Mechanical forces generated in utero by repetitive breathing movements and by fluid distension are essential to mammalian lung development. However, the mechanisms by which pulmonary cells sense and transduce mechanical signals are largely unknown. The long-term goals are to define how mechanical forces promote lung maturation. Epidermal growth factor receptor (EGFR) is critical for fetal lung development. Although past studies indicate that EGFR is important for differentiation of type II cells and stretch-mediated compensatory growth after pneumonectomy, the mechanisms by which EGFR is activated are not known. Our investigations have identified potential roles for the EGFR and specific integrins in stretch-induced fetal type II cell differentiation. Further studies have shown that this process may be mediated by force-induced release of EGFR ligands, since strain-induced type II cell differentiation was markedly inhibited when the ligand-binding domain of the EGFR was blocked with neutralizing antibodies. We also showed that conditioned medium from stretched cells promoted type II cell differentiation when added to unstretched cells. This hypothesis is further supported by experiments performed in fetal lambs, which demonstrate that lung fluid composition after tracheal ligation, and not just increase in intrapulmonary pressure, is critical to accelerate lung growth and differentiation. Therefore, the specific hypothesis of this application is that strain-induced differentiation of fetal type II cells is mediated via autocrine release of membrane-anchored EGFR ligands.
Our Specific Aims are: 1) To identify EGFR ligands released by lung epithelial cells in response to mechanical strain that promote type II cell differentiation. 2) To analyze the signaling mechanisms by which mechanical stretch induces EGFR ligand release. 3) To demonstrate the physiological role of force-induced release of soluble growth factors in organotypic models of epithelial strain. Using the Flexercell Strain Unit apparatus, cell signaling techniques, modification of the proposed key signaling proteins by inducible or knockdown expression and EGFR and ADAM17 knockout mice, we will examine EGFR ligands released by force in fetal type II cells that promote lung differentiation. We will analyze the role of ADAM17 as the protease that cleaves membrane-anchored EGFR ligands after mechanical stimulation of integrin receptors. Finally, we will validate our in vitro findings using ex vivo fetal lung explant models. Based on the critical role played by mechanical forces during normal fetal lung development, the identification of key regulatory pathways activated by strain in fetal lungs may provide a unique opportunity to rescue the phenotype and to facilitate development of new approaches to accelerate lung maturation in clinical conditions where lung development is impaired, including pulmonary hypoplasia, bronchopulmonary dysplasia and postnatal lung growth in extremely-low-birth-weight infants.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Raju, Tonse N
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Women and Infants Hospital-Rhode Island
United States
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Nayak, Pritha S; Wang, Yulian; Najrana, Tanbir et al. (2015) Mechanotransduction via TRPV4 regulates inflammation and differentiation in fetal mouse distal lung epithelial cells. Respir Res 16:60
Giordani, Victoria M; DeBenedictus, Christina M; Wang, Yulian et al. (2014) Epidermal growth factor receptor (EGFR) contributes to fetal lung fibroblast injury induced by mechanical stretch. J Recept Signal Transduct Res 34:58-63
Hokenson, Michael A; Wang, Yulian; Hawwa, Renda L et al. (2013) Reduced IL-10 production in fetal type II epithelial cells exposed to mechanical stretch is mediated via activation of IL-6-SOCS3 signaling pathway. PLoS One 8:e59598
Wang, Yulian; Huang, Zheping; Nayak, Pritha S et al. (2013) Strain-induced differentiation of fetal type II epithelial cells is mediated via the integrin ?6?1-ADAM17/tumor necrosis factor-?-converting enzyme (TACE) signaling pathway. J Biol Chem 288:25646-57
Huang, Zheping; Wang, Yulian; Nayak, Pritha S et al. (2012) Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions. J Biol Chem 287:18091-102
Wang, Yulian; Huang, Zheping; Nayak, Pritha S et al. (2012) An experimental system to study mechanotransduction in fetal lung cells. J Vis Exp :
Hawwa, Renda L; Hokenson, Michael A; Wang, Yulian et al. (2011) IL-10 inhibits inflammatory cytokines released by fetal mouse lung fibroblasts exposed to mechanical stretch. Pediatr Pulmonol 46:640-9
Hawwa, Renda L; Hokenson, Michael A; Wang, Yulian et al. (2011) Differential expression of MMP-2 and -9 and their inhibitors in fetal lung cells exposed to mechanical stretch: regulation by IL-10. Lung 189:341-9
Wang, Yulian; Maciejewski, Benjamin S; Drouillard, Diana et al. (2010) A role for caveolin-1 in mechanotransduction of fetal type II epithelial cells. Am J Physiol Lung Cell Mol Physiol 298:L775-83
Wang, Yulian; Maciejewski, Benjamin S; Soto-Reyes, Dariana et al. (2009) Mechanical stretch promotes fetal type II epithelial cell differentiation via shedding of HB-EGF and TGF-alpha. J Physiol 587:1739-53

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