Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 14, Issue 641, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abl8146
Keywords
-
Categories
Funding
- Genentech
- Cancer Prevention & Research Institute of Texas (CPRIT) [RP190612]
- NIH: NCATS [UL1TR003017]
- NHLBI [PO1HL114471]
Ask authors/readers for more resources
Asthma and inflammatory airway diseases restrict lung airflow and function. Inhaled corticosteroids (ICSs) can reduce inflammation and improve symptoms, but some severe asthma patients do not benefit from ICS. This study identified a corticosteroid-driven fibroblast growth factor (FGF)-dependent inflammatory axis and found that combination therapy with pan-FGF receptor inhibitors and corticosteroids can prevent both eosinophilic and steroid-induced neutrophilic inflammation.
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available