title: Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation.
abstract: Acute lung injury (ALI) is accompanied by decreased lung compliance. However, a role of tissue mechanics in modulation of inflammation remains unclear. We hypothesized that bacterial lipopolysacharide (LPS) stimulates extracellular matrix (ECM) production and vascular stiffening leading to stiffness-dependent exacerbation of endothelial cell (EC) inflammatory activation and lung barrier dysfunction. Expression of GEF-H1, ICAM-1, VCAM-1, ECM proteins fibronectin and collagen, lysyl oxidase (LOX) activity, interleukin-8 and activation of Rho signaling were analyzed in lung samples and pulmonary EC grown on soft (1.5 or 2.8 kPa) and stiff (40 kPa) substrates. LPS induced EC inflammatory activation accompanied by expression of ECM proteins, increase in LOX activity, and activation of Rho signaling. These effects were augmented in EC grown on stiff substrate. Stiffness-dependent enhancement of inflammation was associated with increased expression of Rho activator, GEF-H1. Inhibition of ECM crosslinking and stiffening by LOX suppression reduced EC inflammatory activation and GEF-H1 expression in response to LPS. In vivo, LOX inhibition attenuated LPS-induced expression of GEF-H1 and lung dysfunction. These findings present a novel mechanism of stiffness-dependent exacerbation of vascular inflammation and escalation of ALI via stimulation of GEF-H1-Rho pathway. This pathway represents a fundamental mechanism of positive feedback regulation of inflammation.
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, 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, 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, United States of America.
authors.forename: Tinghuai
authors.initials: T
authors.lastname: Wu
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Tera
authors.initials: T
authors.lastname: Lavoie
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Konstantin G
authors.initials: KG
authors.lastname: Birukov
authors.affiliation: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Birukova
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D025461:Feedback, Physiological; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism; D012234:Rho Factor / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C577356:ARHGEF2 protein, human; D005353:Fibronectins; D016209:Interleukin-8; D008070:Lipopolysaccharides; D012234:Rho Factor; D064067:Rho Guanine Nucleotide Exchange Factors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase
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