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Biomedical subjects

H S Jacob

Publications and source records attributed to H S Jacob.

At least 91 records · Page 5Linked to original sources
PubMed1984

Role of endothelial cells in human hematopoiesis: modulation of mixed colony growth in vitro.

The identification of clonal human multipotent hematopoietic progenitors has permitted an analysis of the growth factor requirements for these cells. Human endothelial cell cultures were used to examine the effects of media conditioned by the endothelial cells on human multipotent (CFU-mix) and committed erythroid (BFU-E, CFU-E) and myeloid (CFU-GM) precursors. These studies demonstrate that endothelial cells produce proteins of approximately 30,000 daltons, with isoelectric focusing points of 4.5 and 7.2, which stimulate the growth of human BFU-E and CFU-mix. A heat-labile protein(s) of 30,000 and 15,000 daltons stimulated the proliferation and differentiation of granulocyte-macrophage (CFU-GM) colonies. No erythropoietin was detected in endothelial cell supernatants. This suggests that endothelial cells, a normal component of marrow stroma, play an active role in the modulation of human hematopoietic stem cell growth.

Animals↗
PubMed1983

Fatal complement-induced leukostasis after diatrizoate injection. Principles of clinicopathologic diagnosis.

A case of fatal radiographic contrast medium (RCM)-induced pulmonary granulocyte aggregation (leukostasis) showed massive elevation of the postmortem histamine level. Suspicion of this phenomenon in diverse clinical settings permits clinical and pathological documentation via increased plasma levels of C3a and other means. The existence of effective prophylaxis stimulates a search for predictive tests.

Aged↗
PubMed1983

Enkephalins modify granulocyte-endothelial interactions by stimulating prostacyclin production.

Granulocyte (PMN)-endothelial interactions have been implicated in the primary events of vascular injury and atherogenesis. We now present data which show that endogenous opioid peptides, e.g. enkephalins (ENK), dampen immune-triggered, granulocyte-induced endothelial damage by enhancing prostacyclin production. Concurrent exposure of human umbilical vein endothelial cells (HUEC) to Met5-enkephalin increased arachidonic acid (AA, 20 muM) and thrombin (T, 10 U/ml) induced 6-keto-PGF1 alpha-release to respectively 197.2 +/- 28.1% and 204.1 +/- 17.8% (mean +/- SEM) of base line stimulation (p less than 0.025). The increases noted were significant at ENK-concentrations as low as 10(-12)M. Simultaneous addition of naloxone with ENK completely abolished the enhanced 6-keto-PGF1 alpha-release. Addition of a protease resistant enkephalin analogue significantly (p less than 0.01 over several different concentrations) reduced PMN adherence to HUEC; concomitantly 51Cr-leakage from HUEC that had been exposed to PMN plus activated serum complement was decreased. The even further enhanced 51Cr-leakage that occurs when platelet release products (e.g. serotonin) are included is also decreased by added enkephalin. These data suggest that endogenous neurotransmitters may affect endothelial prostaglandin metabolism, and by so doing provide a protective effect during in vitro, and perhaps in vivo, PMN mediated endothelial injury. This link between neurohumoral and inflammatory systems might enhance our understanding of stress-related phenomena in inflammation and vascular diseases.

Cell Adhesion↗
PubMed1983

Mechanisms of vascular damage in gout and oxalosis: crystal induced, granulocyte mediated, endothelial injury.

Immune triggered granulocyte (PMN)-endothelial interactions have been implicated in the pathogenesis of vascular diseases. While hyperuricemia and gout are associated with an increased risk of atherogenesis, we studied the modulation by monosodium-urate (MSU) crystals of PMN-endothelial interactions in vitro. The relationship between calcium oxalate (COX) crystals - implicated in the vasculitis of primary oxalosis - and immunologically mediated endothelial injury was also explored. Both MSU- and COX-crystal treated sera stimulate PMN to adhere to and induce significant 51Cr-release from endothelial cells in vitro. Platelets significantly increase crystal-triggered PMN endothelial cell adherence and 51Cr-release. This platelet augmenting effect depends on the release of platelet constituents (e.g. serotonin). Microcrystalline material present in vessel walls, thus may cause C-activation and may trigger PMN and platelets to damage endothelium in vitro and in vivo. These findings may have relevance to the understanding of the accelerated atherogenesis of hyperuricemia and the fulminant vasculitis of oxalosis or ethylene glycol poisoning.

Blood Physiological Phenomena↗
PubMed1983

Hyperacute pulmonary vasculitis in rabbits receiving prolonged infusions of activated complement. A possible model for triggering events in adult respiratory distress syndrome.

