@article{TEXTUAL,
      recid = {8801},
      author = {Mambetsariev, Isa and Tian, Yufeng and Wu, Tinghuai and  Lavoie, Tera and Solway, Julian and Konstantin G. Birukov  and Birukova, Anna A.},
      title = {Stiffness-Activated GEF-H1 Expression Exacerbates  LPS-Induced Lung Inflammation},
      journal = {PLOS ONE},
      address = {2014-04-16},
      number = {TEXTUAL},
      abstract = {<p>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. <em>In vivo</em>, 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.</p>},
      url = {http://knowledge.uchicago.edu/record/8801},
}