ABSTRACT

Airway microenvironment played an important role in the progression of chronic respiratory disease. Here we showed that standardized pondus hydrogenii (pH) of exhaled breath condensate (EBC) of bronchiectasis patients was significantly lower than that of controls and was significantly correlated with bronchiectasis severity index (BSI) scores and disease prognosis. EBC pH was lower in severe patients than that in mild and moderate patients. Besides, acidic microenvironment deteriorated Pseudomonas aeruginosa (P. aeruginosa) pulmonary infection in mice models. Mechanistically, acidic microenvironment increased P. aeruginosa outer membrane vesicles (PA_OMVs) released and boosted it induced the activation of interferon regulatory factor3 (IRF3)-interferonβ (IFN-β) signalling pathway, ultimately compromised the anti-bacteria immunity. Targeted knockout of IRF3 or type 1 interferon receptor (IFNAR1) alleviated lung damage and lethality of mice after P. aeruginosa infection that aggravated by acidic microenvironment. Together, these findings identified airway acidification impaired host resistance to P. aeruginosa infection by enhancing it induced the activation of IRF3-IFN-β signalling pathway. Standardized EBC pH may be a useful biomarker of disease severity and a potential therapeutic target for the refractory P. aeruginosa infection. The study also provided one more reference parameter for drug selection and new drug discovery for bronchiectasis.

摘要

气道微环境在慢性呼吸道疾病的进展中发挥了重要作用。在这里，我们发现支气管扩张患者呼出气冷凝液 (EBC) 的标准化氢水池 (pH) 显着低于对照组，并且与支气管扩张严重指数 (BSI) 评分和疾病预后显着相关。重症患者的EBC pH值低于轻度和中度患者。此外，酸性微环境恶化了小鼠模型中的铜绿假单胞菌 (P. aeruginosa)肺部感染。机械地，酸性微环境增加了铜绿假单胞菌外膜囊泡 (PA_OMVs) 释放并促进它诱导干扰素调节因子 3 (IRF3)-干扰素β (IFN-β) 信号通路的激活，最终损害抗菌免疫。靶向敲除 IRF3 或 1 型干扰素受体 (IFNAR1) 可减轻因酸性微环境而加重的铜绿假单胞菌感染后小鼠的肺损伤和致死率。总之，这些发现确定了气道酸化通过增强其诱导 IRF3-IFN-β 信号通路的激活而损害了宿主对铜绿假单胞菌感染的抵抗力。标准化 EBC pH 可能是疾病严重程度的有用生物标志物，也是难治性铜绿假单胞菌的潜在治疗靶点感染。该研究还为支气管扩张的药物选择和新药发现提供了更多的参考参数。