ABSTRACT

Chronic obstructive pulmonary disease (COPD) patients undergo infectious exacerbations whose frequency identifies a clinically meaningful phenotype. Mouse models have been mostly used to separately study both COPD and the infectious processes, but a reliable model of the COPD frequent exacerbator phenotype is still lacking. Accordingly, we first established a model of single bacterial exacerbation by nontypeable Haemophilus influenzae (NTHi) infection on mice with emphysema-like lesions. We characterized this single exacerbation model combining both noninvasive in vivo imaging and ex vivo techniques, obtaining longitudinal information about bacterial load and the extent of the developing lesions and host responses. Bacterial load disappeared 48 hours post-infection (hpi). However, lung recovery, measured using tests of pulmonary function and the disappearance of lung inflammation as revealed by micro-computed X-ray tomography, was delayed until 3 weeks post-infection (wpi). Then, to emulate the frequent exacerbator phenotype, we performed two recurrent episodes of NTHi infection on the emphysematous murine lung. Consistent with the amplified infectious insult, bacterial load reduction was now observed 96 hpi, and lung function recovery and disappearance of lesions on anatomical lung images did not happen until 12 wpi. Finally, as a proof of principle of the use of the model, we showed that azithromycin successfully cleared the recurrent infection, confirming this macrolide utility to ameliorate infectious exacerbation. In conclusion, we present a mouse model of recurrent bacterial infection of the emphysematous lung, aimed to facilitate investigating the COPD frequent exacerbator phenotype by providing complementary, dynamic information of both infectious and inflammatory processes.

摘要

慢性阻塞性肺病（COPD）患者会经历感染性加重，其频率确定了具有临床意义的表型。小鼠模型主要用于单独研究慢性阻塞性肺病和感染过程，但仍然缺乏慢性阻塞性肺病频繁加重表型的可靠模型。因此，我们首先在患有肺气肿样病变的小鼠上建立了不可分型流感嗜血杆菌（NTHi）感染引起的单一细菌恶化模型。我们对这种单一恶化模型进行了描述，结合了无创体内成像和离体技术，获得了有关细菌负荷以及病变发展程度和宿主反应的纵向信息。感染后 48 小时 (hpi) 细菌负荷消失。然而，通过肺功能测试和微型计算机 X 射线断层扫描显示的肺部炎症消失来测量的肺部恢复被推迟到感染后 3 周 (wpi)。然后，为了模拟频繁的加重表型，我们对肺气肿小鼠肺进行了两次 NTHi 感染复发。与放大的感染性损伤一致，感染后 96 周时观察到细菌负荷减少，直到感染后 12 周后肺功能恢复和解剖肺部图像上的病变消失。最后，作为模型使用原理的证明，我们证明阿奇霉素成功清除了复发感染，证实了这种大环内酯类药物可改善感染恶化。总之，我们提出了肺气肿肺复发性细菌感染的小鼠模型，旨在通过提供感染和炎症过程的补充动态信息来促进研究 COPD 频繁加重表型。