Abstract：
Although tobramycin increases lung function in people with cystic fibrosis (pwCF), the density of Pseudomonas aeruginosa (P. aeruginosa) in the lungs is only modestly reduced by tobramycin; hence, the mechanism whereby tobramycin improves lung function is not completely understood. Here, we demonstrate that tobramycin increases 5\' tRNA-fMet halves in outer membrane vesicles (OMVs) secreted by laboratory and CF clinical isolates of P. aeruginosa. The 5\' tRNA-fMet halves are transferred from OMVs into primary CF human bronchial epithelial cells (CF-HBEC), decreasing OMV-induced IL-8 and IP-10 secretion. In mouse lungs, increased expression of the 5\' tRNA-fMet halves in OMVs attenuated KC (murine homolog of IL-8) secretion and neutrophil recruitment. Furthermore, there was less IL-8 and neutrophils in bronchoalveolar lavage fluid isolated from pwCF during the period of exposure to tobramycin versus the period off tobramycin. In conclusion, we have shown in mice and in vitro studies on CF-HBEC that tobramycin reduces inflammation by increasing 5\' tRNA-fMet halves in OMVs that are delivered to CF-HBEC and reduce IL-8 and neutrophilic airway inflammation. This effect is predicted to improve lung function in pwCF receiving tobramycin for P. aeruginosa infection.NEW & NOTEWORTHY The experiments in this report identify a novel mechanism, whereby tobramycin reduces inflammation in two models of CF. Tobramycin increased the secretion of tRNA-fMet halves in OMVs secreted by P. aeruginosa, which reduced the OMV-LPS-induced inflammatory response in primary cultures of CF-HBEC and in mouse lung, an effect predicted to reduce lung damage in pwCF.
摘要：
尽管妥布霉素可增加囊性纤维化（pwCF）患者的肺功能，铜绿假单胞菌的密度(P.铜绿假）在肺部仅被妥布霉素适度减少；因此，妥布霉素改善肺功能的机制尚不完全清楚。这里,我们证明妥布霉素增加了铜绿假单胞菌实验室和CF临床分离株分泌的外膜囊泡（OMV）中的5'tRNA-fMet一半。将5'tRNA-fMet两半从OMV转移到原代CF人支气管上皮细胞（CF-HBEC）中，降低OMV诱导的IL-8和IP-10分泌。在小鼠肺部，OMV中5'tRNA-fMet一半的表达增加减弱了KC分泌和中性粒细胞募集。此外，与妥布霉素停药期相比,从pwCF分离的支气管肺泡灌洗液中IL-8和中性粒细胞较少.总之,我们已经在小鼠和CF-HBEC的体外研究中显示,妥布霉素通过增加递送至CF-HBEC的OMV中的5'tRNA-fMet一半来减少炎症,并减少IL-8和嗜中性粒细胞气道炎症。预计这种作用改善接受妥布霉素治疗铜绿假单胞菌感染的pwCF的肺功能。
