BACKGROUND Chronic inflammation is a hallmark among patients with cystic fibrosis (CF). We explored whether mutation-induced (F508del) misfolding of the cystic fibrosis transmembrane conductance regulator (CFTR), and/or secondary colonization with opportunistic pathogens, activate tissue remodeling and innate immune response drivers. METHODS Using RNA-seq to interrogate global gene expression profiles, we analyzed stress response signaling cascades in primary human bronchial epithelia (HBE) and intestinal organoids. RESULTS Primary HBE acquired from CF patients with advanced disease and prolonged exposure to pathogenic microorganisms display a clear molecular signature of activated tissue remodeling pathways, unfolded protein response (UPR), and chronic inflammation. Furthermore, CFTR misfolding induces inflammatory signaling cascades in F508del patient-derived organoids from both the distal small intestine and colon. CONCLUSION Despite the small patient cohort size, this proof-of-principle study supports the use of RNA-seq as a means to both identify CF-specific signaling profiles in various tissues and evaluate disease heterogeneity. Our global transcriptomic data is a useful resource for the CF research community for analyzing other gene expression sets influencing CF disease signature but also transcriptionally contributing to CF heterogeneity.

中文翻译：

---

对 CF 患者气道和肠道组织的综合应激反应进行全面评估

背景技术慢性炎症是囊性纤维化（CF）患者的一个标志。我们探讨了突变诱导的囊性纤维化跨膜电导调节因子（CFTR）的错误折叠（F508del）和/或机会性病原体的二次定植是否会激活组织重塑和先天免疫反应驱动因素。方法使用 RNA-seq 询问全局基因表达谱，我们分析了原代人支气管上皮 (HBE) 和肠类器官中的应激反应信号级联。结果从患有晚期疾病和长期暴露于病原微生物的 CF 患者获得的原发性 HBE 显示出激活的组织重塑途径、未折叠蛋白反应 (UPR) 和慢性炎症的清晰分子特征。此外，CFTR 错误折叠会在 F508del 患者来源的远端小肠和结肠类器官中诱导炎症信号级联反应。结论 尽管患者队列规模较小，但这项原理验证研究支持使用 RNA-seq 作为识别各种组织中 CF 特异性信号传导谱和评估疾病异质性的手段。我们的全球转录组数据对于 CF 研究界来说是有用的资源，可用于分析影响 CF 疾病特征的其他基因表达集，但也可在转录上促进 CF 异质性。