title: Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction.
abstract: Increased vascular endothelial permeability and inflammation are major pathological mechanisms of pulmonary edema and its life-threatening complication, the acute respiratory distress syndrome (ARDS). We have previously described potent protective effects of hepatocyte growth factor (HGF) against thrombin-induced hyperpermeability and identified the Rac pathway as a key mechanism of HGF-mediated endothelial barrier protection. However, anti-inflammatory effects of HGF are less understood. This study examined effects of HGF on the pulmonary endothelial cell (EC) inflammatory activation and barrier dysfunction caused by the gram-negative bacterial pathogen lipopolysaccharide (LPS). We tested involvement of the novel Rac-specific guanine nucleotide exchange factor Asef in the HGF anti-inflammatory effects. HGF protected the pulmonary EC monolayer against LPS-induced hyperpermeability, disruption of monolayer integrity, activation of NF-kB signaling, expression of adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and production of IL-8. These effects were critically dependent on Asef. Small-interfering RNA-induced downregulation of Asef attenuated HGF protective effects against LPS-induced EC barrier failure. Protective effects of HGF against LPS-induced lung inflammation and vascular leak were also diminished in Asef knockout mice. Taken together, these results demonstrate potent anti-inflammatory effects by HGF and delineate a key role of Asef in the mediation of the HGF barrier protective and anti-inflammatory effects. Modulation of Asef activity may have important implications in therapeutic strategies aimed at the treatment of sepsis and acute lung injury/ARDS-induced gram-negative bacterial pathogens.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and.
authors.forename: Fanyong
authors.initials: F
authors.lastname: Meng
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and.
authors.forename: Angelo
authors.initials: A
authors.lastname: Meliton
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and.
authors.forename: Nurgul
authors.initials: N
authors.lastname: Moldobaeva
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and.
authors.forename: Gokhan
authors.initials: G
authors.lastname: Mutlu
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawasaki
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois; and abirukov@medicine.bsd.uchicago.edu.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D055370:Lung Injury / Q000473:pathology* / Q000503:physiopathology*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C576602:ARHGEF4 protein, human; C547838:Arhgef4 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D008070:Lipopolysaccharides; D020011:Protective Agents; D064067:Rho Guanine Nucleotide Exchange Factors; D017228:Hepatocyte Growth Factor
keywords: cytoskeleton; guanine nucleotide exchange factors; hepatocyte growth factor; inflammation; permeability; pulmonary endothelium; vascular leak