Simvastatin Treatment Modulates Mechanically-Induced Injury and Inflammation in Respiratory Epithelial Cells

Abstract

Mechanical forces in the respiratory system, including surface tension forces during airway reopening and high transmural pressures, can result in epithelial cell injury, barrier disruption and inflammation. In this study, we investigated if a clinically relevant pharmaceutical agent, Simvastatin, could mitigate mechanically induced injury and inflammation in respiratory epithelia. Pulmonary alveolar epithelial cells (A549) were exposed to either cyclic airway reopening forces or oscillatory transmural pressure in vitro and treated with a wide range of Simvastatin concentrations. Simvastatin induced reversible depolymerization of the actin cytoskeleton and a statistically significant reduction the cell’s elastic modulus. However, Simvastatin treatment did not result in an appreciable change in the cell’s viscoelastic properties. Simvastatin treated cells did exhibit a reduced height-to-width aspect ratio and these changes in cell morphology resulted in a significant decrease in epithelial cell injury during airway reopening. Interestingly, although very high concentrations (25–50 μM) of Simvastatin resulted in dramatically less IL-6 and IL-8 pro-inflammatory cytokine secretion, 2.5 μM Simvastatin did not reduce the total amount of pro-inflammatory cytokines secreted during mechanical stimulation. These results indicate that although Simvastatin treatment may be useful in reducing cell injury during airway reopening, elevated local concentrations of Simvastatin might be needed to reduce mechanically-induced injury and inflammation in respiratory epithelia.

Using a Novel Microfabricated Model of the Alveolar-Capillary Barrier to Investigate the Effect of Matrix Structure on Atelectrauma

“…As described in our previous studies 15 , 16 , 22 , 28 , airway reopening was simulated by propagating air bubbles over the epithelial monolayer in the top chamber. Briefly, the top microfluidic channel was connected to a programmable PHD 2000 syringe pump (Harvard Apparatus, Holliston, MA) and PBS was injected into the top microfluidic channel, to simulate a surfactant-deficient airway fluid.…”

“…Recently, we used similar techniques to demonstrate that clinically approved drugs, i.e. Simvastatin, can be used to prevent cell injury during reopening 22 . Tschumperlin and collaborators pioneered the use of cell stretching devices to model over-distension injury where primary lung epithelial cells are cultured on a flexible non-porous membrane and exposed to ~12–50% equibiaxial strain 21 .…”

Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I

“…Statins may exert anti-inflammatory action through inhibition of microglia and astrocytes cells, according to previously described ( Cordle and Landreth, 2005 ; Lindberg et al, 2005 ; Li et al, 2009 ). More precisely, simvastatin have showed its anti-inflammatory properties in different other preclinical studies ( Higuita-Castro et al, 2016 ; Wang et al, 2016 ; Barbosa et al, 2017 ). In addition, Qiu and colleagues ( Qiu et al, 2016 ) showed that simvastatin attenuated neuropathic pain through inhibition of RhoA/LIMK/Cofilin pathway, which is activated after chronic constriction injury and related to actin dynamic regulation ( Qiu et al, 2016 ).…”

Integrating molecular pathogenesis and clinical translation in sepsis-induced acute respiratory distress syndrome

“…HMG CoA reductase inhibitors (i.e., statins) have also been investigated as a potential therapy in ARDS through protection of the endothelial barrier (118,119). A recent report suggested that statins can also dampen inflammation from injurious mechanical forces during mechanical ventilation (120). Despite benefit in preclinical models, a randomized clinical trial of rosuvastatin versus placebo in sepsis-induced ARDS failed to show a difference in 60-day mortality and was stopped early for futility (121).…”