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European journal of pharmacology

High-dose tobramycin inhibits lipopolysaccharide-induced MUC5AC production in human lung epithelial cells.


PMID 21414310

Abstract

Tobramycin inhalation therapy is an effective therapy for cystic fibrosis as well as severe bronchiectasis that is colonized with Pseudomonas aeruginosa. The mechanism responsible for the efficacy of tobramycin in the treatment of severe chronic infectious diseases has not been elucidated. We demonstrate that high-dose tobramycin decreases MUC5AC gene expression and protein production in NCI-H292 cell stimulated with lipopolysaccharide of P. aeruginosa. MUC5AC protein of NCI-H292 cell stimulated by lipopolysaccharide was analyzed by an enzyme-linked immunosorbent assay and MUC5AC expression at the mRNA level was analyzed by RT-PCR. Western blot was performed to examine a potential role for the signaling molecules upstream of NFκB. High-dose tobramycin (500μg/ml) decreased the level of MUC5AC protein released into the supernatant of the NCI-H292 cell line at 24h after lipopolysaccharide stimulation (P<0.001). The tobramycin treatment also inhibited MUC5AC mRNA expression at 12h after lipopolysaccharide stimulation (P<0.05) and suppressed NFκB activation 60min after lipopolysaccharide stimulation (P<0.001). Tobramycin suppressed the phosphorylation of extracellular signal-regulated protein kinase, p38 MAP kinase. These results suggest that high-dose tobramycin, such as inhalation therapy, can inhibit MUC5AC gene expression and MUC5AC protein production in NCI-H292 cells, in part through the mitogen-activated protein kinase pathway. Thus, the activation of TLR4 and the subsequent immune/inflammatory responses induced by chronic infections such as P. aeruginosa might be modulated by tobramycin. Our data may reveal one of the mechanisms responsible for the clinical effect of tobramycin inhalation therapy against severe chronic respiratory diseases due to P. aeruginosa.

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NCI-H292