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- Title
Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma.
- Authors
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
- Abstract
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. Ameliorating asthma: Many individuals with mild or moderate asthma benefit from treatment with inhaled corticosteroids. However, patients with severe asthma often do not benefit from inhaled corticosteroid treatment. Here, Guidi and colleagues investigated the mechanism behind these poor responses. The authors found that patients with severe asthma had increased corticosteroid-driven fibroblast growth factor (FGF) expression. In mice, FGF exposure increased hyaluronan production and neutrophil infiltration into the lungs, worsening allergic responses. This could be reversed by treating mice with pan-FGF receptor inhibitors, suggesting that a combination of corticosteroids and FGF inhibition may be a therapeutic option for those with severe asthma.
- Subjects
FIBROBLAST growth factors; GRANULOCYTE-colony stimulating factor; ASTHMATICS; STEROID drugs; ASTHMA; LUNGS; FLUTICASONE propionate; GRANULOCYTES
- Publication
Science Translational Medicine, 2022, Vol 14, Issue 641, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abl8146