Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation.

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  • Author(s): El Kebir D;El Kebir D; Gjorstrup P; Filep JG
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Sep 11; Vol. 109 (37), pp. 14983-8. Date of Electronic Publication: 2012 Aug 27.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Apoptosis/*drug effects ; Eicosapentaenoic Acid/*analogs & derivatives ; Neutrophils/*drug effects ; Phagocytosis/*drug effects ; Pneumonia/*drug therapy; Amino Acid Chloromethyl Ketones ; Analysis of Variance ; Animals ; Caspase 3/metabolism ; Caspase 8/metabolism ; Cells, Cultured ; Eicosapentaenoic Acid/antagonists & inhibitors ; Eicosapentaenoic Acid/pharmacology ; Escherichia coli ; Humans ; Mice ; Mitochondria/drug effects ; Reactive Oxygen Species/metabolism ; Receptors, Leukotriene B4/metabolism ; Statistics, Nonparametric ; Yeasts
    • Abstract:
      Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. Because the balance of prosurvival and proapoptosis signals determines the fate of neutrophils, we investigated the impact of RvE1 on neutrophil apoptosis and the outcome of neutrophil-mediated pulmonary inflammation in mice. Culture of human neutrophils with RvE1 accelerated apoptosis evoked by phagocytosis of opsonized Escherichia coli or yeast. RvE1 through the leukotriene B(4) receptor BLT1 enhanced NADPH oxidase-derived reactive oxygen species generation and subsequent activation of caspase-8 and caspase-3. RvE1 also attenuated ERK and Akt-mediated apoptosis-suppressing signals from myeloperoxidase, serum amyloid A, and bacterial DNA, shifting the balance of pro- and anti-survival signals toward apoptosis via induction of mitochondrial dysfunction. In mice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live E. coli or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pan-caspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation.
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    • Grant Information:
      MOP-97742 Canada Canadian Institutes of Health Research
    • Accession Number:
      0 (Amino Acid Chloromethyl Ketones)
      0 (Ltb4r1 protein, mouse)
      0 (Reactive Oxygen Species)
      0 (Receptors, Leukotriene B4)
      0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
      AAN7QOV9EA (Eicosapentaenoic Acid)
      EC 3.4.22.- (Caspase 3)
      EC 3.4.22.- (Caspase 8)
      GND3JH08JA (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid)
    • Publication Date:
      Date Created: 20120829 Date Completed: 20121210 Latest Revision: 20211021
    • Publication Date:
      20221213
    • Accession Number:
      PMC3443132
    • Accession Number:
      10.1073/pnas.1206641109
    • Accession Number:
      22927428