Enhanced susceptibility to pulmonary infection with Burkholderia cepacia in Cftr(-/-) mice.
Enhanced susceptibility to pulmonary infection with Burkholderia cepacia in Cftr(-/-) mice.
复制标题
Cftr(-/-) 小鼠对洋葱伯克霍尔德菌肺部感染的易感性增强。
DOI：
10.1128/iai.69.8.5138-5150.2001
复制
发表时间：
2001
影响因子：
3.1
通讯作者：
Downey,GP
中科院分区：
文献类型：
--
作者：
Sajjan,U;Thanassoulis,G;Cherapanov,V;Lu,A;Sjolin,C;Steer,B;Wu,YJ;Rotstein,OD;Kent,G;McKerlie,C;Forstner,J;Downey,GP
进行性肺部感染是囊性纤维化(CF)的主要临床特征，但这种易感性的分子基础仍不完全清楚。为了研究这一问题，我们建立了一种慢性肺炎的模型，方法是将临床分离的洋葱伯克霍尔德氏菌(Genomovar III，ET12株)从一例Cftrm1unc−/−(CFtr−/−)和Cftr+/+对照的肺中反复滴注，这种细菌是一种机会型革兰氏阴性菌。最后一次滴注9天后，CF跨膜调节基因敲除小鼠显示出患有慢性重症支气管炎的活菌持续存在，而野生型小鼠保持健康。易感Cftr−/−小鼠的肺组织病理学改变的特征是混合炎性细胞群渗入细支气管区和血管周围间隙，Clara细胞增生，呼吸道粘液高分泌，以及巨噬细胞和中性粒细胞混合群渗入肺泡腔。在Cftr−/−小鼠的支气管肺泡灌洗液中观察到中性粒细胞比例增加，尽管细菌负荷增加，但激活的证据很少。Cftr−/−小鼠的肺泡巨噬细胞也表现出次佳的激活。这些观察表明，患有CF的动物的肺宿主防御系统受到损害，表现为对细菌感染和肺损伤的易感性增加。因此，这种慢性肺炎的小鼠模型在一定程度上反映了人类患者的情况，并可能有助于阐明导致CF宿主防御缺陷的机制。
Progressive pulmonary infection is the dominant clinical feature of cystic fibrosis (CF), but the molecular basis for this susceptibility remains incompletely understood. To study this problem, we developed a model of chronic pneumonia by repeated instillation of a clinical isolate ofBurkholderia cepacia(genomovar III, ET12 strain), an opportunistic gram-negative bacterium, from a case of CF into the lungs ofCftrm1unc−/−(Cftr−/−) and congenicCftr+/+controls. Nine days after the last instillation, the CF transmembrane regulator knockout mice showed persistence of viable bacteria with chronic severe bronchopneumonia while wild-type mice remained healthy. The histopathological changes in the lungs of the susceptibleCftr−/−mice were characterized by infiltration of a mixed inflammatory-cell population into the peribronchiolar and perivascular spaces, Clara cell hyperplasia, mucus hypersecretion in airways, and exudation into alveolar airspaces by a mixed population of macrophages and neutrophils. An increased proportion of neutrophils was observed in bronchoalveolar lavage fluid from theCftr−/−mice, which, despite an increased bacterial load, demonstrated minimal evidence of activation. Alveolar macrophages fromCftr−/−mice also demonstrated suboptimal activation. These observations suggest that the pulmonary host defenses are compromised in lungs from animals with CF, as manifested by increased susceptibility to bacterial infection and lung injury. This murine model of chronic pneumonia thus reflects, in part, the situation in human patients and may help elucidate the mechanisms leading to defective host defense in CF.