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Stiffness-activated GEF-H1 expression exacerbates LPS-induced lung inflammation
Isa Mambetsariev1, Yufeng Tian1, Tinghuai Wu1
1Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
Plos One
|April 18, 2014
Summary
Bacterial lipopolysaccharide (LPS) worsens acute lung injury (ALI) by increasing tissue stiffness, which amplifies inflammation. Inhibiting lysyl oxidase (LOX) reduces this stiffness-dependent inflammation, offering a potential therapeutic target for ALI.
Area of Science:
- Biomedical Engineering
- Cell Biology
- Pulmonary Medicine
Background:
- Acute lung injury (ALI) involves decreased lung compliance, but the role of tissue mechanics in inflammation is not fully understood.
- Bacterial lipopolysaccharide (LPS) is a known trigger for inflammation in ALI.
- Endothelial cell (EC) dysfunction contributes to lung barrier compromise in ALI.
Purpose of the Study:
- To investigate if bacterial lipopolysaccharide (LPS) stimulates extracellular matrix (ECM) production and vascular stiffening.
- To determine if increased tissue stiffness exacerbates endothelial cell (EC) inflammatory activation and lung barrier dysfunction.
- To elucidate the role of the GEF-H1-Rho signaling pathway in stiffness-dependent inflammation in ALI.
Main Methods:
- Analysis of GEF-H1, ICAM-1, VCAM-1, ECM proteins (fibronectin, collagen), lysyl oxidase (LOX) activity, interleukin-8, and Rho signaling activation.
- Experiments conducted on pulmonary EC cultured on soft (1.5 or 2.8 kPa) and stiff (40 kPa) substrates.
- In vivo studies involving LPS administration and LOX inhibition in a murine model.
Main Results:
- LPS induced EC inflammatory activation, ECM protein expression, increased LOX activity, and Rho signaling activation, effects augmented on stiff substrates.
- Stiffness-dependent inflammation was linked to elevated expression of the Rho activator GEF-H1.
- LOX inhibition reduced EC inflammatory activation and GEF-H1 expression in response to LPS, and attenuated LPS-induced GEF-H1 expression and lung dysfunction in vivo.
Conclusions:
- Increased tissue stiffness exacerbates LPS-induced vascular inflammation and ALI progression via the GEF-H1-Rho pathway.
- This pathway represents a novel mechanism of stiffness-dependent positive feedback regulation of inflammation in ALI.
- Lysyl oxidase (LOX) inhibition presents a potential therapeutic strategy to mitigate stiffness-dependent vascular inflammation in ALI.
