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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Aspirin and Salicylate Suppress Polymorphonuclear Apoptosis Delay Mediated by Proinflammatory Stimuli

Soledad Negrotto, Elisa Malaver, María Eugenia Alvarez, Natalia Pacienza, Lina Paola D'Atri, Roberto Gabriel Pozner, Ricardo Martín Gómez and Mirta Schattner
Journal of Pharmacology and Experimental Therapeutics November 2006, 319 (2) 972-979; DOI: https://doi.org/10.1124/jpet.106.109389
Soledad Negrotto
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Elisa Malaver
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María Eugenia Alvarez
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Natalia Pacienza
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Lina Paola D'Atri
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Roberto Gabriel Pozner
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Ricardo Martín Gómez
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Mirta Schattner
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Abstract

During inflammation, polymorphonuclear leukocyte (PMN) apoptosis can be delayed by different proinflammatory mediators. Classically, it has been accepted that the widely used anti-inflammatory drug acetyl salicylic acid (ASA) exerts its action through inhibition of cyclooxygenases and subsequent prostaglandin synthesis. We hypothesized that another anti-inflammatory action of ASA could be the shortening of PMN survival. We found that at therapeutic concentrations (1–3 mM), ASA and its metabolite salicylate (NaSal), but not indomethacin or ibuprofen, counteracted the prolonged PMN survival mediated by lipopolysaccharide (LPS) through inhibition of nuclear factor-κB (NF-κB) activation. Both salicylates also inhibited interleukin (IL)-1α or acidic conditions antiapoptotic activity. Higher concentrations of both drugs had a direct apoptotic effect. Salicylates were not effective when PMN apoptosis delay was induced by granulocyte macrophage–colony-stimulating factor (GM-CSF), a NF-κB-independent cytokine. Promotion of PMN survival by the combination of IL-1α and LPS was also reversed by salicylates, but higher concentrations were required. ASA concentrations that did not trigger PMN death increase the zymosan- or tumor necrosis factor-α-mediated proapoptotic effect. The LPS- and IL-1α- but not GM-CSF-mediated antiapoptotic effect was markedly reduced in PMNs from donors who had ingested ASA. Using a thioglycolate-induced peritonitis model, we showed that in ASA- or NaSal-treated mice there was not only a decrease in the number of cells recruited but also an increase in the percentage of apoptotic PMNs as well as an enhancement of phagocytosis compared with controls. Our findings demonstrate that acceleration of PMN apoptosis by turning off the NF-κB-mediated survival signals elicited by proinflammatory stimuli is another anti-inflammatory action of ASA and NaSal.

Footnotes

  • This work was supported by the National Agency of Scientific and Technological Support Grant PICT 14353.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.109389.

  • ABBREVIATIONS: PMN, polymorphonuclear leukocyte; IL, interleukin; GM-CSF, granulocyte macrophage–colony-stimulating factor; LPS, lipopolysaccharide; ASA, acetyl salicylic acid; COX, cyclooxygenase; NaSal, sodium salicylate; PI, propidium iodide; FITC, fluorescein isothiocyanate; NF-κB, nuclear factor-κB; TNF, tumor necrosis factor.

    • Received June 14, 2006.
    • Accepted August 24, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 387 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 387, Issue 1
1 Oct 2023
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Aspirin and Salicylate Suppress Polymorphonuclear Apoptosis Delay Mediated by Proinflammatory Stimuli

Soledad Negrotto, Elisa Malaver, María Eugenia Alvarez, Natalia Pacienza, Lina Paola D'Atri, Roberto Gabriel Pozner, Ricardo Martín Gómez and Mirta Schattner
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 972-979; DOI: https://doi.org/10.1124/jpet.106.109389

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Aspirin and Salicylate Suppress Polymorphonuclear Apoptosis Delay Mediated by Proinflammatory Stimuli

Soledad Negrotto, Elisa Malaver, María Eugenia Alvarez, Natalia Pacienza, Lina Paola D'Atri, Roberto Gabriel Pozner, Ricardo Martín Gómez and Mirta Schattner
Journal of Pharmacology and Experimental Therapeutics November 1, 2006, 319 (2) 972-979; DOI: https://doi.org/10.1124/jpet.106.109389
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