence of thrombin--is relatively reduced on HP-EC compared to LP-EC (respectively, 4.98 +/- 4.43 vs. 5.83 +/- 4.37 pM APC/min/cm2; p = .03, n = 12). Furthermore, HP-EC more efficiently assemble the prothrombinase complex on their cellular surface, resulting in an increased rate of thrombin generation from prothrombin (9.81 +/- 3.10 (HP-EC) vs. 7.96 +/- 3.20 nM thrombin/min/cm2 (LP-EC); p less than .03, n = 7). The combination of reduced TM expression and increased prothrombinase complex assembly on HP-EC suggests a prothrombotic phenotype in these cells. These findings may be important in the pathogenesis of thrombosis associated with atherosclerotic plaques.

Aorta↗
PubMed1992

Endothelial cell heme oxygenase and ferritin induction by heme proteins: a possible mechanism limiting shock damage.

Acutely, hemin sensitizes endothelial cells to oxidants but chronically protects the endothelium through the induction of ferritin. By releasing its heme, methemoglobin can sensitize endothelial cells in a fashion similar to free hemin. Furthermore, prolonged incubation with the endothelium allows methemoglobin to induce heme oxygenase and ferritin and concomitantly to modulate oxidant-mediated cytotoxicity. Methemoglobin but not hemoglobin, metmyoglobin or cytochrome c induces heme oxygenase and ferritin. Heme needs to be released from methemoglobin, since sodium cyanide, haptoglobin, and hemopexin inhibit the induction of these proteins. Neutrophils can oxidize hemoglobin to methemoglobin, which can subsequently induce both heme oxygenase and ferritin. We speculate that in shock with disseminated intravascular coagulation, marginated PMNs oxidize hemoglobin to heme-releasing methemoglobin. If critical defenses such as haptoglobin and hemopexin are overwhelmed, heme enters the endothelin cells, sensitizing them to oxidant damage. Endothelial cell adaptation via heme-induced heme oxygenase and ferritin production might limit ultimate progression to pulmonary and other vascular leak syndromes.

Animals↗
PubMed1992

Herpes virus infection of endothelium: new insights into atherosclerosis.

Several pieces of evidence suggest that vascular endothelium may be a site of latent herpetic viral infection, and that activation of such infection might cause or aggravate atherosclerosis. The present studies which utilized HSV-1 infection of cultured endothelial monolayers, provide insights into two phenomena seemingly relevant in considerations of atherosclerosis. Thus, mechanisms are reported by which infected endothelium may be damaged by marginated inflammatory cells, and be transformed from an anticoagulant to a procoagulant tissue. First, granulocytes are attracted to, and avidly bind, endothelium infected for very brief periods. This interaction is associated with denudation of intact cells as well as actual cytolysis through release of PMN proteases and toxic oxygen species. Second, several potentially additive abnormalities of HSV-infected endothelium would seem to foster coagulation. These include: a) its loss of surface heparans and thrombomodulin; b) its inability to synthesize prostacyclin with associated incapacity to deter platelet adhesion; c) its disordered membrane lipid conformation which is likely associated with excessive surface thrombin generation; and d) its unique ability to generate and release tissue factor. We speculate that mechanical abrasion may reactivate latent herpes (HSV or CMV) infection in endothelial cells particularly those exposed to high shear forces--for instance, at vessel bifurcations. This may underlie the endothelial damage, clotting and atheroma formation commonly found at these sites.

Animals↗
PubMed1979

Corticosteroids inhibit complement-induced granulocyte aggregation. A possible mechanism for their efficacy in shock states.

Granulocyte (PMN) aggregation and embolization may underlie complement (C)-mediated organ dysfunction in such syndromes as hemodialysis neutropenia and Purtscher's ischem;c retinopathy. Because of clinical and pathologic parallels, we have further suggested a role for this phenomenon in the genesis of the adult respiratory distress syndrome (ARDS). Because corticosteroids are commonly used in immune diseases, and have particularly been claimed efficacious in shock and ARDS, we tested the capability of methylprednisolone (MP), hydrocortisone (HC), and dexamethasone (DEX) to inhibit PMN aggregation. Aggregation engendered in vitro by zymosan-activated plasma (ZAP) was inhibited by MP and HC at concentrations approximating plasma levels achieved with the large bolus (30 mg/kg i.v) therapy advocated in shock states; DEX was almost without effect. Using intravital fluorescence microscopy, we observed PMN aggregation and embolization in the mesenteric vessels of rats given intra-arterial infusions of ZAP; this was also prevented by pretreatment with 30 mg/kg MP. Steroid inhibition of aggregation seemed not to involve disruption of receptor function, because aggregation induced by alternative agents, n-formyl-Met-Leu-Phe and the ionophore A23187, was also inhibited by MP. Moreover, corticosteroid inhibition of PMN prostaglandin synthesis is also an unlikely explanation for our results, since aspirin and ibuprofen failed to block aggregation and arachidonic acid neither effected aggregation itself nor ameliorated the steroid effect. Our studies provide a plausible rationale for the empiric observation that high-dose corticosteroids may benefit patients with syndromes associated with microvascular leukostasis.

