Abstract
Stretch is an essential mechanism for lung growth and development. Animal models in which fetal lungs have been chronically over or underdistended demonstrate a disrupted mix of type II and type I cells, with static overdistention typically promoting a type I cell phenotype. The Rho GTPase family, key regulators of cytoskeletal signaling, are known to mediate cellular differentiation in response to stretch in other organs. Using a well-described model of alveolar epithelial cell differentiation and a validated stretch device, we investigated the effects of supraphysiologic stretch on human fetal lung alveolar epithelial cell phenotype. Static stretch applied to epithelial cells suppressed type II cell markers (SP-B and Pepsinogen C, PGC), and induced type I cell markers (Caveolin-1, Claudin 7 and Plasminogen Activator Inhibitor-1, PAI-1) as predicted. Static stretch was also associated with Rho A activation. Furthermore, the Rho kinase inhibitor Y27632 decreased Rho A activation and blunted the stretch-induced changes in alveolar epithelial cell marker expression. Together these data provide further evidence that mechanical stimulation of the cytoskeleton and Rho activation are key upstream events in mechanotransduction-associated alveolar epithelial cell differentiation.
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Abbreviations
- DCI:
-
Dexamethasone, isobutyl methylxanthine, and 8-bromo-cAMP
- GAPDH:
-
Glyceraldehyde-3-phosphate dehydrogenase
- PGC:
-
Pepsinogen C
- PAI-1:
-
Plasminogen Activator Inhibitor-1
- ROCK:
-
Rho kinase
- SP-B:
-
Surfactant Protein B
- HFL:
-
human fetal lung
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Acknowledgements
We thank Ping Wang for cell preparation and James Hayden and Frederick Keeney, from the Wistar Institute Microscopy Facility for assistance with the stress fiber imaging and image quantitation studies.
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Supported by grants HL-077266 (C.D.F.) and HL059959 (S.H.G.) from the National Institutes of Health.
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Foster, C., Varghese, L., Gonzales, L. et al. The Rho Pathway Mediates Transition to an Alveolar Type I Cell Phenotype During Static Stretch of Alveolar Type II Cells. Pediatr Res 67, 585–590 (2010). https://doi.org/10.1203/PDR.0b013e3181dbc708
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DOI: https://doi.org/10.1203/PDR.0b013e3181dbc708
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