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Biomedical subjects

A H Gordon

Publications and source records attributed to A H Gordon.

At least 19 recordsLinked to original sources
PubMed1990

Tubular lysosomes and their drug reactivity in cultured resident macrophages and in cell-free medium.

Lysosomes were assessed in normal living resident mouse peritoneal macrophages, using mainly phase-contrast microscopy (PCM), darkfield microscopy (DFM), and fluorescence microscopy (FM) after terminal acridine orange (AO) staining; these procedures avoided dyes during experimentation. After a few hours of culture a variable proportion of the normal spherical lysosomes began to assemble in a linear fashion. Fully formed tubular structures, with appearances generally recognized as characteristic of tubular lysosomes (TL), could be seen by PCM or, after labeling, by FM, at 2-5 days (best usually at 4-5 days). This peak was followed by a reduction, and at 8-10 days most of the TL had disappeared, leaving only spherical lysosomes. Renewal of the medium at this stage was followed by a temporary reappearance of TL, suggesting that the medium was a major factor in their initial development also. Formation of TL was enhanced by chloroquine (Cq), though to a lesser degree than by phorbol ester (PMA); in contrast NH4Cl (like Cq a weakly basic amine) caused their disassembly into spherical lysosomes. Manual disruption of the monolayer macrophages enabled TL to be transferred to a cell-free medium, in which they remained apparently stable for several hours. Two known microtubule depolymerizers caused disassembly of TL in the intact cells, reinforcing the idea that the TL are associated with the cytoplasmic microtubule (MT) system; but these agents were inactive in vitro, suggesting that disorganization of the system was responsible for this change.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonium Chloride↗
PubMed1990

Epidermal growth factor and transforming growth factor-beta differently modulate the acute phase response elicited by interleukin-6 in cultured liver cells from man, rat and mouse.

1. Complex effects of principal inflammatory cytokines (IL-6, IL-1, TNF, IFN-gamma) on acute phase protein synthesis and other metabolic processes in cultured liver cells are briefly reviewed. 2. Molecular properties and biological functions of transforming growth factor-beta and epidermal growth factor are compared. 3. The effects of these factors with respect to both amino acid uptake and acute phase protein synthesis are described in detail. The results are found to be different for rat or mouse hepatocytes and human hepatoma cells.

Acute-Phase Proteins↗
PubMed1990

Esophageal tuberculosis: definitive diagnosis by endoscopy.

This report describes a patient with a 2-wk history of epigastric pain and dysphagia, and a mid-esophageal ulceration resulting from infection with Mycobacterium tuberculosis. This is an uncommon site of tuberculous involvement, and usually results from direct extension from adjacent mediastinal or hilar lymph nodes, reactivated lung infection, infected vertebral bodies or aortic aneurysms, or from extension from the pharynx or larynx. The endoscopic lesion is ulcerative, with shallow, smooth edges, granular, with small mucosal miliary granulomas, or hyperplastic, with fibrosis, luminal narrowing, and stricture formation. The patient responded well to antituberculous therapy, and is healthy 4 yr after therapy.

Aged↗
PubMed1987

Inhibition of phagosome-lysosome fusion in macrophages by certain mycobacteria can be explained by inhibition of lysosomal movements observed after phagocytosis.

We have investigated the mechanism of the inhibition of phagosome-lysosome (P-L) fusion in macrophages known to occur after infection by Mycobacterium tuberculosis and by the mouse pathogen Mycobacterium microti. We have used an M. microti infection and have studied, first, the saltatory movements of periphagosomal secondary lysosomes by means of visual phase-contrast microscopy (a similar use of the method having been previously supported by computer analyses). The movements became slow or static after ingestion of live but not of heat-killed M. microti. They were unaffected by a fusiogenic mycobacterium M. lepraemurium. Second, we studied the behavior of a normally fusiogenic unrelated organism, Saccharomyces cerevisiae, after its phagocytosis by cells already containing live M. microti ingested 18 h previously. We observed, using a fluorescent assay of fusion, that many of these yeast phagosomes now also failed to fuse with the lysosomes; in contrast, when the host M. microti had been heat killed the yeast phagosomes fused normally. These observations were extended by ultrastructural quantitative analyses of P-L fusion, which confirmed the nonfusion of phagosomes of live M. microti and, more particularly, the change to nonfusion from the normal fusion behavior of the separate phagosomes of accompanying yeasts. Third, we have assembled evidence against the likelihood that these M. microti-induced phenomena are nonspecific, i.e., secondary to a general depression of activity of heavily infected host cells. The evidence includes the feasibility of adjusting the degree of infection so as to facilitate visual assessment of organelle movements without the presence of detectable damage to the cells studied; the absence of lysosomal stasis after comparable infection with another mycobacterium of comparable virulence (M. lepraemurium); and the reversibility of the stasis. We conclude that inhibition of lysosome saltatory movements (and consequently its secondary effect on the associated yeasts) is a significant, specifically induced phenomenon. From these observations and considerations, therefore, in conjunction with the analogous inhibition of lysosomal movements in normal macrophages by some chemical inhibitors of P-L fusion, and our suggestion that this association is causally related, we now suggest that M. microti-induced focal lysosomal stasis is also the main means by which the inhibition of P-L fusion is brought about by this organism. This concept is strengthened by the observations on S. cerevisiae, which provide strong evidence that stasis can cause suppression of fusion.

