Sepsis-induced lung injury in rats increases alveolar epithelial vulnerability to stretch*

Levine, Glenn; Deutschman, Clifford S.; Helfaer, Mark A.; Margulies, Susan S.

doi:10.1097/01.ccm.0000218813.77367.e2

Cited by 22 publications

(19 citation statements)

References 36 publications

(40 reference statements)

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“…10). These results agree with data from type I-like alveolar epithelial cell monolayers that were stretched at the same magnitude and duration (21). In a recent study, we have linked NF-B activation by stretch to increases in the epithelial barrier permeability in type I-like cell monolayers (13).…”

Section: Discussionsupporting

confidence: 86%

Reproducible uniform equibiaxial stretch of precision-cut lung slices

Davidovich

Huang

Margulies

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Simulating ventilator-induced lung injury (VILI) in the laboratory requires stretching of lung alveolar tissue. Whereas precision-cut lung slices (PCLSs) are widely used for studying paracrine signaling pathways in the lungs, their use in stretch studies is very limited because of the technical challenge of fixing them to a stretchable substrate, stretching them uniformly, or holding them in a stretch device without causing rupture. We describe a novel method for attaching PCLSs to silicone membranes by stitching them together in a star-shaped pattern. Using a device that was previously designed in our laboratory for stretching primary alveolar epithelial cell monolayers, we demonstrate that in the central region of the PCLSs stretch is uniform, equibiaxial, and, after a short preconditioning period, also reproducible. The stitched and stretched PCLSs showed equal or better viability outcomes after 60 min of cyclic stretch at different magnitudes of physiological stretch compared with primary pulmonary alveolar epithelial cell monolayers. Preparing and stitching the PCLSs before stretch is relatively easy to perform, yields repeatable outcomes, and can be used with tissue from any species. Together with the ensuring uniform and equibiaxial stretch, the proposed methods provide an optimal model for VILI studies with PCLSs.

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Section: Discussionsupporting

confidence: 86%

Reproducible uniform equibiaxial stretch of precision-cut lung slices

Davidovich

Huang

Margulies

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Furthermore, laminar shear stress (5-20 dynes=cm 2 ) and low magnitude cyclic stretch (5% elongation) selectively activates small GTPase Rac that results in peripheral translocation of actin polymerization proteins and enhancement of cortical actin cytoskeleton (21,169), whereas high magnitude cyclic stretch (18% elongation) stimulates small GTPase Rho without affecting Rac and potentiates stress fiber formation and barrier dysfunction induced by edemagenic agonists (23,25,129,176). Excessive stretch also activated NFkB pathway in rat and in cell models of VILI via PI3K-dependent manner (95,155) and exacerbated sepsis-induced NFkB activation in the isolated lung cells (95). Remarkably, selective inhibition of VILI-induced NFkB signaling is possible without inhibiting the NF-kappaB signaling activated by endotoxin.…”

Section: Stretch-activated Cellular Signalingmentioning

confidence: 99%

Cyclic Stretch, Reactive Oxygen Species, and Vascular Remodeling

Birukov

2009

Antioxidants & Redox Signaling

195

155

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Blood vessels respond to changes in mechanical load from circulating blood in the form of shear stress and mechanical strain as the result of heart propulsions by changes in intracellular signaling leading to changes in vascular tone, production of vasoactive molecules, and changes in vascular permeability, gene regulation, and vascular remodeling. In addition to hemodynamic forces, microvasculature in the lung is also exposed to stretch resulting from respiratory cycles during autonomous breathing or mechanical ventilation. Among various cell signaling pathways induced by mechanical forces and reported to date, a role of reactive oxygen species (ROS) produced by vascular cells receives increasing attention. ROS play an essential role in signal transduction and physiologic regulation of vascular function. However, in the settings of chronic hypertension, inflammation, or acute injury, ROS may trigger signaling events that further exacerbate smooth muscle hypercontractility and vascular remodeling associated with hypertension and endothelial barrier dysfunction associated with acute lung injury and pulmonary edema. These conditions are also characterized by altered patterns of mechanical stimulation experienced by vasculature. This review will discuss signaling pathways regulated by ROS and mechanical stretch in the pulmonary and systemic vasculature and will summarize functional interactions between cyclic stretch-and ROS-induced signaling in mechanochemical regulation of vascular structure and function.

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“…Type II cells were seeded onto fibronectin coated (10 ug/cm 2 ) flexible silastic membranes (Specialty Manufacturing, Saginaw, MI) mounted in custom designed wells at a density of 10 6 cells/cm 2 . The cells were cultured for 5 days with MEM supplemented with 10% fetal bovine serum, until they were flattened, formed domes and tight junctions [24], and demonstrated phenotypic traits associated with alveolar type I cells [28,29]. Then these RAEC were serum-deprived with 20 mM Hepes supplemented with DMEM (CO 2 free buffering system) for 2 hours, subjected to biaxial cyclic stretch at 37°C, with a calibrated customized system with a hollow cylindrical post contacting the deformable membrane [17], at one of two amplitudes (12% or 25% change is surface area, ΔSA) for one of two durations (1 or 6 hours) at a frequency of 0.25 Hz (15 cycles/min).…”

Section: Primary Rat Alveolar Epithelial Cell Isolationmentioning

confidence: 99%

Cyclic Stretch Magnitude and Duration Affect Rat Alveolar Epithelial Gene Expression

Yerrapureddy¹,

Tobias

Margulies³

2010

Cell Physiol Biochem

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Mechanical ventilation with large tidal volumes can increase lung alveolar permeability and initiate inflammatory responses; but the mechanisms that regulate ventilator-associated lung injury and inflammation remain unclear. Analysis of the genomic response of the lung has been performed in intact lungs ventilated at large tidal volumes. This study is the first to study the genomic response of cultured primary alveolar epithelial cells undergoing large and moderate physiologic cyclic stretch. Responses were dependent on stretch magnitude and duration. Genomic expression was validated for 5 genes of interest: Amphiregulin, Glutamate-Cysteine Ligase Catalytic subunit, Matrix Metalloproteinase 7, Protein Phosphatase 1 regulatory inhibitor subunit 10, and Serpine-1, and protein expression mirrored genomic responses. Differences between results reported from homogenized intact lungs and monolayers of alveolar epithelial cells with type-I like phenotype provide provocative evidence that the whole lung preparation may mask the response of individual cell types.

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Sepsis-induced lung injury in rats increases alveolar epithelial vulnerability to stretch*

Abstract: AECs isolated from septic rats are more vulnerable to mechanical deformation injury than AECs from nonseptic animals.

Cited by 22 publications

References 36 publications

Reproducible uniform equibiaxial stretch of precision-cut lung slices

Reproducible uniform equibiaxial stretch of precision-cut lung slices

Cyclic Stretch, Reactive Oxygen Species, and Vascular Remodeling

Cyclic Stretch Magnitude and Duration Affect Rat Alveolar Epithelial Gene Expression

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