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Oxygen differentially affects the hox proteins Hoxb5 and Hoxa5 altering airway branching and lung vascular formation

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Hoxb5 and Hoxa5 transcription factor proteins uniquely impact lung morphogenesis at the developmental time point when extremely preterm infants are born. The effect of O2 exposure (0.4 FiO2) used in preterm infant care on these Hox proteins is unknown. We used ex vivo fetal mouse lung organ cultures to explore the effects of 0.4 FiO2 on lung airway and vascular formation in the context of Hoxb5 and Hoxa5 expression and regulation. Compared to room air, 48 h (h) 0.4 FiO2 adversely attenuated airway and microvasculature formation while reducing lung growth and epithelial cell volume, and increasing mesenchymal volume. 0.4 FiO2 decreased pro-angiogenic Hoxb5 and VEGFR2 while not altering protein levels of angiostatic Hoxa5. Lungs returned to RA after 24 h 0.4FiO2 had partial structural recovery but remained smaller and less developed. Mesenchymal cell apoptosis increased and proliferation decreased with time in O2 while epithelial cell proliferation significantly increased. Hoxb5 overexpression led to prominent peri-airway VEGFR2 expression and promoted lung vascular and airway patterning. Hoxa5 overexpression had the opposite effects. We conclude that 0.4 FiO2 exposure causes a profound loss of airway and lung microvascular development that occurs partially via reduction in pro-angiogenic Hoxb5 while angiostatic Hoxa5 expression is maintained.

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Abbreviations

ELBW:

Extremely low birth weight

∆SA:

Change in surface area

E:

Embryonic day

h:

Hour

RA:

Room air

VEGFR:

Vascular endothelial growth factor receptor

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Acknowledgments

Funding: HD044784, Tufts Medical Center Research Grant, AAP Klaus Award, Ikaria Research Award, HL037930, P30 NS047243, Peabody Foundation.

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Authors and Affiliations

  1. Division of Newborn Medicine, Department of Pediatrics, Floating Hospital for Children at Tufts Medical Center, Boston, MA, USA

    Francheyska Silfa-Mazara, Courtney Thomas, Thxuan Vong, Heber C. Nielsen & MaryAnn V. Volpe

  2. Tufts University School of Medicine, Boston, MA, USA

    Ingrid Larsson, Heber C. Nielsen & MaryAnn V. Volpe

  3. Program in Cell, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA

    Sana Mujahid & Heber C. Nielsen

Authors
  1. Francheyska Silfa-Mazara
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  2. Sana Mujahid
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  3. Courtney Thomas
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  4. Thxuan Vong
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  5. Ingrid Larsson
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  6. Heber C. Nielsen
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  7. MaryAnn V. Volpe
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Correspondence to MaryAnn V. Volpe.

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Francheyska Silfa-Mazara and Sana Mujahid contributed equally.

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Silfa-Mazara, F., Mujahid, S., Thomas, C. et al. Oxygen differentially affects the hox proteins Hoxb5 and Hoxa5 altering airway branching and lung vascular formation. J. Cell Commun. Signal. 8, 231–244 (2014). https://doi.org/10.1007/s12079-014-0237-7

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  • DOI: https://doi.org/10.1007/s12079-014-0237-7

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