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Published ahead of print on June 26, 2003, doi:10.1165/rcmb.2003-0121OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 1, January 2004, 76-83

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Submitted on April 1, 2003
Revised on June 26, 2003

Mechanical Stretch Induces Fetal Type II Cell Differentiation via an EGFR-ERK Signaling Pathway

Juan Sanchez-Esteban1*, Yulian Wang1, Philip A Gruppuso2, and Lewis P Rubin1

1 Pediatrics, Women and Infants' Hospital, Providence, RI, USA, 2 Pediatrics, Hasbro Children's Hospital, Providence, RI, USA

* To whom correspondence should be addressed. 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 (more than three-fold) after 15 minutes 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 maybe a mechanosensor during fetal lung development. These findings may have significant implications for the design of strategies to accelerate lung maturation.




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