Intracellular Digestion: Lysosomes and Cellular Injury

Goldstein, Ira M.; Weissmann, Gerald

doi:10.1002/cphy.cp090139

Cited by 4 publications

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“…Previous investigations of silica cytotoxicity led to the suggestion that intracellular lysosomal rupture is responsible for the cell death produced by this as well as other toxins and environmental hazards (16) . The present study has subjected this hypothesis to critical evaluation .…”

Section: Discussionmentioning

confidence: 99%

“…In various pathological states, cell injury may be produced by either extracellular or intracellular release of lysosomal enzymes (16). Extracellular release of lysosomal enzymes ac-THE JOURNAL OF CELL BIOLOGY " VOLUME 87 DECEMBER 1980 643-651 ©The Rockefeller University Press -0021-9525/80/12/0643/09$1 .00 companies endocytosis by phagocytic cells (5,41), exposure to immobilized immune complexes (10), and lysis of necrotic cells (40).…”

mentioning

confidence: 99%

“…Extracellular release of lysosomal enzymes ac-THE JOURNAL OF CELL BIOLOGY " VOLUME 87 DECEMBER 1980 643-651 ©The Rockefeller University Press -0021-9525/80/12/0643/09$1 .00 companies endocytosis by phagocytic cells (5,41), exposure to immobilized immune complexes (10), and lysis of necrotic cells (40). When released extracellularly, lysosomal enzymes may damage surrounding tissues and trigger an acute inflammatory response (16). Intracellular lysosomal rupture occurs when cells are exposed to a variety of toxic or environmental hazards.…”

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confidence: 99%

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Dissociation of intracellular lysosomal rupture from the cell death caused by silica

Kane¹,

Stanton²,

Raymond³

et al. 1980

The Journal of Cell Biology

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The relationship between intracellular lysosomal rupture and cell death caused by silica was studied in P388D, macrophages. After 3 h of exposure to 150 Jig silica in medium containing 1 .8 mM Ca", 60% of the cells were unable to exclude trypan blue . In the absence of extracellular Ca", however, all of the cells remained viable . Phagocytosis of silica particles occurred to the same extent in the presence or absence of Ca" . The percentage of P388D, cells killed by silica depended on the dose and the concentration of Ca" in the medium . Intracellular lysosomal rupture after exposure to silica was measured by acridine orange fluorescence or histochemical assay of horseradish peroxidase . With either assay, 60% of the cells exposed to 150 Ftg silica for 3 h in the presence or absence of Ca" showed intracellular lysosomal rupture, whereas cell death occurred only in the presence of Ca" . Intracellular lysosomal rupture was not associated with measurable degradation of total DNA, RNA, protein, or phospholipid or accelerated turnover of exogenous horseradish peroxidase . Pretreatment with promethazine (20 pg/ml) protected 80% of P388D, macrophages against silica toxicity although lysosomal rupture occurred in 60-70% of the cells. Intracellular lysosomal rupture was prevented in 80% of the cells by pretreatment with indomethacin (5 x 10 -5 M), yet 40-50% of the cells died after 3 h of exposure to 150 p,g silica in 1 .8 mM extracellular Ca" . The calcium ionophore A23187 also caused intracellular lysosomal rupture in 90-98% of the cells treated for 1 h in either the presence or absence of extracellular Ca t+ . With the addition of 1 .8 mM Ca 2+, 80% of the cells was killed after 3 h, whereas all of the cells remained viable in the absence ofCa". These experiments suggest that intracellular lysosomal rupture is not causally related to the cell death caused by silica or A23187 . Cell death is dependent on extracellular Ca 2+ and may be mediated by an influx of these ions across the plasma membrane permeability barrier damaged directly by exposure to these toxins .Lysosomes participate in the physiological turnover of cellular macromolecules (15), limited autophagy of cellular organelles, and storage of undegradable materials (13). At least 60 different enzymes capable of digesting nucleic acids, proteins, lipids, and carbohydrates (6) are contained in these membrane-bound organelles, separated from their potential substrates. Endogenous or exogenous substances enter the lysosome by fusion of autophagic (13) or endocytic vacuoles (34) with lysosomes. This confines hydrolytic processes to the lysosome and presumably prevents unregulated intracellular digestion (13) .In various pathological states, cell injury may be produced by either extracellular or intracellular release of lysosomal enzymes (16). Extracellular release of lysosomal enzymes ac-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Dissociation of intracellular lysosomal rupture from the cell death caused by silica

Kane¹,

Stanton²,

Raymond³

et al. 1980

The Journal of Cell Biology

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“…This sequence of events, in which ligandreceptor interactions signal rapid cellular rearrangements designed to eliminate foreign invaders, is initiated at the level of the plasma membrane (1). Because a membrane potential (A21) has been demonstrated in nonexcitable cells, as well as in nerve and muscle, it was considered possible that changes in membrane potential could antecede other responses of the PMN, such as 02--generation which is only detected after a "lag" period of 30-42 sec (1). Membrane potential changes associated with receptor-ligand interaction have been demonstrated in other cell types.…”

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Changes in membrane potential of human granulocytes antecede the metabolic responses to surface stimulation

Korchak

Weissmann

1978

Proc. Natl. Acad. Sci. U.S.A.

