Bronchiolitis obliterans syndrome remains the leading cause of morbidity and mortality in the pulmonary transplant population. Previous studies show that macrolide antibiotics may be efficacious in the treatment of panbronchiolitis and cystic fibrosis. In the latter, azithromycin decreases the number of respiratory exacerbations, improves FEV1, and improves quality of life. We hypothesized that oral azithromycin therapy may improve lung function in patients with bronchiolitis obliterans syndrome. To test this hypothesis, we conducted an open-label pilot trial using maintenance azithromycin therapy in six lung transplant recipients (250 mg orally three times per week for a mean of 13.7 weeks). In this study, five of these six individuals demonstrated significant improvement in pulmonary function, as assessed by FEV1, as compared with their baseline values at the start of azithromycin therapy. The mean increase in the percentage of predicted FEV1 values in these individuals was 17.1% (p = 0.05). In addition, the absolute FEV1 increased by 0.50 L (range -0.18 to 1.36 L). These data suggest a potential role for maintenance macrolide therapy in the treatment of bronchiolitis obliterans syndrome in lung transplant recipients.
SummaryThe adjacent, divergently transcribed glpACB and glpTQ operons of Escherichia coli encode the anaerobic glycerol 3-phosphate dehydrogenase and glycerol 3-phosphate transporter/phosphodiesterase, respectively. These operons are negatively controlled by glp repressor binding to operators that overlap the glpA promoter elements. Using DNase I footprinting, three additional operators (O T 1-3) were identified at positions þ307 to þ359 within the glpT coding region. To assess a potential regulatory role for these remote operators in vivo, a glpT-lacZ transcriptional fusion containing all of the glpA and glpT operators was constructed. The response of this fusion to the glp repressor was compared to fusion constructs in which O T 1 and O T 3 were inactivated, either by deletion or by sitedirected mutagenesis. It was found that repression of glpT conferred by binding of glp repressor to glpA operators was increased about three-to fourfold upon introduction of the remote glpT operators. In addition, two integration host factor (IHF) binding sites were identified downstream of the glpT transcriptional start site at positions þ15 to þ51 and þ193 to þ227. A regulatory role for IHF was demonstrated by showing that repression of glpT mediated by GlpR was decreased about twofold in strains deficient in IHF and that mutations in IHF1 and/or IHF2 decreased repression about two-to threefold. The effect of IHF was apparent only when the remote operators were present. All of the results are consistent with a model of repression involving GlpR binding simultaneously to the glpA and remote glpT operators, with intervening DNA forming a loop.
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