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Biomedical subjects

G Weissmann

Publications and source records attributed to G Weissmann.

At least 199 records · Page 11Linked to original sources
PubMed1980

Increased levels of cyclic adenosine-3',5'-monophosphate in human polymorphonuclear leukocytes after surface stimulation.

Levels of cyclic AMP (cAMP) (but not cyclic GMP) in suspensions of human polymorphonuclear leukocytes (PMN) increased promptly after exposure of the cells to stimuli such as the chemotactic peptide N-formyl methionyl leucyl phenylalanine, the immune complex bovine serum albumin/anti-bovine serum albumin and calcium ionophore A23187. cAMP increased rapidly, reaching a maximum of twice the basal level 10--45 s after stimulation; after 2--5 min the amount of cAMP had subsided to basal levels. Elevations in cAMP levels were concurrent with, or followed, membrane hyperpolarization (measured by uptake of the lipophilic cation triphenylmethyl phosphonium) and always preceded lysosomal enzyme release and superoxide anion (O2) production. Elevated cAMP levels could be uncoupled from these later events by removal of extracellular divalent cations, replacement of extracellular Na+ with K+ or choline+, and by use of low concentrations of stimulus; each of these conditions virtually abolished lysosomal enzyme release and O2 generation, while leaving the stimulated elevation of cAMP levels unimpaired. Calcium ionophore A23187 did not provoke membrane hyperpolarization, thus uncoupling changes in membrane potential from changes in cAMP levels. These data suggested that cAMP is not a critical component in the earliest steps of stimulus-secretion coupling. Surface stimulation of cells pretreated with prostaglandins E1 or I2 yielded very high levels of cAMP; these high levels may be an important part of the mechanism by which stable prostaglandins inhibit lysosomal enzyme release and O2 generation.

Adult↗
PubMed1980

PGBX, a prostagandin derivative, mimics the action of the calcium ionophore A23187 on human neutrophils.

The interactions have been studied of a water-soluble, polymeric derivative of prostaglandin B1, PGBX, with human polymorphonuclear leukocytes (PMN). PGBX, which is a potent ionophore of divalent cations, provoked superoxide anion (O2.-) generation and lysosomal enzyme release in cytochalasin B-treated PMN in the presence of extracellular divalent cations (Ca2+, Sr2+, Mg2+, Mn2+, Ba2+). Kinetic and dose-response studies showed that PGBX mimicked te action of ionophore A23187 in PMN. Both ionophores induced superoxide generation and release of enzymes from specific and azurophil granules (lysozyme > beta-glucuronidase) without provoking release of the cytoplasmic marker enzyme lactic dehydrogenase. In contrast, the precursor of PGBX, prostaglandin B1 (PGB1), and arachidonate did not mimic ionophore-induced stimulation of PMN. PGBX induced enzyme release both in the presence of extracellular Ca2+ and Ba2+ (both of which it translocates in model liposomes), whereas A23187 showed specificity for Ca2+ (which it translocates preferentially over Ba2+). These studies indicate that the actions of a water-soluble polymer (PGBX) derived from a naturally occurring prostaglandin (PGB1) on human neutrophils resemble those of a classical ionophore (A23187). Moreover, they provide additional evidence that increments in the intracellular levels of divalent cations may signal stimulus-secretion coupling in human neutrophils.

Anti-Bacterial Agents↗
PubMed1979

Enzyme replacement via liposomes. Variations in lipid compositions determine liposomal integrity in biological fluids.

Liposomes survive exposure to biological fluids poorly, extruding trapped enzymes, drugs, or solutes upon interaction with serum or plasma constituents. We have quantified the disruptive effects of human serum on liposomes and have studied whether various modifications in their phospholipid composition might produce liposomes with an increased carrier potential for application in vivo. Multilamellar liposomes (phosphatidycholine 70:dicetyl phosphate 20:cholesterol 10) were prepared with 3H-labeled phosphatidylcholine as the lipid phase marker and [14C]inulin and horseradish peroxidase as aqueous phase markers. Gel exclusion chromatography showed that 32 +/- 3% of [14C]inulin and 27 +/- 7% of horseradish peroxidase were lost after 1 h incubation with 10% (v/v) human serum. Loss of aqueous solutes was reduced to 20 +/- 5%/h and 17 +/- 2%/h, respectively, after treatment with decomplemented serum (56 degrees C, 30 min). Loss induced by serum was concentration and time dependent: to 57 +/- 2% at 1 h and 67 +/- 14% at 24 h, with 50% serum; plasma was slightly less perturbing whereas human serum albumin was not at all disruptive. By incorporating sphingomyelin (35 mol%) into multilamellar liposomes, the leakage of [14c]-inulin in the presence of 10% serum was reduced to 12 +/- 4%/h; increasing the molar percentage of cholesterol to 35% also stabilized the lipid bilayers, reducing leakage to 20 +/- 7%/h. Both small and large unilamellar vesicles could not be stablilized against serum-mediated leakage by the incorporation of sphingomyelin. The data suggest that cholesterol and sphingomyelin enhance liposomal integrity in the presence of serum or plasma and promise to yield enhanced survival of drug-laden lipid vesicles in biological fluids in vivo.

