title: Modulation of Endothelial Inflammation by Low and High Magnitude Cyclic Stretch.
abstract: Excessive mechanical ventilation exerts pathologic mechanical strain on lung vascular endothelium and promotes endothelial cell (EC) inflammatory activation; however, the specific mechanisms underlying EC inflammatory response caused by mechanical ventilation related cyclic stretch (CS) remain unclear. This study investigated the effects of chronic exposure to CS at physiologic (5%) and pathologic (18%) magnitude on pulmonary EC inflammatory status in control conditions and bacterial lipopolysacharide (LPS)-stimulated conditions. EC exposure to high or low CS magnitudes for 28-72 hrs had distinct effects on EC inflammatory activation. 18% CS increased surface expression of endothelial adhesion molecule ICAM1 and release of its soluble form (sICAM1) and inflammatory cytokine IL-8 by CS-stimulated pulmonary endothelial cells (EC). EC inflammatory activation was not observed in EC exposed to 5% CS. Chronic exposure to 18% CS, but not to 5% CS, augmented ICAM1 and IL-8 production and EC monolayer barrier disruption induced by LPS. 18% CS, but not 5% CS, stimulated expression of RhoA GTPase-specific guanine nucleotide exchange factor GEF-H1. GEF-H1 knockdown using gene-specific siRNA abolished 18% CS-induced ICAM1 expression and sICAM1 and IL-8 release by EC. GEF-H1 knockdown also prevented disruption of EC monolayer integrity and attenuated sICAM1 and IL-8 release in the two-hit model of EC barrier dysfunction caused by combined stimulation with 18% CS and LPS. These data demonstrate that exacerbation of inflammatory response by pulmonary endothelium exposed to excessive mechanical stretch is mediated by CS-induced induction of Rho activating protein GEF-H1.
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, United States of America.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, United States of America.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Gawlak
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: O'Donnell
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, United States of America.
authors.forename: Isa
authors.initials: I
authors.lastname: Mambetsariev
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, United States of America.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
mesh_terms: D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology*; D012121:Respiration, Artificial / Q000009:adverse effects; D064067:Rho Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D013314:Stress, Mechanical
chemical_list: C577356:ARHGEF2 protein, human; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D064067:Rho Guanine Nucleotide Exchange Factors