H2O2 renders cells accessible to lysis by exogenous phospholipase A2: a novel mechanism for cell damage in inflammatory processes

Dan, Phyllis; Nitzan, Dorrit W.; Dagan, Arie; Ginsburg, Isaac; Yedgar, Saul

doi:10.1016/0014-5793(96)00227-x

Cited by 49 publications

(41 citation statements)

References 26 publications

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“…29 35 In a study of the synergistic action of hydrogen peroxide and sPLA 2 we have previously observed that only after the cell surface GAGs are degraded by hydrogen peroxide is the cell membrane rendered accessible to lysis by exogenous sPLA 2 . 32 Although the relationship between GAG function and the action of inflammatory mediators is not unequivocally clear, it is well documented that GAG stripping exposes cells and tissues to damaging agents. Accordingly, it has been proposed that enrichment of cell surface GAGs would assist in protecting the cell from infection and inflammatory/allergic assaults.…”

Section: Discussionmentioning

confidence: 99%

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

Shoseyov¹,

Bibi²,

Offer³

et al. 2005

Thorax

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Background: The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A 2 (PLA 2 ). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA 2 (sPLA 2 ) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA 2 and prostaglandin E 2 . These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA 2 inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA 2 inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways. Methods: Rats sensitised with OVA were treated with the sPLA 2 inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mg) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor a (TNFa) by BAL macrophages were determined. Results: Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFa and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge. Conclusions: These findings confirm the pivotal role of sPLA 2 in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA 2 may be a new therapeutic approach to the treatment of asthma.

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Section: Discussionmentioning

confidence: 99%

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

Shoseyov¹,

Bibi²,

Offer³

et al. 2005

Thorax

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“…Then reactive oxygen entered into the cells and broke the balance between antioxidant defenses (antioxidant enzymes) and free radicals generation, which caused molecular damage and cell injury. In addition, H 2 O 2 reacted with metal ions in cells to generate extremely highly toxic hydroxyl radicals through the Fenton reaction (Dan et al, 1996). The additional CE or fraction concentration in the medium was 1 mg/mL.…”

Section: Antioxidant Activity Of Molecular-weight Fractions Throughmentioning

confidence: 99%

Evaluation of Antioxidant Activities of Extract from Beijing Roast Duck

Zhou

Fan

Wang

et al. 2014

FSTR

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“…The mechanisms by which combinations of oxidants, membrane-perforators and proteinases injure cells might involve a removal, by oxidants and perhaps also by proteinases, of membrane-associated glycosaminoglycans which facilitated the exposure the 'naked' plasma membrane to an attack by the membrane-perforating agents (Dan et al, 1996).…”

Section: The Synergism Concept Of Cellular Injurymentioning

confidence: 99%

Multi-drug strategies are necessary to inhibit the synergistic mechanism causing tissue damage and organ failure in post infectious sequelae

Ginsburg

1999

Inflammopharmacol

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The paper discusses the principal evidence that supports the concept that cell and tissue injury in infectious and post-infectious and inflammatory sequelae might involve a deleterious synergistic interaction among microbial- and host-derived pro-inflammatory agonists. Experimental models had proposed that a rapid cell and tissue injury might be induced by combinations among subtoxic amounts of three major groups of agonists generated both by microorganisms and by the host's own defense systems. These include: (1) oxidants: Superoxide, H(2)O(2), OH', oxidants generated by xanthine-xanthine-oxidase, ROO; HOC1, NO, OONO'-, (2) the membrane-injuring and perforating agents, microbial hemolysins, phospholipases A(2) and C, lysophosphatides, bactericidal cationic proteins, fatty acids, bile salts and the attack complex of complement a, certain xenobics and (3) the highly cationic proteinases, elastase and cathepsin G, as well as collagenase, plasmin, trypsin and a variety of microbial proteinases. Cell killing by combinations among the various agonists also results in the release of membrane-associated arachidonate and metabolites. Cell damage might be further enhanced by certain cytokines either acting directly on targets or through their capacity to prime phagocytes to generate excessive amounts of oxidants. The microbial cell wall components, lipoteichoic acid (LTA), lipopolysaccharides (LPS) and peptidoglycan (PPG), released following bacteriolysis, induced either by cationic proteins from neutrophils and eosinophils or by beta lactam antibiotics, are potent activators of macrophages which can release oxidants, cytolytic cytokines and NO. The microbial cell wall components can also activate the cascades of coagulation, complement and fibrinolysis. All these cascades might further synergize with microbial toxins and metabolites and with phagocyte-derived agonsits to amplify tissue damage and to induce septic shock, multiple organ failure, 'flesh-eating' syndromes, etc. The long persistence of non-biodegradable bacterial cell wall components within activated macrophages in granulomatous inflammation might be the result of the inactivation by oxidants and proteinases of bacterial autolytic wall enzymes (muramidases). The unsuccessful attempts in recent clinical trials to prevent septic shock by the administration of single antagonists is disconcerting. It does suggest however that, since tissue damage in post-infectious syndromes is most probably the end result of synergistic interactions among a multiplicity of agents, only agents which might depress bacteriolysis in vivo and 'cocktails' of appropriate antagonists, but not single antagonists, if administered at the early phases of infection especially to patients at high risk, might help to control the development of post-infectious syndromes. However, the use of adequate predictive markers for sepsis and other post-infectious complications is highly desirable. Although it is conceivable that anti-inflammatory strategies might also be counter-productive as they might...

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H₂O₂ renders cells accessible to lysis by exogenous phospholipase A₂: a novel mechanism for cell damage in inflammatory processes

Cited by 49 publications

References 26 publications

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

Evaluation of Antioxidant Activities of Extract from Beijing Roast Duck

Multi-drug strategies are necessary to inhibit the synergistic mechanism causing tissue damage and organ failure in post infectious sequelae

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