Cholesterol↗
PubMed1979

Inhibitors of membrane transport reduce lysosomal enzyme secretion from dogfish phagocytes and their killing of sea urchin eggs.

Blood phagocytes of the dogfish Mustelus canis attack oocytes of the sea urchin Arbacia punctulata, first provoking a surrogate fertilization response and then killing the eggs. To test the hypothesis that secretion of lysosomal contents is critical in this model of phagocyte-mediated cell injury, we studied effects of agents that modify lysosomal enzyme secretion. Inhibitors of membrane transport (>0.1 mM) inhibited postphagocytic secretion of lysosomal beta-glucuronidase from dogfish phagocytes: phloretin > ethacrynate > furosemide > 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid >> pyridoxal phosphate > ouabain. The same order of activity was found for inhibition by these agents of killing of Arbacia eggs by phagocytes. Cell activation (fertilization response) and cytotoxicity were quantitated both morphologically and by measurements of enzyme (beta-glucuronidase, catalase) release. The agents neither inhibited fertilization responses of eggs to calcium ionophore A23187 nor impaired their viability. Vital staining demonstrated that ethacrynate prevented phagocytes from degranulating upon contact with zymosan particles. The data not only suggest that agents primarily known for their capacity to inhibit membrane transport systems can inhibit lysosomal enzyme secretion from phagocytes but also support the hypothesis that secretion of lysosomal contents mediates activation and killing of target cells in phagocyte-mediated tissue injury.

Animals↗
PubMed1979

A new function for ceruloplasmin as an acute-phase reactant in inflammation: a scavenger of superoxide anion radicals.

In summary, purified human ceruloplasmin inhibits several reactions mediated by superoxide anion in a fashion consistent with an ability to scavenge this free radical. It must be pointed out, however, that on a weight basis, the superoxide-scavenging activity of ceruloplasmin is substantially less than that of purified human erythrocyte superoxide dismutase. Nevertheless, since superoxide dismutase is almost exclusively an intracellular enzyme, ceruloplasmin probably represents the major circulating scavenger of superoxide anion radicals. The level of superoxide dismutase in human plasma has been reported to be 0.7 microgram/ml. It is not clear, however, how this was measured. We have found that concentrations of plasma exceeding 10% (v/v) interfere significantly with the assays routinely employed for detecting superoxide-scavenging activity. Consequently, we have not yet been able to quantify the superoxide-scavenging activity of either ceruloplasmin or superoxide dismutase in whole human plasma. Thus, we can only speculate that under conditions where levels of ceruloplasmin are markedly elevated, as during pregnancy, during acute infections, or in association with inflammatory diseases (such as rheumatoid arthritis), this acute-phase reactant may play a major role as a circulating scavenger of oxygen-derived free radicals.

Ceruloplasmin↗
PubMed1978

[Synchronous and metachronous processes in colo-rectal carcinoma].

Polyps are often associated with carcinoma in the colon. The incidence of colorectal polyps with single carcinoma is up to 25% and with multiple carcinoma up to 75%. Not infrequently both synchronous and metachronous carcinoma are found in the colon and rectum. These findings emanate from a sample of 367 patients (in this hospital) with colorectal carcinoma during the period 1973 to 1977. The incidence of synchronous and metachronous carcinoma as well as severe dysplasia (focal carcinoma) in adenomatous polyps was nearly 8%. In slightly more than 50% of cases involving a single carcinoma, there was no evidence of an accompanying condition or later development. In more than 20% of the cases single carcinoma was accompanied by synchronous and metachronous polyps. These figures eloquently illustrate the necessity for closely coordinated postoperative care of patients with colorectal carcinoma.

Adenoma↗