We have postulated a role for activated plasma complement and for stimulated granulocytes in the triggering events of the adult respiratory distress syndrome (ARDS). Because brief periods of complement activation have proved to be pale mimics of the clinical syndrome, we extended our earlier models by infusing potently activated plasma complement into rabbits over a prolonged period of time (3 h). The expected leukostasis occurred, but pulmonary dysfunction remained modest. Nonetheless, piecemeal microvascular necrosis did develop, rendering this current model more credible than former models as a mimic of triggering events in ARDS; longer-term follow-up of such animals will be necessary to determine if this is indeed the case. Perhaps of even greater interest, the neutrophilic leukostasis was observed to progress over the 3 h to a predominantly lymphocytic leukostasis, a dramatically more rapid progression than is typical of such immune complex diseases as serum sickness and the Arthus reaction; further studies are in progress to elucidate the mechanism of this lymphostasis.

Acute Disease↗
PubMed1983

Neutrophil activation as a mechanism of tissue injury.

C5A is capable of causing granulocyte/granulocyte interactions that lead to clumping, vasoocclusion, and the extension of infarctive damage in patients with coronary artery disease. Employing a new rheologic procedure, laser transillumination of thin vascular beds, one directly observes in vivo granulocyte aggregation in the mesentery of the rat. Nonsteroidal antiinflammatory drugs (NSAIDs) were shown to stop granulocyte agglomeration and to limit the extension of experimental myocardial infarcts in the cat. There may be application for NSAIDs for myocardial infarction in humans. NSAIDs block granulocyte aggregation to both a traditional activated complement and a complement activated by cryoglobulins. Patients with severe cryoglobulinemic cutaneous vasculitis who failed on steroids responded to NSAID administration.

Animals↗
PubMed1983

Symptoms and activation of granulocytes and complement with two dialysis membranes.

Complement (C) activation, neutropenia, and mild pulmonary dysfunction attend hemodialysis (HD) with cellophane [for example, cuprophan (Cu)] membranes. While usually asymptomatic, these phenomena may cause distress in patients with cardiopulmonary disease, and "start-up" symptoms of HD might be mediated by C-stimulated granulocytes (PMNs). Cellulose acetate (CA) hemodialysis membranes have been devised and claimed more blood compatible than Cu. In a blinded series of HD patients, pruritus, fatigue, and sense of well-being were each scored statistically more favorably by the patients during HD with CA than during HD with Cu (P less than 0.05). Postulating that less C activation might underlie the benefit, we showed that neutropenia was less severe with CA (nadir 77.6% of initial count, +/- 4 SEM) than with Cu (38.3% +/- 2.9; P less than 0.01). In vitro, incubation of CA membranes with plasma led to less C3 conversion (20% vs. 40%), less PMN aggregating activity (5.9 ZAP units vs. 36.3) and less decrement in CH50 (6.5% vs. 22%) than like incubations of Cu. C activation was also less potent in vivo: During HD plasma C3a rose from a mean 401 ng/ml to a peak 6,325 in patients on Cu dialyzers, but from 426 to only 3,637 in patients on CA devices (P less than 0.05). Time-course studies suggested CA was initially as potent an activator as Cu but rapidly lost ability to activate C, possibly because of saturation of C3b binding sites. As an index of PMN activation, we also assayed plasma lactoferrin and found levels significantly higher during Cu than CA dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylatoxins↗
PubMed1983

Antithymocyte globulin treatment of severe aplastic anaemia.

Nineteen patients with severe aplastic anaemia were treated with antithymocyte globulin. Ten patients obtained remissions (transfusion independent, at least 45000 platelets and 2000 PMN/mm3) within 2-3 months and continue in remission 5-35 months after antithymocyte globulin. Ages of responders ranged from 17 to 71. Complications of antithymocyte globulin included arthralgias, rash, serum sickness, angioedema and fever. Two patients died during, two shortly after, and one 10 months after therapy. One patient with a previous remission following antithymocyte globulin relapsed and achieved a second remission with retreatment. Previous androgen therapy did not affect outcome since two of four patients with and eight of 15 patients without previous androgen therapy achieved remission with ATG. Treatment with antithymocyte globulin is a promising alternative to bone marrow transplantation in the treatment of severe aplastic anaemia.

Adolescent↗
PubMed1983

Fat embolism prophylaxis with corticosteroids. A prospective study in high-risk patients.

The efficacy of corticosteroid treatment in the prophylaxis of the fat embolism syndrome was evaluated in a prospective, randomized, double-blind study of high-risk patients with long-bone fractures. Using a set of objective diagnostic criteria, we saw a significant difference in the incidence of the syndrome between corticosteroid- (0 of 21) and placebo-treated patients (9 of 41) (p less than 0.05). There were no complications related to corticosteroid treatment. No routine laboratory or physical findings reliably predicted the development of the fat embolism syndrome except petechial rash, which occurred only in 5 placebo-treated patients who developed the syndrome. Complement activation was present in all patients studied who had the syndrome (5 of 27) but also in many patients who did not meet our diagnostic criteria, suggesting a multifactorial cause. These data support the prophylactic value of corticosteroid treatment in patients at high risk for the fat embolism syndrome, particularly if several unfavorable predictors are present.

