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Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates

View ORCID ProfileAndrea Toth, Shelby Steinmeyer, Paranthaman Kannan, Jerilyn Gray, Courtney M. Jackson, Shibabrata Mukherjee, Martin Demmert, Joshua R. Sheak, Daniel Benson, Joe Kitzmiller, Joseph A. Wayman, Pietro Presicce, Christopher Cates, Rhea Rubin, View ORCID ProfileKashish Chetal, Yina Du, Yifei Miao, Mingxia Gu, Minzhe Guo, Vladimir V. Kalinichenko, Suhas G. Kallapur, Emily R. Miraldi, View ORCID ProfileYan Xu, Daniel Swarr, Ian Lewkowich, View ORCID ProfileNathan Salomonis, Lisa Miller, View ORCID ProfileJennifer S. Sucre, View ORCID ProfileJeffrey A. Whitsett, Claire A. Chougnet, Alan H. Jobe, Hitesh Deshmukh, View ORCID ProfileWilliam J. Zacharias
doi: https://doi.org/10.1101/2021.06.24.449766
Andrea Toth
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
8Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH USA
9Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH USA
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  • ORCID record for Andrea Toth
Shelby Steinmeyer
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Paranthaman Kannan
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Jerilyn Gray
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Courtney M. Jackson
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
10Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH USA
11Department of Pediatrics, University of Rochester, Rochester, NY USA
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Shibabrata Mukherjee
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Martin Demmert
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
12Department of Pediatrics, Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
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Joshua R. Sheak
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Daniel Benson
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Joe Kitzmiller
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Joseph A. Wayman
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Pietro Presicce
13Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA USA
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Christopher Cates
7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Rhea Rubin
7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Kashish Chetal
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Yina Du
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
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Yifei Miao
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Mingxia Gu
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Minzhe Guo
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Vladimir V. Kalinichenko
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Suhas G. Kallapur
13Divisions of Neonatology and Developmental Biology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA USA
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Emily R. Miraldi
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Yan Xu
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Daniel Swarr
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Ian Lewkowich
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Nathan Salomonis
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
5Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Lisa Miller
14California National Primate Research Center, University of California Davis, Davis, CA USA
15Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA USA
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Jennifer S. Sucre
16Division of Neonatology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN USA
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Jeffrey A. Whitsett
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Claire A. Chougnet
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Alan H. Jobe
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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Hitesh Deshmukh
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
4Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
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William J. Zacharias
1Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
2Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
3Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA
6Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA
7Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH USA
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  • ORCID record for William J. Zacharias
  • For correspondence: William.Zacharias@cchmc.org
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Abstract

Malformations of or injuries to the developing lung are associated with perinatal morbidity and mortality with lifelong consequences for subsequent pulmonary health. One fetal exposure linked with poor health outcomes is chorioamnionitis, which impacts up to 25-40% of preterm births. Severe chorioamnionitis with prematurity is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may significantly alter developmental ontogeny of the lung. To test this hypothesis, we used intra-amniotic lipopolysaccharide (LPS, endotoxin) to generate experimental chorioamnionitis in prenatal Rhesus macaque (Macaca mulatta), a model which shares critical structural and temporal aspects of human lung development. Inflammatory injury directly disrupts the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis which was extensively disrupted by perinatal inflammation, leading to loss of gas exchange surface and alveolar simplification similar to that found in chronic lung disease of newborns. Blockade of IL1β and TNFα ameliorated endotoxin-induced inflammatory lung injury by blunting stromal response to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://research.cchmc.org/pbge/lunggens/mainportal.html

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates
Andrea Toth, Shelby Steinmeyer, Paranthaman Kannan, Jerilyn Gray, Courtney M. Jackson, Shibabrata Mukherjee, Martin Demmert, Joshua R. Sheak, Daniel Benson, Joe Kitzmiller, Joseph A. Wayman, Pietro Presicce, Christopher Cates, Rhea Rubin, Kashish Chetal, Yina Du, Yifei Miao, Mingxia Gu, Minzhe Guo, Vladimir V. Kalinichenko, Suhas G. Kallapur, Emily R. Miraldi, Yan Xu, Daniel Swarr, Ian Lewkowich, Nathan Salomonis, Lisa Miller, Jennifer S. Sucre, Jeffrey A. Whitsett, Claire A. Chougnet, Alan H. Jobe, Hitesh Deshmukh, William J. Zacharias
bioRxiv 2021.06.24.449766; doi: https://doi.org/10.1101/2021.06.24.449766
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Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates
Andrea Toth, Shelby Steinmeyer, Paranthaman Kannan, Jerilyn Gray, Courtney M. Jackson, Shibabrata Mukherjee, Martin Demmert, Joshua R. Sheak, Daniel Benson, Joe Kitzmiller, Joseph A. Wayman, Pietro Presicce, Christopher Cates, Rhea Rubin, Kashish Chetal, Yina Du, Yifei Miao, Mingxia Gu, Minzhe Guo, Vladimir V. Kalinichenko, Suhas G. Kallapur, Emily R. Miraldi, Yan Xu, Daniel Swarr, Ian Lewkowich, Nathan Salomonis, Lisa Miller, Jennifer S. Sucre, Jeffrey A. Whitsett, Claire A. Chougnet, Alan H. Jobe, Hitesh Deshmukh, William J. Zacharias
bioRxiv 2021.06.24.449766; doi: https://doi.org/10.1101/2021.06.24.449766

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