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

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.

• Authors: Riccardo Guidi, Daqi Xu, David F Choy, Thirumalai R Ramalingam, Wyne P Lee, Zora Modrusan, Yuxin Liang, Scot Marsters, Avi Ashkenazi, Alison Huynh, Jessica Mills, Sean Flanagan, Shannon Hambro, Victor Nunez, Laurie Leong, Ashley Cook, Tiffany Hao Tran, Cary D Austin, Yi Cao, Christine Clarke, Reynold A Panettieri Jr, Cynthia Koziol-White, William F Jester Jr, Fen Wang, Mark S Wilson
• Journal: Science translational medicine (Sci Transl Med) Vol. 14 Issue 641 Pg. eabl8146 (04 20 2022) ISSN: 1946-6242 [Electronic] United States
• PMID: 35442706 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenal Cortex Hormones
• Granulocyte Colony-Stimulating Factor
• Fibroblast Growth Factors
• Hyaluronic Acid
• Fluticasone

Topics

• Adrenal Cortex Hormones (pharmacology, therapeutic use)
• Animals
• Asthma
• Fibroblast Growth Factors
• Fluticasone (pharmacology, therapeutic use)
• Granulocyte Colony-Stimulating Factor (therapeutic use)
• Humans
• Hyaluronic Acid
• Inflammation (drug therapy)
• Mice