A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity
There is a critical need to understand pathophysiological mechanisms involved in injury from acute chlorine gas (Cl2) exposure. Limited information is available regarding the time course and mechanisms of injury after acute Cl2 exposure due to a lack of human clinical data and limited fidelity of pre-clinical animal models. We designed and integrated a Cl2 exposure platform to generate and deliver precise concentrations of Cl2 to a microfluidic human airway-on-a-chip microphysiological system. Chemical, biological, structural, and functional airway-on-a-chip responses to Cl2 exposure were characterized across multiple concentrations, exposure times, and post-exposure timepoints. Transcriptomics and metabolomics analyses delineated key molecular, cellular, and physiological pathways involved in the acute response to Cl2 exposure. This work represents a significant advancement towards high-throughput, human-relevant characterization of pulmonary toxicants and medical countermeasure development, addressing critical gaps in toxicology modeling while reducing reliance on animal studies.
Authors
- Julie T. Ziegler
- Jeannie D. Chan
- Emily E. Whitaker (ORCID: https://orcid.org/0000-0003-3570-0261)
- Tony E. Reeves (ORCID: https://orcid.org/0000-0002-8209-6020)
- Stephen J. Walker (ORCID: https://orcid.org/0000-0002-0732-2366)
- Lysette Mutkus (ORCID: https://orcid.org/0000-0002-7378-7137)
- Carl D. Langefeld
- Tracey Young (ORCID: https://orcid.org/0000-0001-8467-0471)
- Trang Simon
- Hannah C. Ainsworth (ORCID: https://orcid.org/0000-0003-1185-0695)
- Sivanandane Sittadjody (ORCID: https://orcid.org/0000-0003-1990-3640)
- Oula Khoury (ORCID: https://orcid.org/0000-0002-8432-9588)
- Douglas Shankle
- Michael Olivier (ORCID: https://orcid.org/0000-0003-1632-1063)
- Kristina Stumpf (ORCID: https://orcid.org/0000-0002-3422-5959)
- Adam R. Hall (ORCID: https://orcid.org/0000-0003-2053-6075)
- Malcolm K. McSwain
- JinGyun Lee
- Laura A. Cox (ORCID: https://orcid.org/0000-0002-8836-3783)
- Gauri Kulkarni
- Khiry Sutton
- Timothy C. Orr
- F. Marini
- Andrew C. Bishop (ORCID: https://orcid.org/0000-0003-0534-0859)
- Ge Li (ORCID: https://orcid.org/0000-0001-9030-884X)
- Yan Jiao (ORCID: https://orcid.org/0000-0002-3913-8918)
- Anthony A. Atala
- Amy Zinnia
- Phillip Clapp
- Alan R. Jacobson
- Kimberly D. Reeves
- Timothy Leach
- Thomas Shupe
- Sobha Puppala
- Kevin Lindert
- Charity Campbell
- Sean V Murphy
- Michael C Seeds
- Steven E Albertson
- Yu Zhou
- Mohammad S Khan
- Zeeshan Hamid
- Shiny A P Rajan
- Cristina M Furdui
Institutions
- Wake Forest University (US)
Publication Details
- Journal
- Toxicological Sciences
- Published
- 2025-12-23
- DOI
- https://doi.org/10.1093/toxsci/kfaf179
- Primary Topic
- 3D Printing in Biomedical Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Health and Human Services
- Wake Forest University
- Comprehensive Cancer Center at Wake Forest Baptist Medical Center
- Wake Forest School of Medicine
- Biomedical Advanced Research and Development Authority
- National Cancer Institute