Lysosomal enzyme release, effect

Neutrophils represent an ideal system for studying osmotic effects on exocytosis. Stimulation of cytochalasin-B-treated neutrophils with the chemotactic peptide Jlf-formylmethionyl-leucyl-phenyl-alanine (FMLP) results in a rapid compound exocytosis up to 80% of lysosomal enzymes are released within 30 s (9-14). Secretion appears to be triggered by a rise in the level of cytosolic free calcium (15-18) promoted in part by entry of extracellular calcium through receptor-gated channels and in part by release of calcium that is sequestered or bound at some intracellular site (19-21). In this presentation, we augment our previously published data (22,23), which demonstrates that lysosomal enzyme release from neutrophils is inhibited under hyperosmotic conditions and that the rise in cytosolic calcium preceding secretion is inhibited as well. 

Figure 4. Effect of hyperosmolality on lysosomal enzyme release from rabbit neutrophils. Cells were preincubated 10 min at 37 C in either regular HEPES buffer at 320 mosmol/kg ( ) or in HEPES buffer with 0.3-M sucrose at 680 mosmol/kg ( ), 5 Mg/mL cyto-chalasin B was added, cells were stimulated with FMLP, and p-glucuronidase was released into the medium during a 6-min period measured.

Mecfianism of Action A corticosteroid that inhibits accumulation of inflammatory cells at inflammation sites, phagocytosis, lysosomal enzyme release, and synthesiser release of mediators of inflammation. Therapeutic Effect Decreases or prevents tissue response to inflammatory process. 

Mechanism of Action A long-acting glucocorticoid that inhibits accumulation of inflammatory cells at inflammation sites, phagocytosis, lysosomal enzyme release and synthesis, and releaseof mediators of inflammation. Therapeutic Effect Prevents and suppresses cell and tissue immune reactions and inflammatory process. Pharmacohinetics Rapidly, completely absorbed from the G1 tract after oral administration. Widely distributed. Protein binding High. Metabolized in the liver. Primarily excreted in urine. Minimally removed by hemodialysis. Half-life 3-4.5 hr. 

The actions of non-steroidal anti-inflammatory drugs appear to be diverse. Phenylbutazone and sulfmpyrzone inhibited several effects of FMLP on PMNs increased adhesiveness, stimulation of the hexosemonophosphate shunt, lysosomal enzyme release, and formation of O These effects were explained by the ability of both phenylbutazone and sulfinpyrazone to inhibit binding of labelled FMLP to PMNs. Both were selective in that neither inhibited responses of PMNs to Csa and neither inhibited the stimulation of the hexose monophosphate shunt by latex or by opsonized Candida. The responses of PMNs to FMLP, including the release of O have also been inhibited by 5,8,11,14 eicosatetraynoic acid, an inhibitor of the metabolism of arachidonic acid h by indomethacin and by... 

Auranofin is a triethylphosphine gold derivative for oral administration. It is in some respects strikingly different from the rest. Some 25% of an oral dose is absorbed through the intestinal wall and blood concentrations are some 15-25% of those reached with parenteral therapy. Auranofin is bound to cellular elements of the blood, is excreted mainly in the feces, and exhibits less tissue retention and total body gold accumulation than parenteral forms. It is more effective in acute inflammatory models and is a potent inhibitor of lysosomal enzyme release, antibody-dependent cellular toxicity, and superoxide production. Auranofin also affects humoral and cellular immune reactions. However, some have found auranofin to be rather less effective than parenteral gold. Auranofin is used in doses of 2-9 mg/day (generally 6 mg/day), which is less than the dose originally recommended. 

Moy, J.N., Gleich, G. and Thomas, L.L. (1990). Noncytotoxic activation of neutrophils by eosinophil granule major basic protein effect on superoxide anion generation and lysosomal enzyme release. J. Immunol. 145, 2626. 

Gl. Goldstein, I. M., Hoffstein, S. T., and Weissmann, G., Mechanisms of lysosomal enzyme release from human polymorphonuclear leukocytes. Effects of phorbol myristate acetate. ]. Cell Biol. 66, 647-652 (1975). 

Tissue damage present in RA is attributed in part to action of lytic lysosomal enzymes released by phagocytic cells in inflammed tissue. Auranofin inhibits the release of lysosomal enzymes from phagocytizing leukocytes at micromolar concentrations (1-10 uM) (44> 45). It did not produce leukocyte cytotoxicity nor inhibition of cell free lysosomal enzyme activity at these effective concentrations. Sodium aurothiomalate, aurothioglucose and odium aurothiosulfate did not exhibit this potent activity. 

Attempts to demonstrate a premature release of lysosomal enzymes that could account for degradation of viral single-stranded MA were negative. Lysosomal enzyme release, as measured by release of 3- glucuronidase activity, accompanied the onset of cytopathic effects of 7 Q hours after infection. The restriction process was not affected by treating cells with hydrocortisone, which has been reported to stabilize lysosomes. 

Lee, T-P., Matteliano, M.L. and Middleton, E., Jr. (1982). Effect of quercetin on human polymorphonuclear leukocyte lysosomal enzyme release and phospholipid metabolism. Life Sci. 31. 2765-2774. 

Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

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