Dual role of lipoxin A4 in pneumosepsis pathogenesis.

Abstract

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.

• Authors: Regina Sordi, Octávio Menezes-de-Lima Jr, Verônica Horewicz, Karin Scheschowitsch, Laís F Santos, Jamil Assreuy
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 17 Issue 2 Pg. 283-92 (Oct 2013) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 23816538 (Publication Type: Journal Article)
• Copyright: Copyright © 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

Topics

• 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)