A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome
Abstract Endothelial cell (EC) dysfunction is a critical mediator of the acute respiratory distress syndrome (ARDS). Recent studies have demonstrated that stromal cell-derived factor 1α (SDF-1α) promotes EC barrier integrity. Our previous studies used a SDF-1α analogue CTCE-0214 (CTCE) in experiment...
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doaj-c542cb5de01747d29d950de8e439ebcd2020-11-25T00:50:07ZengBMCMolecular Medicine1076-15511528-36582016-03-0122111512310.2119/molmed.2015.00240A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress SyndromeChangrun Guo0Andrew Goodwin1Joy N Jones Buie2James Cook3Perry Halushka4Kelley Argraves5Basilia Zingarelli6Xian Zhang7Liping Wang8Hongkuan Fan9Department of Neurosciences, Medical University of South CarolinaPulmonary, Critical Care, Allergy, and Sleep Medicine, Medical University of South CarolinaDepartment of Neurosciences, Medical University of South CarolinaDepartment of Neurosciences, Medical University of South CarolinaMedicine, Medical University of South CarolinaRegenerative Medicine and Cell Biology, Medical University of South CarolinaDivision of Critical Care Medicine, Cincinnati Children’s Hospital Medical CenterDivision of Rheumatology and Immunology, Medical University of South CarolinaCollege of Life Science, Jilin UniversityDepartment of Neurosciences, Medical University of South CarolinaAbstract Endothelial cell (EC) dysfunction is a critical mediator of the acute respiratory distress syndrome (ARDS). Recent studies have demonstrated that stromal cell-derived factor 1α (SDF-1α) promotes EC barrier integrity. Our previous studies used a SDF-1α analogue CTCE-0214 (CTCE) in experimental sepsis and demonstrated that it attenuated vascular leak and modulated microRNA (miR) levels. We examined the hypothesis that CTCE improves EC function in lipopolysaccharide (LPS)-induced ARDS through increasing miR-126 expression. Human microvascular endothelial cells (HMVECs) were treated with thrombin to disrupt the EC integrity followed by incubation with CTCE or SDF-1α. Barrier function was determined by trans-endothelial electrical resistance assay. CTCE-induced alterations in miRNA expression and signaling pathways involved in barrier function were determined. Thrombin-induced vascular leak was abrogated by both CTCE and SDF-1α. CTCE also prevented thrombin-induced decreases of vascular endothelial (VE)-cadherin cell surface expression and expansion of the intercellular space. CTCE increased miR-126 levels and induced activation of AKT/Rac 1 signaling. Cotreatment with a miR-126 inhibitor blocked the protective effects of CTCE on AKT activation and endothelial permeability. In subsequent in vivo studies, ARDS was induced by intratracheal instillation of LPS. Intravenous injection of CTCE diminished the injury severity as evidenced by significant reductions in protein, immune cells, inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid, increased miR-126 expression and decreased pulmonary vascular leak and alveolar edema. Taken together, our data show that CTCE improves endothelial barrier integrity through increased expression of miR-126 and activation of Rac 1 signaling and represents an important potential therapeutic strategy in ARDS.http://link.springer.com/article/10.2119/molmed.2015.00240 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Changrun Guo Andrew Goodwin Joy N Jones Buie James Cook Perry Halushka Kelley Argraves Basilia Zingarelli Xian Zhang Liping Wang Hongkuan Fan |
spellingShingle |
Changrun Guo Andrew Goodwin Joy N Jones Buie James Cook Perry Halushka Kelley Argraves Basilia Zingarelli Xian Zhang Liping Wang Hongkuan Fan A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome Molecular Medicine |
author_facet |
Changrun Guo Andrew Goodwin Joy N Jones Buie James Cook Perry Halushka Kelley Argraves Basilia Zingarelli Xian Zhang Liping Wang Hongkuan Fan |
author_sort |
Changrun Guo |
title |
A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome |
title_short |
A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome |
title_full |
A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome |
title_fullStr |
A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome |
title_full_unstemmed |
A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome |
title_sort |
stromal cell-derived factor 1α analogue improves endothelial cell function in lipopolysaccharide-induced acute respiratory distress syndrome |
publisher |
BMC |
series |
Molecular Medicine |
issn |
1076-1551 1528-3658 |
publishDate |
2016-03-01 |
description |
Abstract Endothelial cell (EC) dysfunction is a critical mediator of the acute respiratory distress syndrome (ARDS). Recent studies have demonstrated that stromal cell-derived factor 1α (SDF-1α) promotes EC barrier integrity. Our previous studies used a SDF-1α analogue CTCE-0214 (CTCE) in experimental sepsis and demonstrated that it attenuated vascular leak and modulated microRNA (miR) levels. We examined the hypothesis that CTCE improves EC function in lipopolysaccharide (LPS)-induced ARDS through increasing miR-126 expression. Human microvascular endothelial cells (HMVECs) were treated with thrombin to disrupt the EC integrity followed by incubation with CTCE or SDF-1α. Barrier function was determined by trans-endothelial electrical resistance assay. CTCE-induced alterations in miRNA expression and signaling pathways involved in barrier function were determined. Thrombin-induced vascular leak was abrogated by both CTCE and SDF-1α. CTCE also prevented thrombin-induced decreases of vascular endothelial (VE)-cadherin cell surface expression and expansion of the intercellular space. CTCE increased miR-126 levels and induced activation of AKT/Rac 1 signaling. Cotreatment with a miR-126 inhibitor blocked the protective effects of CTCE on AKT activation and endothelial permeability. In subsequent in vivo studies, ARDS was induced by intratracheal instillation of LPS. Intravenous injection of CTCE diminished the injury severity as evidenced by significant reductions in protein, immune cells, inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid, increased miR-126 expression and decreased pulmonary vascular leak and alveolar edema. Taken together, our data show that CTCE improves endothelial barrier integrity through increased expression of miR-126 and activation of Rac 1 signaling and represents an important potential therapeutic strategy in ARDS. |
url |
http://link.springer.com/article/10.2119/molmed.2015.00240 |
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