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A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard

Josh Bateman, Kirsty Meldrum, Sarah M. Mitchell, Ulla Vogel, Martin Clift Orcid Logo

Scientific Reports, Volume: 15, Issue: 1

Swansea University Authors: Josh Bateman, Kirsty Meldrum, Martin Clift Orcid Logo

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DOI (Published version): 10.1038/s41598-025-23768-4

Abstract

Relevant in vitro models could reduce the requirement for in vivo testing and allow higher throughput for imperative toxicological or pharmaceutical hazard testing. Models of the alveolar barrier are invaluable when assessing the toxicity of inhaled xenobiotics, though there is a requirement that th...

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Published in: Scientific Reports
ISSN: 2045-2322
Published: Springer Science and Business Media LLC 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70908
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Models of the alveolar barrier are invaluable when assessing the toxicity of inhaled xenobiotics, though there is a requirement that these models are well-characterised and accurately resemble the relevant human cellular architecture. Here, a triple cell co-culture has been developed using hAELVi, NCI-H441 and differentiated THP-1 cells as models of type 1 and type 2 pneumocytes, and alveolar macrophages, respectively. Through pre-staining each cell type, confocal microscopy was first used to determine cell seeding ratios to hAELVi and NCI-H441 required to achieve a human-relevant 16.44:1&#x2009;&#xB1;&#x2009;3.29 ratio at the time of air-liquid interface exposure. CellTrackers were then used to ensure that the density of differentiated THP-1 cells was in line with previously published anatomical research at 1 cell/18&#x2009;&#xD7;&#x2009;103 &#xB5;m2. We were able to show that the triple culture forms a tight barrier and that the macrophages can respond to a (pro)-inflammatory stimulus (lipopolysaccharide). 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spelling 2025-11-17T11:51:24.9875977 v2 70908 2025-11-14 A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard 9046b92fe972861a67aec6be5e093c00 Josh Bateman Josh Bateman true false bbb7bd27bfa3c6ffc73da8facfebc793 Kirsty Meldrum Kirsty Meldrum true false 71bf49b157691e541950f5c3f49c9169 0000-0001-6133-3368 Martin Clift Martin Clift true false 2025-11-14 MEDS Relevant in vitro models could reduce the requirement for in vivo testing and allow higher throughput for imperative toxicological or pharmaceutical hazard testing. Models of the alveolar barrier are invaluable when assessing the toxicity of inhaled xenobiotics, though there is a requirement that these models are well-characterised and accurately resemble the relevant human cellular architecture. Here, a triple cell co-culture has been developed using hAELVi, NCI-H441 and differentiated THP-1 cells as models of type 1 and type 2 pneumocytes, and alveolar macrophages, respectively. Through pre-staining each cell type, confocal microscopy was first used to determine cell seeding ratios to hAELVi and NCI-H441 required to achieve a human-relevant 16.44:1 ± 3.29 ratio at the time of air-liquid interface exposure. CellTrackers were then used to ensure that the density of differentiated THP-1 cells was in line with previously published anatomical research at 1 cell/18 × 103 µm2. We were able to show that the triple culture forms a tight barrier and that the macrophages can respond to a (pro)-inflammatory stimulus (lipopolysaccharide). Given the anatomical relevancy and its ability to react to stimuli, this model may provide a useful platform to assess the toxicological hazard potential of a range of inhaled, respirable xenobiotics. Journal Article Scientific Reports 15 1 Springer Science and Business Media LLC 2045-2322 Multi-cellular model, Alveoli, In vitro, Toxicology 14 11 2025 2025-11-14 10.1038/s41598-025-23768-4 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University External research funder(s) paid the OA fee (includes OA grants disbursed by the Library) This research was funded by the UK Health Security Agency (PhD Studentship Awarded to M.J.D.C and J.W.P.B), the UKRI (NERC) funded ‘RESPIRE’ study (Grant No. NE/W002264/1) (M.J.D.C and K.M), the COLT Foundation, and the Knowledge Economy Skills Scholarship (KESS) 2 (M.J.D.C. and S.M). 2025-11-17T11:51:24.9875977 2025-11-14T19:48:34.5040072 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Josh Bateman 1 Kirsty Meldrum 2 Sarah M. Mitchell 3 Ulla Vogel 4 Martin Clift 0000-0001-6133-3368 5 70908__35638__53205c34f0404533b7aa0d524a7a2e4c.pdf Bateman_et_al-2025-Scientific_Reports.pdf 2025-11-14T19:51:35.7824019 Output 2397049 application/pdf Version of Record true © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/
title A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard
spellingShingle A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard
Josh Bateman
Kirsty Meldrum
Martin Clift
title_short A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard
title_full A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard
title_fullStr A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard
title_full_unstemmed A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard
title_sort A human relevant in vitro alveolar epithelial barrier model to assess inhaled pollutant hazard
author_id_str_mv 9046b92fe972861a67aec6be5e093c00
bbb7bd27bfa3c6ffc73da8facfebc793
71bf49b157691e541950f5c3f49c9169
author_id_fullname_str_mv 9046b92fe972861a67aec6be5e093c00_***_Josh Bateman
bbb7bd27bfa3c6ffc73da8facfebc793_***_Kirsty Meldrum
71bf49b157691e541950f5c3f49c9169_***_Martin Clift
author Josh Bateman
Kirsty Meldrum
Martin Clift
author2 Josh Bateman
Kirsty Meldrum
Sarah M. Mitchell
Ulla Vogel
Martin Clift
format Journal article
container_title Scientific Reports
container_volume 15
container_issue 1
publishDate 2025
institution Swansea University
issn 2045-2322
doi_str_mv 10.1038/s41598-025-23768-4
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
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description Relevant in vitro models could reduce the requirement for in vivo testing and allow higher throughput for imperative toxicological or pharmaceutical hazard testing. Models of the alveolar barrier are invaluable when assessing the toxicity of inhaled xenobiotics, though there is a requirement that these models are well-characterised and accurately resemble the relevant human cellular architecture. Here, a triple cell co-culture has been developed using hAELVi, NCI-H441 and differentiated THP-1 cells as models of type 1 and type 2 pneumocytes, and alveolar macrophages, respectively. Through pre-staining each cell type, confocal microscopy was first used to determine cell seeding ratios to hAELVi and NCI-H441 required to achieve a human-relevant 16.44:1 ± 3.29 ratio at the time of air-liquid interface exposure. CellTrackers were then used to ensure that the density of differentiated THP-1 cells was in line with previously published anatomical research at 1 cell/18 × 103 µm2. We were able to show that the triple culture forms a tight barrier and that the macrophages can respond to a (pro)-inflammatory stimulus (lipopolysaccharide). Given the anatomical relevancy and its ability to react to stimuli, this model may provide a useful platform to assess the toxicological hazard potential of a range of inhaled, respirable xenobiotics.
published_date 2025-11-14T05:28:28Z
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