Aerosolized prolastin suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection
Aerosolized prolastin suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection
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DOI：
10.1164/ajrccm.160.4.9807166
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发表时间：
1999-10-01
影响因子：
24.7
通讯作者：
Woods, DE
中科院分区：
文献类型：
--
作者：
Cantin, AM;Woods, DE
囊性纤维化（CF）患者的呼吸道分泌物中存在高水平的活性中性粒细胞弹性蛋白酶（HNE）。我们假设，雾化Prolastin（α（1）-蛋白酶抑制剂或α（1）PI，从人血液中纯化）可以抑制气道中性粒细胞炎症，并加速细菌清除从肺部慢性铜绿假单胞菌肺部感染模型。由于人α（1）PI在体外有效抑制大鼠和人中性粒细胞弹性蛋白酶（NE）活性，我们选择使用慢性铜绿假单胞菌肺部感染的大鼠琼脂珠模型来检验这一假设。在该模型中，雾化Prolastin显著降低弹性蛋白酶活性（p < 0.01）、肺中性粒细胞计数（p < 0.01）和细菌菌落计数（p < 0.01）。Prolastin在体外对铜绿假单胞菌无直接杀菌作用。肺组织组织病理学显示用Prolastin处理的动物的肺部炎症显著减少。这些研究表明，Prolastin可显著降低慢性感染肺中的弹性蛋白酶负荷。此外，Prolastin不仅抑制肺部炎症，而且还显著降低慢性铜绿假单胞菌肺部感染大鼠模型中的铜绿假单胞菌密度。这些数据表明，雾化α（1）PI可能代表一个有用的非抗生素辅助治疗和控制感染和炎症与CF肺部疾病。
High levels of active neutrophil elastase (HNE) are present in the respiratory secretions of patients with cystic fibrosis (CF). We hypothesized that aerosolized Prolastin (alpha(1)-protease inhibitor or alpha(1)PI, purified from human blood) could suppress airway neutrophil inflammation and accelerate bacterial clearance from the lung in a model of chronic Pseudomonas aeruginosa lung infection. Because human alpha(1)PI effectively inhibits rat as well as human neutrophil elastase (NE) activity in vitro, we choose to test this hypothesis using a rat agar bead model of chronic P. aeruginosa lung infection. In this model, aerosolized Prolastin significantly decreased elastase activity (p < 0.01), lung neutrophil counts (p < 0.01), and bacterial colony counts (p < 0.01). Prolastin had no direct bactericidal effect on P. aeruginosa in vitro. Lung tissue histopathology revealed a marked decrease in lung inflammation in animals treated with Prolastin. These studies indicate that Prolastin can significantly decrease the elastase burden in the chronically infected lung. In addition, not only does Prolastin suppress lung inflammation, but it also markedly decreases P. aeruginosa density in a rat model of chronic P. aeruginosa lung infection. These data suggest that aerosolized alpha(1)PI may represent a useful nonantibiotic adjunct in the treatment and control of infection and inflammation associated with CF lung disease.