Center for Innovative Therapies in Cystic Fibrosis, University of Ferrara, Ferrara, Italy.
Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
Front Immunol. 2020 Aug 4;11:1438. doi: 10.3389/fimmu.2020.01438. eCollection 2020.
A hallmark of cystic fibrosis (CF) chronic respiratory disease is an extensive neutrophil infiltrate in the mucosa filling the bronchial lumen, starting early in life for CF infants. The genetic defect of the CF Transmembrane conductance Regulator (CFTR) ion channel promotes dehydration of the airway surface liquid, alters mucus properties, and decreases mucociliary clearance, favoring the onset of recurrent and, ultimately, chronic bacterial infection. Neutrophil infiltrates are unable to clear bacterial infection and, as an adverse effect, contribute to mucosal tissue damage by releasing proteases and reactive oxygen species. Moreover, the rapid cellular turnover of lumenal neutrophils releases nucleic acids that further alter the mucus viscosity. A prominent role in the recruitment of neutrophil in bronchial mucosa is played by CF bronchial epithelial cells carrying the defective CFTR protein and are exposed to whole bacteria and bacterial products, making pharmacological approaches to regulate the exaggerated neutrophil chemotaxis in CF a relevant therapeutic target. Here we revise: (a) the major receptors, kinases, and transcription factors leading to the expression, and release of neutrophil chemokines in bronchial epithelial cells; (b) the role of intracellular calcium homeostasis and, in particular, the calcium crosstalk between endoplasmic reticulum and mitochondria; (c) the epigenetic regulation of the key chemokines; (d) the role of mutant CFTR protein as a co-regulator of chemokines together with the host-pathogen interactions; and (e) different pharmacological strategies to regulate the expression of chemokines in CF bronchial epithelial cells through novel drug discovery and drug repurposing.
囊性纤维化 (CF) 慢性呼吸道疾病的一个标志是在支气管腔中充满了大量的中性粒细胞浸润，这在 CF 婴儿的生命早期就已经开始了。CF 跨膜电导调节蛋白 (CFTR) 离子通道的遗传缺陷促进了气道表面液体的脱水，改变了黏液的性质，并降低了黏液纤毛清除功能，从而有利于反复发生并最终导致慢性细菌感染。中性粒细胞浸润无法清除细菌感染，并且作为一种不良反应，通过释放蛋白酶和活性氧物质，导致黏膜组织损伤。此外，腔道中性粒细胞的快速细胞更新释放出的核酸进一步改变了黏液的粘度。携带缺陷 CFTR 蛋白的 CF 支气管上皮细胞在支气管黏膜中性粒细胞募集中起着重要作用，它们暴露于完整的细菌和细菌产物，使得针对调节 CF 中过度中性粒细胞趋化作用的药理学方法成为一个相关的治疗靶点。在这里，我们复习了：(a) 导致支气管上皮细胞中性粒细胞趋化因子表达和释放的主要受体、激酶和转录因子；(b) 细胞内钙稳态的作用，特别是内质网和线粒体之间的钙串扰；(c) 关键趋化因子的表观遗传调控；(d) 突变 CFTR 蛋白作为趋化因子共同调节剂的作用，以及宿主-病原体相互作用；(e) 通过新药发现和药物再利用来调节 CF 支气管上皮细胞中趋化因子表达的不同药理学策略。