Adolescent↗
PubMed1983

Antineoplastic effects of Bordetella pertussis adenylate cyclase.

Urea extracts of B. pertussis, but not B. bronchiseptica, cause large and sustained intracellular cAMP elevation in several neoplastic cell lines. These cAMP elevations are associated with growth inhibition (HL-60, Friend erythroleukemia) and a phenotypic change/differentiation (HL-60, L1210). B. pertussis extract injections prolong survival of L1210 tumor-bearing mice. Pretreatment of L1210 cells with B. pertussis extract both delays mortality and induces growth of solid tumors instead of ascites in subsequently inoculated mice. We conclude that B. pertussis adenylate cyclase is capable of invading a variety of neoplastic cells to catalyze the intracellular formation of large amounts of cAMP. These cAMP elevations are durable and promote growth arrest, differentiation, or phenotypic alterations reflected in altered biologic behavior. B. pertussis adenylate cyclase should prove to be a useful tool for manipulating cAMP levels in neoplastic cells to elucidate the role of cAMP in malignant transformation.

Adenylyl Cyclases↗
PubMed1983

Inflamed fibronectin: an altered fibronectin enhances neutrophil adhesion.

Recent investigations have emphasized the role of activated granulocytes in mediating vascular endothelial injury in the pathogenesis of shock lung. In vitro studies have indicated that tight adherence of the neutrophil to the endothelium is crucial for the development of cellular injury. Fibronectin is critical to cell-to-substratum and cell-to-cell interactions. Since fibronectin resides in plasma, on endothelial cell surfaces and is secreted into cell matrices, the adhesive properties of fibronectin must be modulated, lest universal cell agglomeration occur, yet be enhanced when cell attachment is appropriate. In these studies, treatment of fibronectin-coated surfaces with neutrophil release products increased the adhesion of activated neutrophils. Similarly, endothelial cells treated with neutrophil release products become a more adherent substrate for neutrophils. This enhanced adherence generated by treatment of fibronectin with neutrophil supernatants is inhibitable by heat and the lysosomal proteinase inhibitor, pepstatin-A. Neutrophil release products cause proteolytic fragmentation of fibronectin and enhanced fibronectin immunofluorescence on endothelial cells. In addition, neutrophils are more injurious to endothelial cells that have been pretreated with neutrophil release products. Neutrophils may enhance their own adherence to endothelial cells by altering fibronectin, and this altered, or "inflamed," fibronectin may serve as an amplifier of inflammation.

Cell Adhesion↗
PubMed1983

Complement-mediated leucoembolization: a mechanism of tissue damage during extracorporeal perfusions, myocardial infarction and in shock--a review.

The complement (C) system evolved as a beneficial antimicrobial system. However, when activated during extracorporeal perfusion as with haemodialysis or cardiopulmonary bypass modest pulmonary dysfunction associated with granulocyte aggregation and embolization can occur. When C activation is massive and prolonged, as with severe sepsis, trauma, or acute pancreatitis, severe pulmonary damage which is recognized as shock lung, or adult respiratory distress syndrome, may occur. Since ulcerating atherosclerotic plaques can also activate C, a mechanism by which myocardial infarcts may extend during the first few hours after infarction is also implied. Therapeutic ramifications of these conclusions are evident. Thus, high doses of corticosteroids or of nonsteroidal anti-inflammatory agents such as ibuprofen share the ability to prevent aggregation and embolization of stimulated granulocytes to patent vessels downstream and also inhibit their production of toxic oxygen radicals. These properties suggest the use of these agents in myocardial infarction and shock states, particularly shock lung, and appropriate clinical trials are awaited with interest.

Adrenal Cortex Hormones↗
PubMed1982

Anisodamine inhibits thromboxane synthesis, granulocyte aggregation, and platelet aggregation. A possible mechanism for its efficacy in bacteremic shock.

Anisodamine hydrochloride is a vasoactive drug produced in the People's Republic of China that appears efficacious in clinical and experimental bacteremic shock, and about whose mode of action little is known. Suspecting that the drug might work by inhibition of platelet or granulocyte aggregation, or both, we tested it in these systems. Anisodamine proved a modest inhibitor of granulocyte aggregation and a powerful inhibitor of platelet aggregation; thromboxane synthesis was inhibited in anisodamine-treated platelets, further suggesting that the biochemical mode of action might be inhibition of cyclo-oxygenase or thromboxane synthetase.

