Aerosol treatment with MNEI suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection.
Aerosol treatment with MNEI suppresses bacterial proliferation in a model of chronic Pseudomonas aeruginosa lung infection.
复制标题
MNEI 气雾剂治疗可抑制慢性铜绿假单胞菌肺部感染模型中的细菌增殖。
DOI：
10.1002/ppul.20167
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发表时间：
2005
影响因子：
3.1
通讯作者：
Remold-O'Donnell,Eileen
中科院分区：
文献类型：
--
作者：
Woods,DonaldE;Cantin,Andre;Cooley,Jessica;Kenney,DianneM;Remold-O'Donnell,Eileen
中性粒细胞弹性蛋白酶在囊性纤维化（CF）患者的气道液中存在高水平，并且是造成相当大的炎症损伤的原因。人单核细胞/中性粒细胞弹性酶抑制剂（MNEI）是一种42 - kDa的蛇形蛋白，是一种有效的中性粒细胞弹性酶、组织蛋白酶G和蛋白酶3的抑制剂，这些蛋白酶是从炎症中性粒细胞释放的相关蛋白酶。在慢性铜绿假单胞菌感染的动物模型中，我们假设重组MNEI可以减少炎症损伤并增强肺部细菌清除。体外研究表明，MNEI对大鼠中性粒细胞弹性酶活性的抑制作用呈剂量依赖性。重组MNEI每日雾化给药于先前接种含有p的琼脂珠的大鼠。铜绿杆菌引起慢性感染。给药的MNEI在处理大鼠的灌洗液中部分恢复为66 - kDa复合物，与蛋白酶结合，表明在体内抑制弹性蛋白酶或相关蛋白酶。MNEI气雾剂治疗显著降低炎症损伤程度，量化为组织病理学评分。MNEI对p无杀菌作用。铜绿糖甙体外，显著提高细菌从感染大鼠肺部的清除率。MNEI单次雾化处理6小时后，组织病理学评分降低，细菌杀灭能力增强。这些发现表明MNEI在保护先天抗菌防御方面具有重要功能。先前对雾化的泌乳素（α1‐抗胰蛋白酶）也获得了类似的结果，表明MNEI增强细菌清除率是由于抑制了中性粒细胞蛋白酶。这些发现证明了这种非抗生素蛋白酶抑制剂作为治疗和预防CF肺部疾病感染成分的辅助药物的价值。儿科肺科杂志。2005;39:141-149。©2005 Wiley‐Liss, Inc。
Neutrophil elastase is present at high levels in airway fluid of patients with cystic fibrosis (CF), and is responsible for considerable inflammatory damage. Human monocyte/neutrophil elastase inhibitor (MNEI), a 42‐kDa serpin protein, is an effective inhibitor of neutrophil elastase, cathepsin G, and proteinase‐3, related proteases released from inflammatory neutrophils. We hypothesized that recombinant MNEI would reduce inflammatory damage and enhance bacterial clearance from the lung in an animal model of chronicPseudomonas aeruginosainfection. In vitro studies showed that MNEI causes dose‐dependent inhibition of the activity of rat neutrophil elastase. Recombinant MNEI was administered daily by aerosolization to rats previously inoculated with agar beads containingP. aeruginosato initiate chronic infection. Administered MNEI was partially recovered in lavage fluid of treated rats as a 66‐kDa complex with protease indicative of in vivo inhibition of elastase or a related protease. Aerosol treatment with MNEI significantly decreased the extent of inflammatory injury, quantified as the histopathology score. MNEI, which had no bactericidal effect onP. aeruginosain vitro, significantly enhanced clearance of bacteria from infected rat lungs. The reduction of histopathology scores and enhancement of bacterial killing were evident 6 hr after a single aerosol treatment with MNEI. These findings indicate an important function of MNEI in protecting innate antimicrobial defense. Similar results were previously obtained for aerosolized prolastin (α1‐antitrypsin), indicating that enhanced bacterial clearance by MNEI is due to inhibition of neutrophil protease. These findings demonstrate the value of this nonantibiotic protease inhibitor as an adjunct for the treatment and prevention of the infection component of CF lung disease. Pediatr Pulmonol. 2005;39:141–149. © 2005 Wiley‐Liss, Inc.