Wuerth Kelli C, Falsafi Reza, Hancock Robert E W
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
PLoS One. 2017 Nov 6;12(11):e0187565. doi: 10.1371/journal.pone.0187565. eCollection 2017.
Pseudomonas aeruginosa is a frequent cause of lung infections, particularly in chronic infections in cystic fibrosis patients. However, treatment is challenging due to P. aeruginosa evasion of the host immune system and the rise of antibiotic resistant strains. Host defense peptides (HDPs) and synthetic derivatives called innate defense regulators (IDRs) have shown promise in several infection models as an alternative to antibiotic treatment. Here we tested peptide IDR-1002 against P. aeruginosa in vitro and in vivo. Treatment of bronchial epithelial cells and macrophages with IDR-1002 or in combination with live P. aeruginosa or its LPS led to the reduction of agonist-induced cytokines and chemokines and limited cell killing by live P. aeruginosa. In an in vivo model using P. aeruginosa combined with alginate to mimic a chronic model, IDR-1002 did not reduce the bacterial burden in the lungs, but IDR-1002 mice showed a significant decrease in IL-6 in the lungs and in gross pathology of infection, while histology revealed that IDR-1002 treated mice had reduced alveolar macrophage infiltration around the site of infection and reduced inflammation. Overall, these results indicate that IDR-1002 has promise for combating P. aeruginosa lung infections and their resulting inflammation.
铜绿假单胞菌是肺部感染的常见病因，尤其是在囊性纤维化患者的慢性感染中。然而，由于铜绿假单胞菌能够逃避宿主免疫系统以及抗生素耐药菌株的出现，治疗具有挑战性。宿主防御肽（HDPs）和称为固有防御调节剂（IDRs）的合成衍生物在多种感染模型中已显示出作为抗生素治疗替代方案的潜力。在此，我们在体外和体内测试了肽IDR-1002对铜绿假单胞菌的作用。用IDR-1002或与活的铜绿假单胞菌或其脂多糖联合处理支气管上皮细胞和巨噬细胞，可导致激动剂诱导的细胞因子和趋化因子减少，并限制活的铜绿假单胞菌对细胞的杀伤。在使用铜绿假单胞菌与藻酸盐联合模拟慢性模型的体内模型中，IDR-1002并未降低肺部的细菌载量，但IDR-1002处理的小鼠肺部的IL-6以及感染的大体病理学显著降低，而组织学显示，IDR-1002处理的小鼠在感染部位周围的肺泡巨噬细胞浸润减少且炎症减轻。总体而言，这些结果表明IDR-1002在对抗铜绿假单胞菌肺部感染及其引发的炎症方面具有潜力。
