title: Mechanical stretch induces fetal type II cell differentiation via an epidermal growth factor receptor-extracellular-regulated protein kinase signaling pathway.
abstract: 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.
authors.affiliation: Department of Pediatrics, Women and Infants' Hospital, 101 Dudley Street, Providence, RI 02905, USA. jsesteba@wihri.org
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Esteban
authors.forename: Yulian
authors.initials: Y
authors.lastname: Wang
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gruppuso
authors.forename: Lewis P
authors.initials: LP
authors.lastname: Rubin
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical
chemical_list: D037721:Pulmonary Surfactant-Associated Protein C; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases