Immunology Discovery, Genentech, South San Francisco, CA 94080, USA.
Biomarker Discovery OMNI, Genentech, South San Francisco, CA 94080, USA.
Sci Transl Med. 2022 Apr 20;14(641):eabl8146. doi: 10.1126/scitranslmed.abl8146.
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.
哮喘和炎症性气道疾病会限制肺部气流，从而影响气体交换和肺功能。吸入性皮质类固醇（ICS）可以减轻炎症、控制症状和改善肺功能；然而，越来越多的严重哮喘患者无法从 ICS 中获益。我们使用严重哮喘患者的支气管气道上皮刷检物或原代人细胞，描绘了一个皮质类固醇驱动的成纤维细胞生长因子（FGF）依赖性炎症轴，其中 FGF 反应性成纤维细胞促进下游粒细胞集落刺激因子（G-CSF）产生、透明质酸分泌和中性粒细胞炎症。在小鼠的变应原挑战研究中，我们证明了 ICS，丙酸氟替卡松，抑制了 2 型驱动的嗜酸性粒细胞增多症，但同时诱导了 FGF、G-CSF、透明质酸和中性粒细胞浸润的增加。我们开发了一种由类固醇诱导的中性粒细胞炎症介导的模型，部分是通过诱导 FGF 依赖性上皮-间充质轴，这可能解释了为什么有些人不能从 ICS 中获益。在进一步的概念验证实验中，我们发现，泛 FGF 受体抑制剂和皮质类固醇的联合治疗可预防嗜酸性粒细胞和类固醇诱导的中性粒细胞炎症。这些结果共同确立了 FGF 作为不能从 ICS 中获益的严重哮喘患者的治疗靶点。
