Lung endothelial ADAM17 regulates the acute inflammatory response to lipopolysaccharide

Daniela Dreymueller, Christian Martin, Tanja Kogel, Jessica Pruessmeyer, Franz M. Hess, Keisuke Horiuchi, Stefan Uhlig, Andreas Ludwig

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Acute lung injury (ALI) is associated with increased vascular permeability, leukocyte recruitment, and pro-inflammatory mediator release. We investigated the role of the metalloproteinase ADAM17 in endotoxin-induced ALI with focus on endothelial ADAM17. In vitro, endotoxin-mediated induction of endothelial permeability and IL-8-induced transmigration of neutrophils through human microvascular endothelial cells required ADAM17 as shown by inhibition with GW280264X or shRNA-mediated knockdown. In vivo, ALI was induced by intranasal endotoxin-challenge combined with GW280264X treatment or endothelial adam17-knockout. Endotoxin-triggered upregulation of ADAM17 mRNA in the lung was abrogated in knockout mice and associated with reduced ectodomain shedding of the junctional adhesion molecule JAM-A and the transmembrane chemokine CX3CL1. Induced vascular permeability, oedema formation, release of TNF-α and IL-6 and pulmonary leukocyte recruitment were all markedly reduced by GW280264X or endothelial adam17-knockout. Intranasal application of TNF-α could not restore leukocyte recruitment and oedema formation in endothelial adam17-knockout animals. Thus, activation of endothelial ADAM17 promotes acute pulmonary inflammation in response to endotoxin by multiple endothelial shedding events most likely independently of endothelial TNF-α release leading to enhanced vascular permeability and leukocyte recruitment.

Original languageEnglish
Pages (from-to)412-423
Number of pages12
JournalEMBO Molecular Medicine
Volume4
Issue number5
DOIs
Publication statusPublished - 2012 May 1

Keywords

  • Inflammation
  • Metalloproteinase
  • Neutrophil recruitment
  • Oedema
  • Shedding

ASJC Scopus subject areas

  • Molecular Medicine

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  • Cite this

    Dreymueller, D., Martin, C., Kogel, T., Pruessmeyer, J., Hess, F. M., Horiuchi, K., Uhlig, S., & Ludwig, A. (2012). Lung endothelial ADAM17 regulates the acute inflammatory response to lipopolysaccharide. EMBO Molecular Medicine, 4(5), 412-423. https://doi.org/10.1002/emmm.201200217