Lipoxin A(4) regulates bronchial epithelial cell responses to acid injury

Am J Pathol. 2006 Apr;168(4):1064-72. doi: 10.2353/ajpath.2006.051056.


Aspiration of gastric acid commonly injures airway epithelium and, if severe, can lead to respiratory failure from acute respiratory distress syndrome. Recently, we identified cyclooxygenase-2 (COX-2)-derived prostaglandin E(2) (PGE(2)) and lipoxin A(4) (LXA(4)) as pivotal mediators in vivo for resolution of acid-initiated acute lung injury. To examine protective mechanisms for these mediators in the airway, we developed an in vitro model of acid injury by transiently exposing well-differentiated normal human bronchial epithelial cells to hydrochloric acid. Transmission electron microscopy revealed selective injury to superficial epithelial cells with disruption of cell attachments and cell shedding. The morphological features of injury were substantially resolved within 6 hours. Acid triggered and early marked increases in COX-2 expression and PGE(2) production, and acid-induced PGE(2) significantly increased epithelial LXA(4) receptor (ALX) expression. LXA(4) is generated in vivo during acute lung injury, and we observed that nanomolar quantities increased basal epithelial cell proliferation and potently blocked acid-triggered interleukin-6 release and neutrophil transmigration across well-differentiated normal human bronchial epithelial cells. Expression of recombinant human ALX in A549 airway epithelial cells uncovered ALX-dependent inhibition of cytokine release by LXA(4). Together, these findings indicate that injured bronchial epithelial cells up-regulate ALX in a COX-2-dependent manner to promote LXA(4)-mediated resolution of airway inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchi / metabolism*
  • Bronchi / ultrastructure
  • Cell Adhesion
  • Cell Proliferation
  • Cells, Cultured
  • Cyclooxygenase 2 / biosynthesis
  • Dinoprostone / biosynthesis
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology*
  • Epithelial Cells / ultrastructure
  • Gastric Acid / physiology*
  • Humans
  • Hydrochloric Acid / toxicity
  • Lipoxins / physiology*
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / biosynthesis
  • Microscopy, Electron, Transmission
  • Nitrobenzenes / pharmacology
  • Receptors, Formyl Peptide / biosynthesis
  • Receptors, Lipoxin / biosynthesis
  • Respiratory Mucosa / metabolism*
  • Respiratory Mucosa / ultrastructure
  • Sulfonamides / pharmacology


  • FPR2 protein, human
  • Lipoxins
  • Membrane Proteins
  • Nitrobenzenes
  • Receptors, Formyl Peptide
  • Receptors, Lipoxin
  • Sulfonamides
  • lipoxin A4
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Dinoprostone
  • Hydrochloric Acid