Dual role of lipoxin A4 in pneumosepsis pathogenesis.

Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae. LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (LXA4 and BML-111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h) sepsis were studied. Sepsis induced an early increase in LXA4, FPR2/ALX lung expression, local and systemic infection and inflammation, and mortality. Treatment with BOC-2 in early sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and 15-lipoxygenase in early sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic LXA4 or BML-111 in early sepsis decreased cell migration and worsened the infection. In late sepsis, treatment with BOC-2 had no effect, but LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator LXA4 and its receptor FPR2/ALX levels were increased in the early phase of sepsis, contributing to the septic inflammatory dysregulation. In addition, LXA4 has a dual role in sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with LXA4 system may be a new therapeutic avenue to treat sepsis.
AuthorsRegina Sordi, Octávio Menezes-de-Lima Jr, Verônica Horewicz, Karin Scheschowitsch, Laís F Santos, Jamil Assreuy
JournalInternational immunopharmacology (Int Immunopharmacol) Vol. 17 Issue 2 Pg. 283-92 (Oct 2013) ISSN: 1878-1705 [Electronic] Netherlands
PMID23816538 (Publication Type: Journal Article)
CopyrightCopyright © 2013 Elsevier B.V. All rights reserved.
Chemical References
  • 5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
  • Heptanoic Acids
  • Interleukin-1beta
  • Lipoxins
  • Oligopeptides
  • Receptors, Formyl Peptide
  • Tumor Necrosis Factor-alpha
  • formyl peptide receptor 2, mouse
  • lipoxin A4
  • tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide
  • butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine
  • Animals
  • Bacterial Load (drug effects)
  • Cell Movement (drug effects)
  • Cells, Cultured
  • Disease Progression
  • Heptanoic Acids (administration & dosage, pharmacology)
  • Interleukin-1beta (blood)
  • Klebsiella Infections (complications, immunology)
  • Klebsiella pneumoniae (immunology)
  • Lipoxins (administration & dosage, immunology, metabolism)
  • Lung (drug effects, immunology, microbiology)
  • Male
  • Mice
  • Oligopeptides (administration & dosage, pharmacology)
  • Receptors, Formyl Peptide (agonists, antagonists & inhibitors)
  • Sepsis (etiology, immunology)
  • Tumor Necrosis Factor-alpha (blood)

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