Lysosomes enzyme complement

Cellular Effects of Complement Activation. C5a is chemotactic for neutrophils, activates their oxidative metabolism, and induces secretion of lysosomal enzymes from the granulocytes and macrophages. C5a may also induce the production of cytokines and prostaglandins (H19, S14). 

Endotoxin activates complement, which then augments the inflammatory response through stimulation of leukocyte chemotaxis, phagocytosis and lysosomal enzyme release, increased platelet adhesion and aggregation, and production of toxic superoxide radicals. 

Prevalence of byssinosis correlates better with airborne endotoxin concentration than with total dust (65). Also, gramnegative bacteria levels in the mill correlate well with disease (66). It has been hypothesized that endotoxins elicit symptoms of byssinosis by activation of both the classical and the alternative pathway of complement with subsequent release of anaphylatoxins, which lead to airway narrowing, and chemotaxins, which cause the influx of PMNs followed by release of lysosomal enzymes and, ultimately, tissue damage. In experiments with guinea pigs using bract, cotton, and gin mill trash extracts, there is a strong correlation between number of PMNs recruited to airways and level of endotoxin (67). 

Type 3, immune complex vasculitis (serum sickness, Arthus reaction). Drug-antibody complexes precipitate on vascular walls, complement is activated, and an inflammatory reaction is triggered. Attracted neutrophils, in a futile attempt to phagocytose the complexes, liberate lysosomal enzymes that damage the vascular walls (inflammation, vasculitis). Symptoms may include fever, exanthema swelling of lymph nodes, arthritis, nephritis, and neuropathy. 

There are thus various autoantibodies present, and if the auto-antigens are released by cellular breakdown, a type III immune reaction can occur where an immune complex is formed, which is deposited in small blood vessels and joints, giving rise to many of the symptoms. The immunoglobulins IgG and IgE act as both autoantibody and antigen, and hence immune complexes form. Such complexes stimulate the complement system leading to inflammation, infiltration by polymorphs and macrophages, and the release of lysosomal enzymes. 

Gold alters the morphology and functional capabilities of human macrophages—possibly its major mode of action. As a result, monocyte chemotactic factor-1, interleukin-8, interleukin-IB production, and vascular endothelial growth factor are all inhibited. Intramuscular gold compounds also alter lysosomal enzyme activity, reduce histamine release from mast cells, inactivate the first component of complement, and suppress the phagocytic activities of polymorphonuclear leukocytes. Auranofin also inhibits release of prostaglandin E2 and leukotriene B4. 

Schorlemmer, H.-U., Davies, P., and Allison, A., Ability of activated complement components to induce lysosomal enzyme release from macrophages. Nature (London) 261, 48-52 (1976). 

Hepatocytes from patients with I-cell disease contain a normal complement of lysosomal enzymes and no Inclusions, even though these cells are defective In mannose phosphorylation. This finding Implies that hepatocytes (the most abundant type of liver cell) employ a MGP-Independent pathway for sorting lysosomal enzymes. The nature of this pathway, which also may operate In other cells types, Is unknown. I... 

The mechanisms of enzyme secretion and chemotaxis have obvious similarities. Thus, many chemotactic factors are also secretagogues for lysosomal enzyme secretion, e.g. fMLP [283,284]. Compounds causing secretion [285] and/or phagocytosis [286] increase the liberation of arachidonic acid from the phospholipids in a Ca -dependent manner [287]. Arachidonic acid in the presence of cytochalasin B causes enzyme release from rabbit peritoneal PMNL but not from human PMNL [152,288,290]. The acetylenic analog of arachidonic acid (5,8,11,14-eicosatetraenoic acid, ETYA) and nordihydroguiaiaretic acid (NDGA), both inhibitors of lipoxygenase, inhibit enzyme secretion induced by arachidonic acid [291,292] or chemotactic peptides and the complement factor C5a [289],... 

The pathophysiology of immune complex reactions occurs in several stages formation of immune complexes in antigen excess, deposition of complexes in tissue, activation of complement followed by attraction at the site of plynuclear neutrophils, and liberation in tissue of proteolytic lysosomal enzymes and inflammatory cationic proteins. The importance of concomitant increase in vascular permeability for the deposition of immune complexes has been shown in vivo by the preventive effect of antihistaminic and antiserotonin drugs on the development of serum sickness to horse antidiphteric serum (Kniker et al. 1971). 

Finally, the rate of degradation can also depend on the activity of the degrading system. The presence or absence of lysosomes and their enzyme complements, for example, may influence the degree of degradation (De Duve, 1963 Weber, 1963). 

It is reasonable that the process of vesiculation occurs at an equilibrium rate, constant for each cell species and modified by the metabolic demands of the cells. We have suggested (Verity and Brown, 1968b), from maturation studies of cerebral lysosomal enzymes, that for a given rate of vesiculation, the enzyme complement of the primary lysosome is directly proportional to the individual rates of synthesis of the component enzymes. Such a hypothesis would account for the heterogeneity in acid hydrolase reaction to injury, the difference in maturation profiles of individual acid hydrolases, and the dysynchrony of acid hydrolase induction. Also suggested is a direct feedback mechanism whereby a stimulation of vesiculation may in turn induce increased enzyme synthesis, possibly through changes in membrane phospholipid metabolism. 

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