Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109-0688, USA.
Am J Pathol. 2012 Jan;180(1):61-72. doi: 10.1016/j.ajpath.2011.09.029. Epub 2011 Nov 8.
Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhibits typical features of COPD. Elastase/LPS-exposed mice infected with NTHi showed persistence of bacteria up to 5 days after infection, whereas mice exposed to elastase, LPS, or PBS cleared all bacteria by 3 days. Elastase/LPS-exposed mice also showed sustained lung neutrophilic inflammation, goblet cell metaplasia, airway hyperresponsiveness, and progression of emphysema at 15 days after infection. Alveolar macrophages isolated from elastase/LPS-exposed mice showed impaired bacterial phagocytosis, reduced expression of MARCO and of mannose receptor, and absent expression of scavenger receptor-A (SR-A). Neutralization of SR-A significantly decreased phagocytosis of NTHi by normal alveolar macrophages. Our results suggest that elastase/LPS-exposed mice show impaired bacterial clearance and sustained lung inflammation. Lack of SR-A expression may, in part, be responsible for impaired phagocytosis of bacteria by alveolar macrophages of elastase/LPS-exposed mice. These data validate the suitability of elastase/LPS model for investigating NTHi pathogenesis and progression of disease in COPD.
无乳链球菌（NTHi）是一种重要的细菌性病原体，与下呼吸道定植以及慢性阻塞性肺疾病（COPD）的急性加重和疾病进展有关。为什么免疫系统无法消除 NTHi，以及该生物体对 COPD 进展的确切贡献尚不清楚，部分原因是我们缺乏模拟 COPD 所有方面的动物模型。在这项研究中，我们使用了一种已建立的、具有 COPD 典型特征的小鼠模型。弹性蛋白酶/LPS 暴露的感染 NTHi 的小鼠在感染后 5 天内仍可检测到细菌持续存在，而暴露于弹性蛋白酶、LPS 或 PBS 的小鼠在 3 天内清除了所有细菌。弹性蛋白酶/LPS 暴露的小鼠在感染后 15 天还表现出持续的肺部中性粒细胞炎症、杯状细胞化生、气道高反应性和肺气肿进展。从弹性蛋白酶/LPS 暴露的小鼠分离出的肺泡巨噬细胞显示出细菌吞噬作用受损、MARCO 和甘露糖受体表达减少以及清道夫受体-A（SR-A）表达缺失。SR-A 的中和显著降低了正常肺泡巨噬细胞对 NTHi 的吞噬作用。我们的结果表明，弹性蛋白酶/LPS 暴露的小鼠表现出细菌清除受损和持续的肺部炎症。缺乏 SR-A 表达可能部分导致弹性蛋白酶/LPS 暴露的肺泡巨噬细胞对细菌吞噬作用受损。这些数据验证了弹性蛋白酶/LPS 模型在研究 NTHi 发病机制和 COPD 疾病进展中的适用性。
