PDF(Pubmed)
Abstract：
Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative facultative anaerobe that has become an important cause of severe infections in humans, particularly in patients with cystic fibrosis. The development of efficacious methods or mendicants against P. aeruginosa is still needed. We previously reported that regenerating islet-derived family member 4 (Reg4) has bactericidal activity against Salmonella Typhimurium, a Gram-negative flagellated bacterium. We herein explore whether Reg4 has bactericidal activity against P. aeruginosa. In the P. aeruginosa PAO1-chronic infection model, Reg4 significantly inhibits the colonization of PAO1 in the lung and subsequently ameliorates pulmonary inflammation and fibrosis. Reg4 recombinant protein suppresses the growth motility and biofilm formation capability of PAO1 in vitro. Mechanistically, Reg4 not only exerts bactericidal action via direct binding to the P. aeruginosa cell wall but also enhances the phagocytosis of alveolar macrophages in the host. Taken together, our study demonstrates that Reg4 may provide protection against P. aeruginosa-induced pulmonary inflammation and fibrosis via its antibacterial activity.IMPORTANCEChronic lung infection with Pseudomonas aeruginosa is a leading cause of morbidity and mortality in patients with cystic fibrosis. Due to the antibiotic resistance of Pseudomonas aeruginosa, antimicrobial peptides appear to be a potential alternative to combat its infection. In this study, we report an antimicrobial peptide, regenerating islet-derived 4 (Reg4), that showed killing activity against clinical strains of Pseudomonas aeruginosa PAO1 and ameliorated PAO1-induced pulmonary inflammation and fibrosis. Experimental data also showed Reg4 directly bound to the bacterial cell membrane and enhanced the phagocytosis of host alveolar macrophages. Our presented study will be a helpful resource in searching for novel antimicrobial peptides that could have the potential to replace conventional antibiotics.
摘要：
铜绿假单胞菌(P.铜绿假单胞菌）是革兰氏阴性兼性厌氧菌，已成为人类严重感染的重要原因，特别是囊性纤维化患者。仍然需要开发针对铜绿假单胞菌的有效方法或药物。我们先前报道，再生胰岛衍生的家族成员4（Reg4）对鼠伤寒沙门氏菌具有杀菌活性，革兰氏阴性鞭毛细菌。我们在此探索Reg4是否对铜绿假单胞菌具有杀菌活性。在铜绿假单胞菌PAO1慢性感染模型中，Reg4显著抑制PAO1在肺中的定植,并随后改善肺部炎症和纤维化。Reg4重组蛋白在体外抑制PAO1的生长运动和生物膜形成能力。机械上,Reg4不仅通过直接结合铜绿假单胞菌细胞壁发挥杀菌作用，而且还增强宿主中肺泡巨噬细胞的吞噬作用。一起来看,我们的研究表明，Reg4可能通过其抗菌活性提供对铜绿假单胞菌诱导的肺部炎症和纤维化的保护作用。重要提示铜绿假单胞菌慢性肺部感染是囊性纤维化患者发病和死亡的主要原因。由于铜绿假单胞菌对抗生素的耐药性,抗菌肽似乎是对抗其感染的潜在替代品。在这项研究中,我们报告了一种抗菌肽，再生胰岛衍生4(Reg4)，显示出对铜绿假单胞菌PAO1临床菌株的杀伤活性，并改善PAO1诱导的肺部炎症和纤维化。实验数据还显示Reg4直接与细菌细胞膜结合并增强宿主肺泡巨噬细胞的吞噬作用。我们提出的研究将是寻找可能替代常规抗生素的新型抗菌肽的有用资源。
