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Loss of Circadian Protection in Adults Exposed to Neonatal Hyperoxia

Yasmine Issah, Amruta Naik, Soon Y Tang, Kaitlyn Forrest, Thomas G Brooke, Nicholas Lahens, Katherine N. Theken, Amita Sehgal, George S. Worthen, Garret A. FitzGerald, Shaon Sengupta
doi: https://doi.org/10.1101/2020.07.10.197277
Yasmine Issah
1The Children’s Hospital of Philadelphia
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Amruta Naik
1The Children’s Hospital of Philadelphia
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Soon Y Tang
2Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia
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Kaitlyn Forrest
1The Children’s Hospital of Philadelphia
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Thomas G Brooke
2Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia
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Nicholas Lahens
2Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia
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Katherine N. Theken
2Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia
3Systems Pharmacology University of Pennsylvania Perelman School of Medicine
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Amita Sehgal
4Chronobiology and sleep Institute, University of Pennsylvania, Philadelphia
5Department of Neuroscience, University of Pennsylvania Perelman School of Medicine
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George S. Worthen
1The Children’s Hospital of Philadelphia
6Department of Pediatrics, University of Pennsylvania Perelman School of Medicine
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Garret A. FitzGerald
2Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia
3Systems Pharmacology University of Pennsylvania Perelman School of Medicine
4Chronobiology and sleep Institute, University of Pennsylvania, Philadelphia
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Shaon Sengupta
1The Children’s Hospital of Philadelphia
2Institute of Translational Medicine and Therapeutics (ITMAT), University of Pennsylvania, Philadelphia
4Chronobiology and sleep Institute, University of Pennsylvania, Philadelphia
6Department of Pediatrics, University of Pennsylvania Perelman School of Medicine
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  • For correspondence: senguptas@email.chop.edu
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Abstract

Adverse early life exposures having a lasting negative impact on health. For examples, neonatal hyperoxia which is a risk factor for chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) confers susceptibility to respiratory infections like Influenza A (IAV) later in life. Given our previous findings that the circadian clock exerts a protective effect on injury from IAV, we asked if the long-term impact of neonatal hyperoxia includes disruption of circadian rhythms. We show here that neonatal hyperoxia abolishes the circadian clock mediated time of day protection from IAV, not through the regulation of viral burden, but through host tolerance pathways. We further discovered that that this dysregulation is mediated through the intrinsic clock in the lung, rather than through central or immune system clocks. Loss of circadian protein, Bmal1, in AT2 cells of the lung recapitulates the increased mortality, loss of temporal gating and other key features of hyperoxia-exposed animals. Taken together, our data suggest a novel role for the circadian clock in AT2 clock in mediating long-term effects of early life exposures to the lungs.

Brief Summary Neonatal hyperoxia abrogates the circadian protection from Influenza infection in recovered adults.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The authors have declared that no conflict of interest exists.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted July 12, 2020.
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Loss of Circadian Protection in Adults Exposed to Neonatal Hyperoxia
Yasmine Issah, Amruta Naik, Soon Y Tang, Kaitlyn Forrest, Thomas G Brooke, Nicholas Lahens, Katherine N. Theken, Amita Sehgal, George S. Worthen, Garret A. FitzGerald, Shaon Sengupta
bioRxiv 2020.07.10.197277; doi: https://doi.org/10.1101/2020.07.10.197277
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Loss of Circadian Protection in Adults Exposed to Neonatal Hyperoxia
Yasmine Issah, Amruta Naik, Soon Y Tang, Kaitlyn Forrest, Thomas G Brooke, Nicholas Lahens, Katherine N. Theken, Amita Sehgal, George S. Worthen, Garret A. FitzGerald, Shaon Sengupta
bioRxiv 2020.07.10.197277; doi: https://doi.org/10.1101/2020.07.10.197277

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