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Guidi, Riccardo; Xu, Daqi; Choy, David F.; Ramalingam, Thirumalai R.; Lee, Wyne P.; Modrusan, Zora; Liang, Yuxin; Marsters, Scot; Ashkenazi, Avi; Huynh, Alison; Mills, Jessica; Flanagan, Sean; Hambro, Shannon; Nunez, Victor; Leong, Laurie; Cook, Ashley; Tran, Tiffany Hao; Austin, Cary D.; Cao, Yi; Clarke, Christine; Panettieri, Reynold A.; Koziol-White, Cynthia; Jester, William F.; Wang, Fen;

Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma

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  • Media type: E-Article
  • Title: Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma
  • Contributor: Guidi, Riccardo; Xu, Daqi; Choy, David F.; Ramalingam, Thirumalai R.; Lee, Wyne P.; Modrusan, Zora; Liang, Yuxin; Marsters, Scot; Ashkenazi, Avi; Huynh, Alison; Mills, Jessica; Flanagan, Sean; Hambro, Shannon; Nunez, Victor; Leong, Laurie; Cook, Ashley; Tran, Tiffany Hao; Austin, Cary D.; Cao, Yi; Clarke, Christine; Panettieri, Reynold A.; Koziol-White, Cynthia; Jester, William F.; Wang, Fen;
  • imprint: American Association for the Advancement of Science (AAAS), 2022
  • Published in: Science Translational Medicine
  • Language: English
  • DOI: 10.1126/scitranslmed.abl8146
  • ISSN: 1946-6234; 1946-6242
  • Keywords: General Medicine
  • Origination:
  • Footnote:
  • Description: <jats:p>Asthma and inflammatory airway diseases restrict airflow in the lung, compromising gas exchange and lung function. Inhaled corticosteroids (ICSs) can reduce inflammation, control symptoms, and improve lung function; however, a growing number of patients with severe asthma do not benefit from ICS. Using bronchial airway epithelial brushings from patients with severe asthma or primary human cells, we delineated a corticosteroid-driven fibroblast growth factor (FGF)–dependent inflammatory axis, with FGF-responsive fibroblasts promoting downstream granulocyte colony-stimulating factor (G-CSF) production, hyaluronan secretion, and neutrophilic inflammation. Allergen challenge studies in mice demonstrate that the ICS, fluticasone propionate, inhibited type 2–driven eosinophilia but induced a concomitant increase in FGFs, G-CSF, hyaluronan, and neutrophil infiltration. We developed a model of steroid-induced neutrophilic inflammation mediated, in part, by induction of an FGF-dependent epithelial-mesenchymal axis, which may explain why some individuals do not benefit from ICS. In further proof-of-concept experiments, we found that combination therapy with pan-FGF receptor inhibitors and corticosteroids prevented both eosinophilic and steroid-induced neutrophilic inflammation. Together, these results establish FGFs as therapeutic targets for severe asthma patients who do not benefit from ICS.</jats:p>