Erythrocytes induce proinflammatory endothelial activation in hypoxia

Am J Respir Cell Mol Biol. 2013 Jan;48(1):78-86. doi: 10.1165/rcmb.2011-0402OC. Epub 2012 Oct 4.


Although exposure to ambient hypoxia is known to cause proinflammatory vascular responses, the mechanisms initiating these responses are not understood. We tested the hypothesis that in systemic hypoxia, erythrocyte-derived H(2)O(2) induces proinflammatory gene transcription in vascular endothelium. We exposed mice or isolated, perfused murine lungs to 4 hours of hypoxia (8% O(2)). Leukocyte counts increased in the bronchoalveolar lavage. The expression of leukocyte adhesion receptors, reactive oxygen species, and protein tyrosine phosphorylation increased in freshly recovered lung endothelial cells (FLECs). These effects were inhibited by extracellular catalase and by the removal of erythrocytes, indicating that the responses were attributable to erythrocyte-derived H(2)O(2). Concomitant nuclear translocation of the p65 subunit of NF-κB and hypoxia-inducible factor-1α stabilization in FLECs occurred only in the presence of erythrocytes. Hemoglobin binding to the erythrocyte membrane protein, band 3, induced the release of H(2)O(2) from erythrocytes and the p65 translocation in FLECs. These data indicate for the first time, to our knowledge, that erythrocytes are responsible for endothelial transcriptional responses in hypoxia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anion Exchange Protein 1, Erythrocyte / metabolism
  • Bronchoalveolar Lavage Fluid / cytology
  • E-Selectin / blood
  • Endothelium, Vascular / physiopathology
  • Erythrocytes / physiology*
  • Hydrogen Peroxide / blood
  • Hypoxia / blood*
  • Hypoxia / genetics
  • Hypoxia / physiopathology*
  • Inflammation Mediators / blood
  • Lung / blood supply
  • Lung / physiopathology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Transcription Factors / metabolism


  • Anion Exchange Protein 1, Erythrocyte
  • E-Selectin
  • Inflammation Mediators
  • Transcription Factors
  • Hydrogen Peroxide