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195

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Human granulocytes (polymorphonuclear leukocytes) exposed to surface stimuli [e.g., immune complexes, concanavalin A (Con A)] generate°2--, undergo a respiratory burst, and secrete lysosomal enzymes. To study the earliest reaction of ligands with surface receptors of granulocytes, purified cells were exposed to bovine serum albumin-anti-albumin complexes (Fc receptors) MATERIALS AND METHODS Preparation of PMN Suspensions. PMN suspensions containing 98 + 1% PMN were prepared from heparinized venous blood (10 units of heparin per ml of blood) obtained from healthy adult donors. Standard techniques (Hypaque/Ficoll gradients) were used (19) followed by dextran sedimentation and hypotonic lysis. The cells were suspended in Krebs-Ringer pH 7.45 phosphate buffer (KRP; Na+, 149 mM; K+, 4.8 mM;Ca2+, 1.3 mM; Mg2+, 1.2 mM; P043-, 15.6 mM; Cl-, 140 mM).This buffer was used throughout unless otherwise indicated. In buffers from which divalent cations were omitted, an equal volume of 0.9% NaCl was substituted. The high-K+ buffer was prepared by substituting KCl for NaCl and potassium phosphate buffer for the sodium phosphate buffer.TPMP+ Distribution Measurements. Uptake of TPMP+ was measured by a minor modification of the method of Schuldiner and Kaback (13). PMNs were incubated in KRP at 370 in the presence of 100MuM [H3]TPMP+ (120 Ci/mol), in a final volume of 100 gl. Incubations were carried out in 5-ml glass culture tubes treated with Siliclad (Clay-Adams) in order to minimize cell adhesion to the tube. The reaction was terminated by the addition of 3 ml of ice-cold 0.9% saline (<1 sec) followed by rapid filtration on a 0.5-,m-pore-diameter Celotate filter (Millipore). This was followed by a further rinse with 3 ml of ice-cold saline. The number of PMNs per assay (usually 4 X 106) was chosen to ensure that the entire filtration and washing procedure could be carried out in less than 20 sec. The Abbreviations: PMN, polymorphonuclear leukocyte; KRP, KrebsRinger phosphate buffer; TPMP+, triphenylmethyl phosphonium ion; Con A, concanavalin A; Ab/Ag, immune complex of bovine serum albumin and anti-bovine serum albumin IgG; Alt', membrane potential; PNa+, Na+ permeability; PK+, K+ permeability; EGTA, ethylene glycol-bis(fl-aminoethyl ether)-N,N'-tetraacetic acid.

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Ethanol Impairs Biliary Lysosomal Enzyme Release in Rats

Sewell

Grinpukel

Yeomans

1986

Clin Exp Pharma Physio

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The effects of ethanol on hepatic lysosomes are poorly documented. This study examined the biliary release of lysosomal enzymes, a marker of the hepatocyte-to-bile excretory pathway, after ethanol administration in the isolated perfused rat liver model. At concentrations similar to those reached in human plasma during social drinking, ethanol markedly decreased biliary lysosomal enzyme output and bile flow in the rat. Ethanol did not affect hepatic activities or the release into perfusate of lysosomal and other subcellular marker enzymes. Hence, ethanol may potentially inhibit hepatocyte-to-bile excretion of other compounds processed through lysosomes.

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Intracellular Digestion: Lysosomes and Cellular Injury

Abstract: The sections in this article are: Origin and Function of Lysosomes Lysosomes and Tissue Injury Lysosomal Enzymes Autophagy Mechanisms of Lysosomal Enzyme Release Interactions of Lysosomes With Chemical and Physical Agents Physical Agents … Show more

Cited by 4 publications

References 122 publications

Dissociation of intracellular lysosomal rupture from the cell death caused by silica

Dissociation of intracellular lysosomal rupture from the cell death caused by silica

Changes in membrane potential of human granulocytes antecede the metabolic responses to surface stimulation

Ethanol Impairs Biliary Lysosomal Enzyme Release in Rats

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