Mechanical stretch induces lung α-epithelial Na⁺channel expression

Abstract

During fetal development physiological stretching helps drive lung growth and maturation. At birth, the α-subunit of the alveolar epithelial sodium channel (α-ENaC) is a critical factor in helping to facilitate clearance of lung fluid during the perinatal period. The effects of stretch, however, on α-ENaC expression in the fetal lung have yet to be elucidated. In an effort to explore this question, we used both an in vitro cell culture model that exposes cells to repetitive cyclic stretch (CS) as well as an in vivo preterm animal model of mechanical ventilation (MV). We found that murine lung epithelial (MLE-12) cells exposed to repetitive CS showed a significant rise in α-ENaC mRNA expression. Total and cell-surface protein abundance of α-ENaC were also elevated after 24 h of CS. Stretch-induced increases in α-ENaC expression were suppressed in the presence of either actinomycin D or cycloheximide. Pharmacological inhibition of the extracellular signal-regulated protein kinase (ERK1/2) did not attenuate stretch-induced increases in α-ENaC protein, whereas inhibition of p38 MAPK or c-Jun NH2-terminal kinase (JNK) did. In 29-day preterm rabbits, alveolar stretching secondary to postnatal MV markedly elevated fetal lung α-ENaC expression compared to spontaneously breathing counterparts. In summary, our findings indicate that mechanical stretch promotes α-ENaC expression.

Mechanical Strain-Mediated Tenogenic Differentiation of Mesenchymal Stromal Cells Is Regulated through Epithelial Sodium Channels

“…Nevertheless, chondrocytes being cells of mesenchyme origin appears to response to mechanical signals through the propagation of signalling cascades initiated by the influx of sodium through mechanosensitive α -ENaC channels [ 11 ]. Hence, our finding of α -ENaC changes in hMSCs being responsive to stretching correlates well to the observations made in previous studies [ 35 , 36 ].…”

Quantitative Phosphoproteomics Reveals Cell Alignment and Mitochondrial Length Change under Cyclic Stretching in Lung Cells

“…Additionally, 20% and 30% changes in CSA resulted in apoptosis in human and rat cells [20,21]. According to previous reports, 10% CSA and a uniaxial stretching direction were commonly applied in cyclic stretched lung cells [22][23][24][25][26][27][28]. Therefore, 10% CSA change and a uniaxial stretching direction are used for the cyclic stretching experiment.…”

A New Role for the Mitochondrial Pro-apoptotic Protein SMAC/Diablo in Phospholipid Synthesis Associated with Tumorigenesis

“…The same is true for the epithelial Na + channel (a-ENaC/SCNN1A), a critical factor during the perinatal period of lung development, involved in clearance of lung fluid. 32 Metabolism-related genes whose expression was altered in sh-hSMAC-A-TTs included dehydrogenases and deaminases responsible for mediating the conversion of oxaloacetate to phosphoenolpyruvate, alcohol dehydrogenase, hexose-6-phosphate dehydrogenase, and adenosine deaminase, all of which were downregulated (Figure S8B; Table S5). Upregulated genes encoded for enzymes involved in nucleotide synthesis (cytidine deaminase, ectonucleoside triphosphate diphosphohydrolase, calcium-activated nucleotidase 1), amino acid metabolism (peptidyl arginine deiminase, glutamic pyruvate transaminase), oligosaccharide biosynthesis, and protein glycosylation (glycosyltransferases, fucosyltransferases, beta-galactoside alpha-2,3-sialyltransferase, polypeptide N-acetylgalactosaminyltransferase) (Figure S8B; Table S5).…”