Animals↗
PubMed1985

Rat plasma kallikrein clearance by perfused rat liver.

Previous studies have shown that perfused rat liver in situ is able to clear recirculating rat plasma kallikrein (RPK) in two phases: an initial clearance lasting a few minutes, followed by a slow exponential phase. Using purified RPK preparations we now show that: RPK is a glycoprotein; clearance was inhibited by human serum against blood group B and 0.1 M melibiose but was not affected by human serum against blood group A, 0.1 M lactose, 0.1 M mannose, 0.05 M N-acetyl galactosamine, 0.05 M galactose or 15 microM asialofetuin. Prolonged incubation of RPK with alpha-galactosidase reduced RPK clearance. Oligosaccharide structures in RPK may have terminal galactose units since treatment of RPK with neuraminidase did not affect the clearance rate; RPK clearance occurs in the absence of added Ca2+, with either EDTA or EGTA in the perfusion fluid; the exponential phase is reversibly inhibited by the addition of NH4Cl or chloroquine to the perfusion fluid. This observation, along with experiments using liver homogenates, suggests that RPK catabolism is carried out by lysosomal enzymes, probably cathepsin B of possible hepatocyte origin.

Animals↗
PubMed1985

Effect of endogenous pyrogen, corticosteroids and inhibitors of prostaglandins and leukotrienes on the plasma concentrations of haptoglobin and fibrinogen in rats.

Injections of endogenous pyrogen (EP) in normal rats significantly increased plasma concentration of haptoglobin and fibrinogen while in adrenalectomized animals the same treatment was ineffective. Nevertheless when cortisone was injected simultaneously with EP into adrenalectomized rats the responses of fibrinogen and haptoglobin were restored. These results suggest that biosynthesis of fibrinogen and haptoglobin is corticosteroid-dependent. Inhibition of the cyclo-oxygenase pathway with ibuprofen or the lipoxygenase pathway with BW755C had no effect on the increase of plasma fibrinogen or haptoglobin levels stimulated by either EP or endotoxin. These data indicate that neither prostaglandins nor leukotrienes are involved in the production of these acute phase reactants induced by either stimulus.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Effect of bacterial endotoxin on body temperature, plasma zinc and plasma concentrations of the acute-phase protein serum amyloid p component in mice.

Bacterial endotoxin and lipid A evoked dose-dependent increases in body temperature and plasma SAP concentrations and dose-dependent falls in plasma zinc concentrations in mice. The respective sensitivities of the three variables to lipid A or to whole endotoxin had the relation SAP greater than Zinc much greater than body temperature; zinc and SAP responses were evoked by less than 1 ng lipid A/endotoxin. Pretreatment with indomethacin prevented only the temperature response to lipid A. Pretreatment with dexamethasone did not affect the temperature response but diminished the zinc response and enhanced the SAP response to lipid A.

Amyloid↗
PubMed1984

Cleavage of human interleukin 1: isolation of a peptide fragment from plasma of febrile humans and activated monocytes.

