Development of an acute lung injury model for drug testing
Abstract A challenge that limits our understanding of the underlying pathobiology of pediatric acute respiratory distress syndrome (PARDS) is the lack of a preclinical airway model that can be leveraged for the study of mechanisms and specific molecules for drug testing. We developed a physiologic m...
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| Format: | Article |
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Nature Portfolio
2025-05-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-02078-9 |
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| author | Jocelyn R. Grunwell Susan T. Stephenson Gail A. Dallalio Badiallo A. Diani Celena Zaworski Natalie Jordan Anne M. Fitzpatrick |
| author_facet | Jocelyn R. Grunwell Susan T. Stephenson Gail A. Dallalio Badiallo A. Diani Celena Zaworski Natalie Jordan Anne M. Fitzpatrick |
| author_sort | Jocelyn R. Grunwell |
| collection | DOAJ |
| description | Abstract A challenge that limits our understanding of the underlying pathobiology of pediatric acute respiratory distress syndrome (PARDS) is the lack of a preclinical airway model that can be leveraged for the study of mechanisms and specific molecules for drug testing. We developed a physiologic model system of the small airways for mechanistic application in PARDS using a co-culture of primary human-derived small airway epithelial cells (SAECs) cultured at the air–liquid interface and umbilical vein endothelial cells in a transwell system. The model was validated by exposing the SAECs to a rhinovirus infection, to an inflammatory lung insult using a mixture of cytokines found in ARDS (cytomix), and to airway fluid samples from children with different severity strata of PARDS. We used a combination of transepithelial electrical resistance, immunofluorescence confocal microscopy of tight junctions, targeted gene expression, and cytokine responses to evaluate the model to the aforementioned insults. We then use the model in drug testing and show the reduction in IL-6 expression in conditioned media and STAT3 phosphorylation following co-treatment of SAECs with cytomix and the Janus kinase inhibitor (JAKi) baricitinib. This model enables mechanistic studies of airway pathobiology and may serve as a novel drug testing platform for PARDS. |
| format | Article |
| id | doaj-art-8d1fe8c4c8af4986a1d554d1adf063e0 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-8d1fe8c4c8af4986a1d554d1adf063e02025-08-20T01:53:22ZengNature PortfolioScientific Reports2045-23222025-05-0115111510.1038/s41598-025-02078-9Development of an acute lung injury model for drug testingJocelyn R. Grunwell0Susan T. Stephenson1Gail A. Dallalio2Badiallo A. Diani3Celena Zaworski4Natalie Jordan5Anne M. Fitzpatrick6Division of Critical Care Medicine, Children’s Healthcare of Atlanta, Arthur M. Blank HospitalDepartment of Pediatrics, Emory University School of MedicineDepartment of Pediatrics, Emory University School of MedicineDepartment of Biomedical Engineering, Georgia Institute of TechnologyDivision of Critical Care Medicine, Children’s Healthcare of Atlanta, Arthur M. Blank HospitalDivision of Critical Care Medicine, Children’s Healthcare of Atlanta, Arthur M. Blank HospitalDepartment of Pediatrics, Emory University School of MedicineAbstract A challenge that limits our understanding of the underlying pathobiology of pediatric acute respiratory distress syndrome (PARDS) is the lack of a preclinical airway model that can be leveraged for the study of mechanisms and specific molecules for drug testing. We developed a physiologic model system of the small airways for mechanistic application in PARDS using a co-culture of primary human-derived small airway epithelial cells (SAECs) cultured at the air–liquid interface and umbilical vein endothelial cells in a transwell system. The model was validated by exposing the SAECs to a rhinovirus infection, to an inflammatory lung insult using a mixture of cytokines found in ARDS (cytomix), and to airway fluid samples from children with different severity strata of PARDS. We used a combination of transepithelial electrical resistance, immunofluorescence confocal microscopy of tight junctions, targeted gene expression, and cytokine responses to evaluate the model to the aforementioned insults. We then use the model in drug testing and show the reduction in IL-6 expression in conditioned media and STAT3 phosphorylation following co-treatment of SAECs with cytomix and the Janus kinase inhibitor (JAKi) baricitinib. This model enables mechanistic studies of airway pathobiology and may serve as a novel drug testing platform for PARDS.https://doi.org/10.1038/s41598-025-02078-9PediatricAcute respiratory distress syndromeBaricitinibSTAT3Small airway epithelial cellsModel |
| spellingShingle | Jocelyn R. Grunwell Susan T. Stephenson Gail A. Dallalio Badiallo A. Diani Celena Zaworski Natalie Jordan Anne M. Fitzpatrick Development of an acute lung injury model for drug testing Scientific Reports Pediatric Acute respiratory distress syndrome Baricitinib STAT3 Small airway epithelial cells Model |
| title | Development of an acute lung injury model for drug testing |
| title_full | Development of an acute lung injury model for drug testing |
| title_fullStr | Development of an acute lung injury model for drug testing |
| title_full_unstemmed | Development of an acute lung injury model for drug testing |
| title_short | Development of an acute lung injury model for drug testing |
| title_sort | development of an acute lung injury model for drug testing |
| topic | Pediatric Acute respiratory distress syndrome Baricitinib STAT3 Small airway epithelial cells Model |
| url | https://doi.org/10.1038/s41598-025-02078-9 |
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