Amifostine reduces lung vascular permeability via suppression of inflammatory signalling

P. Fu, A. A. Birukova, J. Xing, S. Sammani, J. S. Murley, J. G.N. Garcia, D. J. Grdina, K. G. Birukov

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Despite an encouraging outcome of antioxidant therapy in animal models of acute lung injury, effective antioxidant agents for clinical application remain to be developed. The present study investigated the effect of pre-treatment with amifostine, a thiol antioxidant compound, on lung endothelial barrier dysfunction induced by Gram-negative bacteria wall-lipopolysaccharide (LPS). Endothelial permeability was monitored by changes in transendothelial electrical resistance. Cytoskeletal remodelling and reactive oxygen species (ROS) production was examined by immunofluorescence. Cell signalling was assessed by Western blot. Measurements of Evans blue extravasation, cell count and protein content in bronchoalveolar lavage fluid were used as in vivo parameters of lung vascular permeability. Hydrogen peroxide, LPS and interleukin-6 caused cytoskeletal reorganisation and increased permeability in the pulmonary endothelial cells, reflecting endothelial barrier dysfunction. These disruptive effects were inhibited by pre-treatment with amifostine and linked to the amifostine-mediated abrogation of ROS production and redox-sensitive signalling cascades, including p38, extracellular signal regulated kinase 1/2, mitogen-activated protein kinases and the nuclear factor-κB pathway. In vivo, concurrent amifostine administration inhibited LPS-induced oxidative stress and p38 mitogen-activated protein kinase activation, which was associated with reduced vascular leak and neutrophil recruitment to the lungs. The present study demonstrates, for the first time, protective effects of amifostine against lipopolysaccharide-induced lung vascular leak in vitro and in animal models of lipopolysaccharide-induced acute lung injury. Copyright

Original languageEnglish (US)
Pages (from-to)612-624
Number of pages13
JournalEuropean Respiratory Journal
Volume33
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Keywords

  • Endothelium
  • Lipopolysaccharide
  • Lung
  • Permeability
  • Reactive oxygen species

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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  • Cite this

    Fu, P., Birukova, A. A., Xing, J., Sammani, S., Murley, J. S., Garcia, J. G. N., Grdina, D. J., & Birukov, K. G. (2009). Amifostine reduces lung vascular permeability via suppression of inflammatory signalling. European Respiratory Journal, 33(3), 612-624. https://doi.org/10.1183/09031936.00014808