Patients with severe asthma produce special substances in their airways when taking medicine during an asthma attack that block the treatment from working.
Two different so-called growth factors – naturally occurring substances that stimulate cell proliferation – activate as they inhale corticosteroids used as an emergency treatment during such an attack.
The discovery was made as researchers investigated an enduring mystery in asthma treatment: Why do some patients who suffer the most from the disease often have the least success with conventional rescue treatments?
The corticosteroids used to decrease swelling and irritation in the airways of people with moderate asthma often fail to work in those with severe asthma. These patients experience more frequent bouts of breathing problems than others.
Reporting in the journal Science Translational Medicine, the researchers said they found inhaled steroids in severe asthma patients promote the secretion of growth factors, fibroblast growth factor (FGF) and granulocytic colony forming growth factor (G-CSF), in airway lining cells known as the epithelium.
“We believe this response explains why patients with severe asthma are unresponsive to such conventional therapy,” said author Reynold Panettieri Jr, a professor of medicine at Rutgers Robert Wood Johnson Medical School and vice-chancellor of Clinical and Translational Science.
Researchers compared samples of bronchial airway epithelial cells (BAECs) that had been exposed to inhaled corticosteroids and were collected from three groups: those with severe asthma, those with moderate asthma and healthy volunteers.
By conducting a genetic analysis to determine what genes had been turned “on” in the BAECs, the scientists were able to see that the FGF and G-CSF growth factors had been expressed only in the cells of the patients with severe asthma.
Growth factors are important for regulating a variety of cellular processes, Panettieri said. In the case of an asthma attack in patients with severe asthma, the growth factors identified in the cells that line the major connecting airways work directly against the action of the corticosteroids. Findings from the study suggest different cellular pathways are at work in the cells of patients with severe asthma, particularly those involved in inflammation.
Here’s how the researchers envision a new medicine may work: In a study in mice, scientists found if they blocked the cascade of chemicals that ultimately triggers the growth factors to be secreted, corticosteroids effectively reversed airway inflammation and even prevented scarring of tissue.
“Our study has uncovered a potential mechanism to explain why patients with severe asthma are unresponsive to conventional therapy,” Panettieri said. “If we could uncover new approaches to treatment that directly affect that mechanism, we may be able to restore a sensitivity to the steroid and improve outcomes.”
Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma.
Riccardo Guidi, Daqi Xu, David Choy, Thirumalai Ramalingam, Wyne 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 Austin, Yi Cao, Christine Clarke, Reynold Panettieri, Cynthia Koziol-White, William Jester, Fen Wang, Mark Wilson.
Published in Science Translational Medicine on 20 April 2022
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.
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.
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