title: Lung endothelial ADAM17 regulates the acute inflammatory response to lipopolysaccharide.
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.
authors.affiliation: Interdisciplinary Center for Clinical Research, RWTH Aachen University, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dreymueller
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
authors.forename: Tanja
authors.initials: T
authors.lastname: Kogel
authors.forename: Jessica
authors.initials: J
authors.lastname: Pruessmeyer
authors.forename: Franz M
authors.initials: FM
authors.lastname: Hess
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology* / Q000633:toxicity; D008168:Lung / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000139:chemically induced*; D011956:Receptors, Cell Surface / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C498686:F11r protein, mouse; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse