Cyclic Stretch–Induced Oxidative Stress Increases Pulmonary Alveolar Epithelial Permeability

Abstract

Mechanical ventilation with high tidal volumes has been associated with pulmonary alveolar flooding. Understanding the mechanisms underlying cyclic stretch-induced increases in alveolar epithelial permeability may be important in designing preventive measures for acute lung injury. In this work, we assessed whether cyclic stretch leads to the generation of reactive oxygen species in type I-like alveolar epithelial cells, which increase monolayer permeability via activation of NF-κB and extracellular signal-regulated kinase (ERK). We cyclically stretched type I-like rat primary alveolar epithelial cells at magnitudes of 12, 25, and 37% change in surface area (ΔSA) for 10 to 120 minutes. High levels of reactive oxygen species and of superoxide and NO specifically were detected in cells stretched at 37% ΔSA for 10 to 120 minutes. Exogenous superoxide and NO stimulation increased epithelial permeability in unstretched cells, which was preventable by the NF-κB inhibitor MG132. The cyclic stretch-induced increase in permeability was decreased by the superoxide scavenger tiron and by MG132. Furthermore, tiron had a dramatic protective effect on in vivo lung permeability under mechanical ventilation conditions. Cyclic stretch increased the activation of the NF-κB signaling pathway, which was significantly decreased with the ERK inhibitor U0126. Altogether, our in vitro and in vivo data demonstrate the sensitivity of permeability to stretch- and ventilation-induced superoxide production, suggesting that using antioxidants may be helpful in the prevention and treatment of ventilator-induced lung injury.

Early Effect of Tidal Volume on Lung Injury Biomarkers in Surgical Patients With Healthy Lungs

“…Nitrite and nitrate levels in EBC, individually or combined, are often used as biomarkers of lung nitrosative stress. Increased nitric oxide metabolites reflect activation of macrophages, neutrophils or other various lung cell types 27,44,45 through the inducible or endothelial nitric oxide synthase 46,47,48 . Nitrite in EBC and nitric oxide in exhaled air are accepted by the American Thoracic Society as complementary but not equivalent measurements of nitrosative stress 42,49,50 .…”

N-Acetylcysteine Inhibits Ventilation-Induced Collagen Accumulation in the Rat Lung

“…Superoxide (O 2 − ) production increased significantly after cyclic mechanical stretch of 2 hours in pulmonary epithelial cells (Chapman et al 2005). Significant increases in reactive oxygen species (ROS) were also measured in type I-like rat alveolar epithelial cells after 10-minute cyclic stretch at 37% change in surface area (Davidovich et al 2013), and increased ROS production was dependent on the time and magnitude of stretch. We also found that high tidal-volume ventilation could cause a decline in lung glutathione (GSH) content and a rise in the levels of serum isoprostane in the same rat model (Syrkina et al 2008).…”

Cyclic Strain Enhances Cellular Uptake of Nanoparticles

“…They mentioned that application of physiological load conditions can increase cell membrane permeability, thereby increasing the concentration of QD nanoparticles in cells. Other research further demonstrated that cyclic stretch leads to the generation of reactive oxygen species, which increase monolayer permeability via activation of NF-B and extracellular signal-regulated kinase (ERK) [28].…”