Open AccessLung endothelial ADAM17 regulates the acute inflammatory response to lipopolysaccharide
Author(s) -
Dreymueller Daniela,
Martin Christian,
Kogel Tanja,
Pruessmeyer Jessica,
Hess Franz M.,
Horiuchi Keisuke,
Uhlig Stefan,
Ludwig Andreas
Publication year - 2012
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201200217
Subject(s) - lipopolysaccharide , chemokine , vascular permeability , immunology , inflammation , endothelial stem cell , knockout mouse , tumor necrosis factor alpha , medicine , microbiology and biotechnology , biology , in vitro , pathology , receptor , biochemistry
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.