Cell Aggregation↗
PubMed1979

Modulation of neutrophil function by lysozyme. Potential negative feedback system of inflammation.

Host responses to infectious organisms should be modulated so that tissue-damaging products of inflammatory cells do not produce excessive destruction of normal tissue. Lysozyme, which is continuously secreted by monocytes, which, in turn, migrate relatively late to inflammatory areas, was found to significantly dampen several responses of neutrophils to inflammatory stimulants. Thus, human lysozyme obtained and purified from the urine of patients with monocytic leukemia (but not its structurally similar and comparably cationic analogue, eggwhite lysozyme) depresses chemotaxis of normal neutrophils to activated complement, bacterial supernate, and N-formylmethionyl-phenylalanine. In addition, human (but not eggwhite) lysozyme depresses oxidative metabolism (hexose monophosphate shunt activity) and superoxide generation of neutrophils. The specificity of the suppressive effects was indicated by inhibition studies with rabbit antihuman lysozyme antibody, and with the trisaccharide of N-acetylglucosamine, a specific inhibitor of lysozyme. The results suggest that lysozyme, a product of inflammatory cells themselves, may function in a negative feedback system to modulate the inflammatory response.

Cell Migration Inhibition↗
PubMed1979

Granulocyte aggregation as a manifestation of membrane interactions with complement: possible role in leukocyte margination, microvascular occlusion, and endothelial damage.

Activation products of the terminal complement cascade potently affect granulocyte function, inducing, for example, their migration toward (chemotaxis), and adherence to (opsonization), microbes, and stimulating their production of microbicidal oxygen radicals such as superoxide anion, and the like. We present studies that demonstrate that a C5-derived peptide, probably C5a, is a potent promoter of granulocyte and monocyte adhesion to endothelium (margination) and, in addition, causes granulocyte autoaggregation in vitro and in vivo. Although possibly beneficial by producing phagocyte clumps to mechanically entrap unwanted microbes, such aggregates may be deleterious, particularly if sustained, especially in the lung.

Animals↗
PubMed1978

Extreme but asymptomatic carboxyhemoglobinemia and chronic lung disease.

Carboxyhemoglobinemia is a well-known consequence of carbon monoxide exposure from smoking. However, only moderately elevated levels have been reported. We report the case of an asymptomatic man with severe chronic obstructive lung disease and carboxyhemoglobin levels repeatedly in excess of 30% (maximum, 38.0%) due to smoking. The mechanism by which such high levels were attained was primrily a combination of arterial hypoxia and a high carbon monoxide yield from tobacco. For a given level of carbon monoxide exposure, the hypoxic person will attain a higher carboxyhemoglobin level than will a person without hypoxia.

Aged↗
PubMed1978

Plasma exchange in the treatment of fulminant idiopathic (autoimmune) thrombocytopenic purpura.

Rapid plasma exchange in a young man with idiopathic (autoimmune) thrombocytopenic purpura and life-threatening haemorrhage acutely increased the platelet-count and enhanced haemostasis. The patient had not responded to steroids, and massive intra-abdominal bleeding had developed after splenectomy, despite numerous platelet transfusions. After plasma exchange, his haemoglobin concentration became normal without further transfusion and his abdominal girth decreased. Therefore emergency reoperation because of intra-abdominal bleeding was no longer required. A cumulative-sums plot of his platelet-count confirmed that plasmapheresis on 2 occasions was followed by a pronounced rise in mean platelet-count. Neither prednisone nor vincristine therapy altered the slope of the plot. The high initial anti-platelet antibody concentration in this patient fell after plasma exchange. These findings indicate that plasmapheresis accelerated clearance of circulating anti-platelet factors in fulminant idiopathic thrombocytopenic purpura.

Adult↗
PubMed1978

Folate-induced remission in aplastic anemia with familial defect of cellular folate uptake.