Interleukin 1 (IL 1) is a product(s) of mononuclear phagocytes, and has multiple biologic activities that mediate several host responses to infection and inflammation. Highly purified IL 1 activates lymphocytes, induces fever, increases hepatic acute phase protein synthesis, and increases muscle protein degradation. A 4.2 kd peptide has been purified from plasma of febrile humans which also induces muscle proteolysis in vitro (termed proteolysis-inducing factor, PIF). Because IL 1 purified from activated human monocytes induces muscle proteolysis in vitro, studies were performed to determine the relationship of human monocyte-derived IL 1 to plasma-derived PIF. Purified PIF was highly active in the IL 1 thymocyte assay. After gel filtration of plasma from febrile patients, fractions with PIF activity also induced thymocyte proliferation and fever in mice. Thus, it seems likely that the plasma peptide PIF has IL 1 properties and probably represents a small m.w. cleavage product of IL 1. Further studies confirmed this finding. Highly purified 15 kd IL 1, rechromatographed over different gel filtration media, consistently fragmented into a 4 kd peptide with both muscle proteolysis-inducing and lymphocyte-activating properties. The breakdown of the 15 kd IL 1 into biologically active smaller fragments increased with time, and could be accelerated by trypsinization. The monocyte-derived IL 1 fragments were partially destroyed by heat. Highly purified 125I-labeled 15 kd IL 1 also fragmented into subunits, and these radioactive subunits produced fever in mice and were active in the thymocyte assay. Fragmentation of 125I-labeled 15 kd IL 1 was reduced by agents that inhibit proteases. These results indicate that some of the biologic activities of human IL 1 are conserved in small m.w. fragments. These studies also provide evidence that IL 1 may circulate in humans as a 4.2 kd peptide, and that this cleavage product can function as an active mediator of IL 1 effects in the host.

Animals↗
PubMed1981

Acute turpentine inflammation and kinin release in rat-paw thermic oedema.

Livers from rats at 2-3 days after s.c. injection of turpentine, when perfused, synthesized prekallikrein nearly 3 times faster than did livers from normal rats. On the other hand paw oedema, produced by heating to 46 degrees, in rats injured in this way was less marked. Likewise in such rats the amount of bradykinin release by 50 min. of coaxial perfusion of the paw was only 13.6 +/- 4.6 compared with 63.1 +/- 13.4 ng in normal rats. A possible explanation for the observed reduction in production of bradykinin may be inhibition of kallikrein due to an increased concentration of alpha 2-macroglobulin.

Animals↗
PubMed1979

Effects of bacterial endotoxin and corticosteroids on plasma concentrations of alpha 2 macroglobulin, haptoglobin and fibrinogen in rats.

Bacterial endotoxin injected into rats resulted in increased plasma concentration of alpha 2 macroglobulin, haptoglobin and fibrinogen. Cortisone acetate injected i.m. by itself was sufficient to increase the plasma concentration of haptoglobin by 54% and to a lesser extent the concentrations of the other two proteins. When cortisone acetate and/or cortisol succinate were injected simultaneously with varying doses of endotoxin, the effects of the corticosteroid differed for each plasma protein. Doubtless because of the effect of cortisone by itself the slope of the dose-response relationship for haptoglobin was greatly reduced. In contrast to this the slope for alpha 2 macroglobulin was reduced and that for fibrinogen was unaffected. These findings suggest that, if effects due to endogenous corticosteroids are to be avoided, increases in plasma fibrinogen will serve best as indicators of stimulation of the acute-phase response. Since, however, the relative increase of alpha 2 macroglobulin due to the lowest dose of endotoxin was much greater than that of fibrinogen, increases in concentration of the former protein represent the most sensitive indication of the acute-phase response. Consideration of the responses in individual rats has made possible division into those with more or less than average increases for all 3 plasma proteins and those showing irregular responses. Especially in the group which had received the lowest dose of endotoxin, a much larger number than would be expected on a random basis was found to respond regularly with either more or less than average increases for all 3 proteins.

Animals↗
PubMed1979

Human blood and rabbit peritoneal leucocytes as sources of endogenous mediators.

"Buffy-coat" residues from human blood have been investigated as a source of leucocytic endogenous mediator (LEM). After separation from most of the erythrocytes and uptake of opsonized zymosan by the polymorphonuclear leucocytes (PML) and macrophages, the cells were incubated in Hanks' medium. To demonstrate the presence of LEM the supernatant thus produced was injected into rats and then after 24 h increases in the plasma concentrations of haptoglobin, alpha 2 macroglobulin and fibrinogen were estimated. For comparison rats were also injected with LEM prepared from rabbit peritoneal cells. Because these cells were obtained from rabbits which had been stimulated by i.p. injection of glycogen, addition of zymosan in vitro was not required. Despite the different species from which the leucocytes were obtained and the different method of preparation of LEM, similar increases in concentration of haptoglobin, fibrinogen and alpha 2 macroglobulin in the plasma of the recipient rats were obtained. Because injection of LEM resulted in very varied increases in concentration of each of the 3 plasma proteins, an attempt was made to ascertain whether positive responses for all 3 proteins occurred in the same rats or whether the rats responded randomly. The presence of endogenous pyrogen as a constituent of the LEM produced from both sources was confirmed using both rabbits and prewarmed mice (Bodel and Miller, 1976).