Animals↗
PubMed1982

Synergy among agents inhibiting granulocyte aggregation.

Recent evidence suggests complement (C) -stimulated granulocytes (PMNs) are important in a variety of diseases, including shock and myocardial infarction (MI). Corticosteroids inhibit PMN response to C and show promise in some studies of shock and MI, but their use has not become routine for several reasons. Synergy was sought among agents inhibiting PMN aggregation in vitro in response to activated C: methylprednisolone (MP), with a 50% inhibitory dose (AD50) of 0.6 mg/ml; ibuprofen (IBU), with AD50 of 1.0 mg/ml, and betahistine (BH), with AD50 of 1.6 mg/ml. Simultaneous use of all three agents produced 3.4-fold synergy; 3-fold synergy obtained between IBU + MP and IBU + BH, while 1.5-fold synergy was noted between MP + BH. Further, MP and IBU were at least additive in inhibiting .O2- generation by FMLP-stimulated PMNs and in blocking directed migration. In a preliminary in vivo test of this finding, cats were given MP and IBU--in known individually ineffective doses--immediately prior to coronary artery ligation. Neither MP nor the low dose of IBU chosen limited the size of the resultant MI, while both agents together reduced MI size by 42%. Synergy among these agents suggests that they inhibit PMN function of distinct cellular mechanisms (as yet not elucidated). Further, early in vivo results encourage speculation that such synergy might ultimately be exploited clinically, although such speculation must presently be regarded as preliminary.

Betahistine↗
PubMed1982

Influence of dietary omega-3 fatty acids on granulocyte function.

Manipulation of dietary fatty acid content has been shown to influence platelet aggregation responses. Because granulocytes and platelets interact in a variety of biologic systems, we wondered whether a similar effect might be observed on granulocytes. Granulocyte function was therefore studied in three donors prior to and after three weeks upon a diet supplemented with large amounts of eicosapentaenoic acid. The previously reported attenuation of platelet aggregation was observed, but no effect was seen on granulocyte aggregation, chemotaxis, or superoxide production. Although several other explanations are possible, we suggest that the most likely explanation for this dichotomy is that granulocyte aggregation and chemotaxis are not centrally dependent upon production of thromboxane A.

Adult↗
PubMed1982

Granulocytes utilize different energy sources for movement and phagocytosis.

Granulocytes depend on anaerobic glycolysis for the energy required for chemotaxis, phagocytosis, and microbial killing. Two potential sources of the needed glucose are available: exogenous glucose and intracellular glycogen. These studies demonstrate that chemotaxin-induced movement of granulocytes induces accelerated uptake of exogenous glucose while phagocytosis does not, presumably utilizing instead the relatively slow process of glycogenolysis. As measured by incorporation of extracellular radiolabeled hexoses [1-14C]glucose or [3H]deoxyglucose), the soluble chemotaxin-aggregants of granulocytes, nF-met-leu-phe, C5ades arg, bacterial filtrate, or arachidonic acid all augment transmembrane hexose uptake. This insulin-like activity closely parallels the dose-related effects of these agents on induction of granulocyte aggregation and chemotaxis. Insulin, itself, affects glucose transport minimally and mainly at supraphysiologic concentrations. In contrast, phagocytic stimuli fail to enhance hexose uptake at all, despite stimulating catabolism of glucose, which in turn is probably generated by glucogenolysis. these data show that granulocytes, whose motile function occurs in glucose-rich milieu, alter in tandem their cellular glucose uptake with their movement response. For phagocytosis, which often occurs in hypoglycotic, purulent exudates, granulocytes depend on stored energy supplies--probably glycogen. This coordination may be crucial in supporting granulocyte antimicrobial activity during acute inflammation.

Arachidonic Acid↗
PubMed1982

Enhancement of granulocyte-endothelial cell adherence and granulocyte-induced cytotoxicity by platelet release products.

Complement-stimulated granulocytes adhere to and induce significant 51Cr release from endothelial cells in vitro. Platelets were stimulated to undergo release, and these release products significantly enhanced granulocyte-endothelial cell adherence and granulocyte-induced 51Cr release from endothelial cells. Platelet serotonin appeared to mediate these phenomena because serotonin antagonists blocked both the enhanced endothelial adherence and 51Cr release. In addition, added serotonin mimicked the effect seen with the stimulated platelets upon granulocyte--endothelial cell adherence and cytotoxicity completely. This enhancement appeared to be due to serotonin effects upon both the granulocyte and endothelial cells. These data suggest that a released platelet constituent might modulate in vivo granulocyte-endothelial cell interactions in clinical disorders.

Blood Platelets↗