Lipoxin A4 prevents tight junction disruption and delays the colonization of cystic fibrosis bronchial epithelial cells by Pseudomonas aeruginosa

Am J Physiol Lung Cell Mol Physiol. 2016 Jun 1;310(11):L1053-61. doi: 10.1152/ajplung.00368.2015. Epub 2016 Apr 15.

Abstract

The specialized proresolution lipid mediator lipoxin A4 (LXA4) is abnormally produced in cystic fibrosis (CF) airways. LXA4 increases the CF airway surface liquid height and stimulates airway epithelial repair and tight junction formation. We report here a protective effect of LXA4 (1 nM) against tight junction disruption caused by Pseudomonas aeruginosa bacterial challenge together with a delaying action against bacterial invasion in CF airway epithelial cells from patients with CF and immortalized cell lines. Bacterial invasion and tight junction integrity were measured by gentamicin exclusion assays and confocal fluorescence microscopy in non-CF (NuLi-1) and CF (CuFi-1) bronchial epithelial cell lines and in primary CF cultures, grown under an air/liquid interface, exposed to either a clinical or laboratory strains of P. aeruginosa LXA4 delayed P. aeruginosa invasion and transepithelial migration in CF and normal bronchial epithelial cell cultures. These protective effects of LXA4 were inhibited by the ALX/FPR2 lipoxin receptor antagonist BOC-2. LXA4 prevented the reduction in mRNA biosynthesis and protein abundance of the tight junction protein ZO-1 and reduced tight junction disruption induced by P. aeruginsosa inoculation. In conclusion, LXA4 plays a protective role in bronchial epithelium by stimulating tight junction repair and by delaying and reducing the invasion of CF bronchial epithelial cells by P. aeruginsosa.

Keywords: Pseudomonas aeruginosa; ZO-1; cystic fibrosis; lipoxin A4; tight junction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Line
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / microbiology
  • Cystic Fibrosis / pathology
  • Drug Evaluation, Preclinical
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Gene Expression
  • Humans
  • Lipoxins / pharmacology*
  • Pseudomonas Infections / microbiology*
  • Pseudomonas Infections / prevention & control
  • Pseudomonas aeruginosa / physiology
  • Receptors, Formyl Peptide / metabolism
  • Receptors, Lipoxin / metabolism
  • Respiratory Mucosa / microbiology
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism*
  • Tight Junctions / microbiology
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • FPR2 protein, human
  • Lipoxins
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
  • TJP1 protein, human
  • Zonula Occludens-1 Protein
  • lipoxin A4