Article ; Online: Asef mediates HGF protective effects against LPS-induced lung injury and endothelial barrier dysfunction.
American journal of physiology. Lung cellular and molecular physiology
2014 Volume 308, Issue 5, Page(s) L452–63
Abstract: ... protective effects against LPS-induced EC barrier failure. Protective effects of HGF against LPS-induced ... of the HGF barrier protective and anti-inflammatory effects. Modulation of Asef activity may have important ... guanine nucleotide exchange factor Asef in the HGF anti-inflammatory effects. HGF protected the pulmonary EC monolayer against LPS ...
| 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. |
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| MeSH term(s) | Cell Adhesion/drug effects ; Cell Membrane Permeability/drug effects ; Cell Movement/drug effects ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/pathology ; Endothelium, Vascular/physiopathology ; Guanine Nucleotide Exchange Factors/metabolism ; Hepatocyte Growth Factor/pharmacology ; Humans ; Inflammation/pathology ; Lipopolysaccharides ; Lung/drug effects ; Lung/pathology ; Lung/physiopathology ; Lung Injury/pathology ; Lung Injury/physiopathology ; Neutrophils/cytology ; Neutrophils/drug effects ; Protective Agents/pharmacology ; Rho Guanine Nucleotide Exchange Factors/metabolism ; Signal Transduction/drug effects | ||||||||||
| Chemical Substances | ARHGEF4 protein, human ; Arhgef4 protein, mouse ; Guanine Nucleotide Exchange Factors ; Lipopolysaccharides ; Protective Agents ; Rho Guanine Nucleotide Exchange Factors ; Hepatocyte Growth Factor (67256-21-7) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2014-12-24 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural | ||||||||||
| ZDB-ID | 1013184-x | ||||||||||
| ISSN | 1522-1504 ; 1040-0605 | ||||||||||
| ISSN (online) | 1522-1504 | ||||||||||
| ISSN | 1040-0605 | ||||||||||
| DOI | 10.1152/ajplung.00170.2014 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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