Animals↗
PubMed1976

The alpha macroglobulins of rat serum.

A three-stage method for isolation of alpha1 macroglobulin and alpha2 macroglobulin from the serum of normal and injured rats is described. The methods successively used, namely gel filtration, ultracentrifugation and chromatography on DEAE-cellulose, were chosen to minimize loss of tryptic esterase-protecting activity. The two proteins differed slightly with respect to the following properties: mol.wt., alpha1 macroglobulin 7.46 X 10(5), alpha2 macroglobulin 7.16 X 10(5); isoelectric focusing, alpha1, macroglobulin pI 4.4, alpha2 macroglobulin pI4.5. Amino acid analyses were identical, except with respect to tyrosine: alpha1 macroglobulin 3.96 +/- 0.24, alpha2 macroglobulin 3.16 +/- 0.32 mol/100 mol of total amino acids. When isolated from the serum of uninjured rats, alpha1 macroglobulin retained the capacity to bind 1.05 mol of trypsin/mol. However, if isolated from serum 2 days after injury only 0.78 mol of trypsin/mol of alpha1 macroglobulin was bound. alpha2 macroglobulin isolated from this latter serum bound on average 0.97 mol of trypsin/mol. When reduced with N-acetylcysteine, both molecules formed subunits of size corresponding to that expected for quarter molecules. When alpha2 macroglobulin was reduced with dithiothreitol, quarter molecules were again produced. alpha1 macroglobulin, however, when thus treated gave a more complex mixture, containing a component having a mol.wt. of less than 6 X 10(4). Antisera raised against the two proteins permitted estimation of the concentration of each protein in the plasmas or sera of normal and injured rats. Plasma from normal male rats contained 3.76 +/- 0.56 mg of alpha1 macroglobulin/ml (n = 33) and 0.016 +/- 0.001 mg of alpha2 macroglobulin/ml (n=33). After injury by injection of turpentine and cortisone, the concentrations in plasma were at 3 days 5.19 +/- 0.81 mg of alpha1 macroglobulin/ml (n = 12) and at 2 days 1.38 +/- 0.35 mg of alpha2 macroglobulin/ml (n = 12). Antisera to the two proteins did not cross-react with one another. The quarter molecules formed by reduction of both proteins showed increased antigenicity.

Amino Acids↗
PubMed1976

Effects of injury on the concentration of alpha1-macroglobulin and alpha2-macroglobulin in the plasmas of male and remale rats.

The effects of injury on the concentration of alpha1-macroglobulin and alpha2-macroglobulin in the plasmas of male and remale rats has been investigates. At 5 days after injury to the male rats the alpha1-macroglobulin concentration increased to 131% of its preinjury value. The alpha2-macroglobulin concentration increased more rapidly to a maximum of 86 times its initial value. In the female rats alpha2-macroglobulin increased only slightly and alpha1-macroglobulin not at all.

Animals↗
PubMed1976

The role of the acute phase reaction in inflammation.

Inflammation and injury to tissue results in a variety of local and systemic events, however although the local events of oedema formation and cellular infiltration have received considerably more attention the systemic response to inflammation is no less profound. The particular systemic event which forms the substance of this communication is the change in the circulating levels of plasma proteins which occurs after inflammatory injury, and the manner in which these changes in plasma concentration are controlled by changes in plasma concentration are controlled by changes in the rate of synthesis. A discussion of the role of the liver in controlling inflammatory events, in relation to the synthesis of an anti-inflammatory protein has been given; the present work is an extension of this and describes the changes in concentration and synthesis rate of albumin, fibrinogen and alpha1 acid glycoprotein during adjuvant arthritis in the rat. The changes which occur are regulated at the liver by alteration of the rate of synthesis of the individual protein. For example albumin at the height of adjuvant arthritis falls to a third of its normal plasma level whereas the level of alpha1 acid glycoprotein increases up to twenty-fold; these changes are reflected by similar changes in their synthesis rate by the liver. The effect of the fall in albumin concentration on the plasma binding of anti-inflammatory drugs (and their toxicity) in relation to these findings will be discussed along with the biological role of the acute phase plasma proteins and hence the influence of the liver in the response to injury.

Animals↗