Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease

  1. Gang Wu
  2. Yin Yeng Lee
  3. Evelyn M Gulla
  4. Andrew Potter
  5. Joseph Kitzmiller
  6. Marc D Ruben
  7. Nathan Salomonis
  8. Jeffery A Whitsett
  9. Lauren J Francey
  10. John B B. Hogenesch
  11. David F Smith  Is a corresponding author
  1. Cincinnati Children's Hospital Medical Center, United States
  2. University of Cincinnati College of Medicine, United States

Abstract

Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia (IH) and is associated with a host of health complications. Although the lung is the first organ to sense changes in oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor- (HIF)-responsive pathways. We hypothesized that exposure to IH would lead to cell-specific up and downregulation of diverse expression pathways. We identified changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells showed the most prominent transcriptional changes. Upregulated genes in myofibroblast cells were enriched for genes associated with pulmonary hypertension and included targets of several drugs currently used to treat chronic pulmonary diseases. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.

Data availability

Sequencing data has been uploaded to GEO (GSE145436), as mentioned in the manuscript 'Data and Materials Availability' section.

The following data sets were generated

Article and author information

Author details

  1. Gang Wu

    Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yin Yeng Lee

    Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Evelyn M Gulla

    Division of Pediatric Otolaryngology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Andrew Potter

    Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Joseph Kitzmiller

    Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Marc D Ruben

    Divisions of Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nathan Salomonis

    Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jeffery A Whitsett

    Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Lauren J Francey

    Divisions of Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. John B B. Hogenesch

    Divisions of Human Genetics and Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. David F Smith

    Divisions of Pediatric Otolaryngology, Pulmonary Medicine, and the Sleep Center, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    For correspondence
    david.smith3@cchmc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0048-4012

Funding

National Institutes of Health (5K08HL148551-02)

  • David F Smith

American Laryngological, Rhinological and Otological Society (2017 Career Development Award)

  • David F Smith

American Society of Pediatric Otolaryngology (2016 Basic Research Award)

  • David F Smith

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2019-0028) of the Cincinnati Children's Hospital Medical Center.

Reviewing Editor

  1. Anurag Agrawal, CSIR Institute of Genomics and Integrative Biology, India

Publication history

  1. Received: September 11, 2020
  2. Accepted: February 17, 2021
  3. Accepted Manuscript published: February 18, 2021 (version 1)
  4. Accepted Manuscript updated: February 19, 2021 (version 2)
  5. Version of Record published: February 26, 2021 (version 3)

Copyright

© 2021, Wu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Gang Wu
  2. Yin Yeng Lee
  3. Evelyn M Gulla
  4. Andrew Potter
  5. Joseph Kitzmiller
  6. Marc D Ruben
  7. Nathan Salomonis
  8. Jeffery A Whitsett
  9. Lauren J Francey
  10. John B B. Hogenesch
  11. David F Smith
(2021)
Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease
eLife 10:e63003.
https://doi.org/10.7554/eLife.63003

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