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Mechanical Stretch Induces Fetal Type II Cell Differentiation Via an Epidermal Growth Factor Receptor–Extracellular-Regulated Protein Kinase Signaling Pathway

Department of Pediatrics, Division of Neonatology, and Program in Fetal Medicine, Women & Infants' Hospital of Rhode Island; Division of Pediatric Endocrinology and Metabolism, Hasbro Children's Hospital; and Brown Medical School, Providence, Rhode Island

Address correspondence to: Juan Sanchez-Esteban, M.D., Department of Pediatrics, Women & Infants' Hospital, 101 Dudley Street, Providence, RI 02905. E-mail: jsesteba{at}wihri.org

Mechanical forces are important for fetal alveolar epithelial cell differentiation. However, the signal transduction pathways regulating this process remain largely unknown. Based on the importance of the extracellular-regulated protein kinase (ERK) pathway in cell differentiation, we hypothesized that this cascade mediates stretch-induced fetal type II cell differentiation. We demonstrate that ERK1/2 was maximally activated (> 3-fold) after 15 min of cyclic stretch. Blockage of the ERK pathway with U0126 (a selective MEK1/2 inhibitor) significantly decreased stretch-inducible surfactant protein-C (SP-C) mRNA expression. We examined upstream activators of ERK1/2 and found that stretch induced phosphorylation of Raf-1 and activation of Ras. Moreover, GW5074, a selective c-Raf-1 inhibitor, decreased stretch-inducible SP-C mRNA accumulation. Mechanical stretch also stimulated epidermal growth factor receptor (EGFR) phosphorylation. Finally, blockage of the EGFR, either with tyrphostin AG1478 or neutralizing antibody, decreased stretch-inducible SP-C mRNA expression. We conclude that stretch, at least in part, induces differentiation of fetal epithelial cells via EGFR activation of the ERK pathway. These results suggest that EGFR may be a mechanosensor during fetal lung development. These findings may have significant implications for the design of strategies to accelerate lung maturation.

Abbreviations: Dulbecco's modified Eagle's medium, DMEM • dithiothreitol, DTT • epidermal growth factor, EGF • EGF receptor, EGFR • extracellular-regulated protein kinase, ERK • G-protein coupled receptors, GPCRs • horseradish peroxidase, HRP • myelin basic protein, MBP • receptor tyrosine kinase, RTK • surfactant protein, SP

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