Tobramycin suppresses cystic fibrosis lung inflammation by increasing 5' tRNA-fMet halves secreted by P. aeruginosa
Li, Z.; Koeppen, K.; Ashare, A.; Hogan, D. A.; Gerber, S.; Stanton, B. A.
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Although inhaled tobramycin increases lung function in people with cystic fibrosis (pwCF), the density of P. aeruginosa in the lungs is only modestly reduced by tobramycin; hence, the mechanism whereby tobramycin improves lung function is unclear. Here, we demonstrate that tobramycin increases the abundance of two 5' tRNA-fMet halves in outer membrane vesicles (OMVs) secreted by P. aeruginosa and that the 5' tRNA-fMet halves reduce IL-8 secretion by CF bronchial epithelial cells (CF-HBECs). In mouse lung, the 5' tRNA-fMet halves attenuate KC secretion and neutrophil recruitment. We also report that the 5' tRNA-fMet halves suppress pro-inflammatory network gene expression by an Argonaut 2 (AGO2)-mediated gene silencing mechanism, thereby reducing IL-8 secretion in CF-HBECs. Moreover, tobramycin reduces the IL-8 concentration and neutrophil content in bronchoalveolar lavage fluid of pwCF. Thus, we conclude that tobramycin improves lung function in part by reducing chronic inflammation and neutrophil-mediated lung damage in pwCF.
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