Hynes Jennifer, Taggart Clifford C, Tirouvanziam Rabindra, Coppinger Judith A
School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland.
Children's Health Ireland Translational Research Centre, Children's Health Ireland at Crumlin, D12 N512 Dublin, Ireland.
Int J Mol Sci. 2025 Mar 14;26(6):2636. doi: 10.3390/ijms26062636.
Cystic Fibrosis (CF) is a life-shortening, multi-organ disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Prominent clinical features of CF take place in the lung, hallmarked by cycles of bacterial infection and a dysfunctional inflammatory airway response, leading to eventual respiratory failure. Bidirectional crosstalk between epithelial cells, leukocytes (e.g., neutrophils, macrophages) and bacteria via release of intra-cellular mediators is key to driving inflammation in CF airways. In recent years, a highly effective combination of therapeutics targeting the CFTR defect have revolutionized treatment in CF. Despite these advancements and due to the complexity of the immune response in the CF airway, the full impact of highly effective modulator therapy (HEMT) on airway inflammation is not fully determined. This review provides the evidence to date on crosstalk mechanisms between host epithelium, leukocytes and bacteria and examines the effect of HEMT on both soluble and membrane-derived immune mediators in clinical samples. The varied effects of HEMT on expression of key proteases, cytokines and extracellular vesicles (EVs) in relation to clinical parameters is assessed. Advances in treatment with HEMT have shown potential in dampening the chronic inflammatory response in CF airways. However, to fully quell inflammation and maximize lung tissue resilience, further interventions may be necessary. Exploring the effects of HEMT on key immune mediators paves the way for identifying new anti-inflammatory approaches targeting host immune cell interactions, such as EV-directed lung therapies.
囊性纤维化（CF）是一种由囊性纤维化跨膜传导调节因子（CFTR）基因突变引起的缩短寿命的多器官疾病。CF的突出临床特征发生在肺部，其标志是细菌感染周期和功能失调的气道炎症反应，最终导致呼吸衰竭。上皮细胞、白细胞（如中性粒细胞、巨噬细胞）和细菌通过释放细胞内介质进行双向串扰是驱动CF气道炎症的关键。近年来，针对CFTR缺陷的高效治疗组合彻底改变了CF的治疗方法。尽管取得了这些进展，但由于CF气道免疫反应的复杂性，高效调节剂疗法（HEMT）对气道炎症的全面影响尚未完全确定。本综述提供了迄今为止关于宿主上皮细胞、白细胞和细菌之间串扰机制的证据，并研究了HEMT对临床样本中可溶性和膜源性免疫介质的影响。评估了HEMT对关键蛋白酶、细胞因子和细胞外囊泡（EVs）表达与临床参数相关的不同影响。HEMT治疗的进展已显示出减轻CF气道慢性炎症反应的潜力。然而，为了完全平息炎症并最大限度地提高肺组织弹性，可能需要进一步的干预措施。探索HEMT对关键免疫介质的影响为确定针对宿主免疫细胞相互作用的新抗炎方法铺平了道路，例如EV导向的肺部治疗。