Severe aplastic anemia developed in a young man with an extensive family history of leukemia, pancytopenia, and neutropenia. Megaloblastic changes became evident, and treatment with high doses of folic acid resulted in striking clinical improvement. However, red-cell folate levels remained persistently low despite high serum folate levels. A defect in cellular folate uptake was suspected, and, indeed, uptake of 5-14CH3-H4-folate by stimulated lymphocytes and by bone-marrow cells from the patient was significantly reduced (P less than 0.05 as compared to normal cells. Further characterization of folate metabolism showed that intestinal absorption of the vitamin, membrane transport of 5-14CH3-H4-folate by mature red cells, folate utilization in the conversion of deoxyuridylate to thymidylate and polyglutamate formation were all normal. At least five other family members manifest decreased uptake of 5-14CH3-H4-folate by stimulated lymphocytes. These studies suggest that a genetically induced abnormality of folate uptake contributed to this patient's severe, but reversible, aplasia.

Adult↗
PubMed1978

Calcium-induced damage of haemoglobin SS and normal erythrocytes.

An ionophore specific for divalent cations has been used to load normal erythrocytes and erythrocytes from patients with sickle cell anaemia (Hb SS disease), with small amounts of calcium. Such calcium accumulation leads to decreased cellular water, potassium, adenosine triphosphate (ATP), and osmotic fragility, all characteristics of irreversibly sickled cells (ISCs). In addition, calcium loading of Hb SS, but not normal, erythrocytes causes a marked decrease of haemoglobin oxygen affinity; another, and specific, hallmark of ISCs. Ionophore-induced accumulation of calcium by deoxygenated Hb SS erythrocytes also leads to temporary retention of sickled shape following reoxygenation, despite the absence of detectable intracellular haemoglobin S fibres. All these effects require calcium in the incubation medium and support the idea that increased intracellular calcium is important in the formation of ISCs in patients with Hb SS disease.

Anemia, Sickle Cell↗
PubMed1978

Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage.

During hemodialysis, alternative pathway complement activation leads to pulmonary sequestration of granulocytes, with loss of pulmonary vascular endothelial integrity and, at times, protein-rich pulmonary edema. An in vitro model of this phenomenon was constructed utilizing 51Cr-labeled human umbilical vein endothelial cell cultures. In this system, granulocytes, when exposed to activated complement (C), induce endothelial damage; this injury is mediated primarily by oxygen radicals produced by the granulocytes. C5a appears to be the C component responsible for granulocyte-induced cytotoxicity; studies with cytochalasin B-treated granulocytes suggest that close approximation of the granulocytes and endothelial cells is necessary for maximal cell injury.

Blood Vessels↗
PubMed1978

The mechanism of 5-methyltetrahydrofolate transport by human erythrocytes.

The mechanism involved in 5-methyltetrahydrofolate uptake by human cells is poorly understood. To more clearly elucidate this physiologically important process, transport of the vitamin was studied in human erythrocytes. 5-methyltetrahydrofolate uptake was found to increase with reticulocytosis, but measurable incorporation occurred in erythrocyte suspensions depleted of reticulocytes, leukocytes, and platelets, indicating uptake by mature erythrocytes. Incubation of erythrocytes with increasing concentrations of [(14)C]5-methyltetrahydrofolate resulted in increasing uptake but decreasing percentage incorporation, consistent with saturation of a carrier system. Both influx and efflux phases of uptake were temperature dependent, with almost no transport at 4 degrees C. Uptake of [(14)C]5-methytetrahydrofolate was effectively inhibited by unlabeled 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and methotrexate, but not by pteroylglutamic acid. Prior incubation with 5-formyltetrahydrofolate increased uptake of [(14)C]5-methyltetrahydrofolate, and extracellular 5-formyltetrahydrofolate enhanced efflux of [(14)C]5-methyltetrahydrofolate. Nearly total depletion of ATP increased uptake of [(14)C]5-methyltetrahydrofolate, but efflux was unchanged. Column chromatography of membrane-free hemolysate after incubation with [(14)C]5-methyltetrahydrofolate showed 95% of radioactivity corresponded to marker radioisotope, and no other peak was noted. Thus peripheral erythrocytes incorporate 5-methyltetrahydrofolate by a saturable, temperature-dependent, substrate-specific process which is influenced by counter-transport. This mechanism is qualitatively similar to the carrier-mediated transport of folate compounds previously described in other cell types. Therefore, human erythrocytes should be useful for detailed characterization of this membrane carrier system.

Anemia, Aplastic↗