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Competing Interests: Non-conditional grants von Boehringer-Ingelheim, Schweiz; Non-conditional grants von Roche Pharma, Schweiz; Speaker-fees von Boehringer-Ingelheim, Schweiz., (© 2024 Aerzteverlag medinfo AG.)

Background: High bacterial burden in the lung microbiota predicts progression of idiopathic pulmonary fibrosis (IPF). Azithromycin (AZT) is a macrolide antibiotic known to alter the lung microbiota in several chronic pulmonary diseases, and observational studies have shown a positive effect of AZT on mortality and hospitalisation rate in IPF. However, the effect of AZT on the lung microbiota in IPF remains unknown., Methods: We sought to determine the impact of a 3-month course of AZT on the lung microbiota in IPF. We assessed sputum and oropharyngeal swab specimens from 24 adults with IPF included in a randomised controlled crossover trial of oral AZT 500 mg 3 times per week. 16S rRNA gene amplicon sequencing and quantitative PCR (qPCR) were performed to assess bacterial communities. Antibiotic resistance genes (ARGs) were assessed using real-time qPCR., Results: AZT significantly decreased community diversity with a stronger and more persistent effect in the lower airways (sputum). AZT treatment altered the temporal kinetics of the upper (oropharyngeal swab) and lower airway microbiota, increasing community similarity between the two sites for 1 month after macrolide cessation. Patients with an increase in ARG carriage had lower bacterial density and enrichment of the genus Streptococcus . In contrast, patients with more stable ARG carriage had higher bacterial density and enrichment in Prevotella ., Conclusions: AZT caused sustained changes in the diversity and composition of the upper and lower airway microbiota in IPF, with effects on the temporal and spatial dynamics between the two sites., Competing Interests: Conflict of interest: C.F. Clarenbach reports consulting fees from GSK, Novartis, Vifo, Boehringer, AstraZeneca, Sanofi and Daiichi Sankyo, outside the submitted work; payment or honoraria from GSK, Novartis, Vifor, Boehringer, AstraZeneca and Sanofi, outside the submitted work; support for attending meetings and/or travel from Boehringer and AstraZeneca, outside the submitted work. S.A. Guler reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, Boehringer Ingelheim and Roche, outside the submitted work. M. Funke-Chambour reports support for the present manuscript from the Research Fund of the Swiss Lung Association, Bern; grants or contracts from Boehringer Ingelheim, Roche and CSL Behring, outside the submitted work; consulting fees from Boehringer Ingelheim and Daiichi Sankyo, outside the submitted work; payment or honoraria from MSD and Novartis, outside the submitted work. C. von Garnier reports grants or contracts from Ligue Pulmonaire Vaudoise, Fondation Juchum and Fondation Placide Nicod, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Because of their large polar surface area, carbohydrates often exhibit insufficient pharmacokinetic properties. Specifically, the carboxylic acid function of the tetrasaccharide sialyl Lewis x , a pharmacophore crucial for the formation of a salt bridge with selectins, prevents oral availability. A common approach is the transfer of carboxylic acid into ester prodrugs. Once the prodrug is either actively or passively absorbed, the active principle is released by hydrolysis. In the present study, ester prodrugs of selectin antagonists with aliphatic promoieties were synthesized and their potential for oral availability was investigated in vitro and in vivo. The addition of lipophilic ester moieties to overcome insufficient lipophilicity improved passive permeation into enterocytes, however at the same time supported efflux back to the small intestines as well as oxidation into non-hydrolysable metabolites. In summary, our examples demonstrate that different modifications of carbohydrates can result in opposing effects and have to be studied in their entirety., (© 2021 Wiley-VCH GmbH.)

Rationale: Patients with idiopathic pulmonary fibrosis (IPF) frequently suffer from chronic cough that is difficult to treat, which substantially affects their quality of life. Azithromycin has been demonstrated to relieve chronic cough in some populations; however, this has not been investigated in patients with IPF. Objectives: To determine the safety and efficacy of azithromycin for the treatment of chronic cough in patients with IPF. Methods: In a double-blind randomized controlled crossover trial, patients with IPF underwent two 12-week intervention periods (azithromycin 500 mg three times per week or placebo three times per week). The primary outcome was the change in cough-related quality of life as measured by the Leicester Cough Questionnaire (LCQ). Secondary outcomes included cough severity as measured by the Visual Analog Scale (VAS), health-related quality of life as assessed by the St. George's Respiratory Questionnaire, and objective cough frequency as measured by audiovisual readings from 24-hour respiratory polygraphy. Results: Twenty-five patients were randomized (23 men, 2 women); 20 patients completed the study. The mean (standard deviation [SD]) age was 67 (8) years, the mean (SD) forced vital capacity was 65 (16) percent predicted, and the diffusing capacity of the lung for carbon monoxide was 43 (16) percent predicted. The mean (SD) baseline LCQ scores were 11.7 (3.7) and 11.3 (3.3) for the azithromycin period and the placebo period, respectively, and the corresponding mean (SD) cough VAS scores were 5.6 (2.3) and 5.8 (2.1). There was no significant change in the LCQ score or the VAS score with azithromycin or with placebo. Similarly, there was no significant difference between the azithromycin period and the placebo period for change in polygraphy-measured cough frequency. Gastrointestinal adverse effects were more frequent with azithromycin than with placebo (diarrhea, 43% vs. 5%; P  = 0.03). Conclusions: This randomized controlled trial does not support the use of low-dose azithromycin for chronic cough in patients with IPF.Clinical trial registered with www.clinicaltrials.gov (NCT02173145).

Idiopathic pulmonary fibrosis (IPF) is a progressive terminal lung disease, and therapies aim to block fibrosis. Fibroblast proliferation is controlled by C/EBP-β, microRNA cluster 17-92 (miR17-92), and Erk1/2 mitogen-activated protein kinase. This study assessed the role of miR17-92 in IPF-fibroblast proliferation and its modification by treprostinil. Fibroblasts were isolated from eight IPF patients, five interstitial lung fibrosis patients, and seven control lungs. Fibroblasts were stimulated with TGF-β1 over 24 h. The miR17-92 expression was analyzed by RT-qPCR, and protein expression by Western blotting. TGF-β1 upregulated C/EBP-β in all fibroblasts, which was reduced by treprostinil in control-fibroblasts, but not in IPF-fibroblasts. Compared to controls, the guide strands miR-19a-3p, miR-19b-3p, miR-20a-5p, and miR-92a-3p, as well as the passenger strands miR-17-3p, miR-18-3p, miR-19a-1-5p, and miR-92a-5p were significantly increased in IPF-fibroblasts. In controls, TGF-β1 and treprostinil significantly reduced specific miR17-92 members. IPF-fibroblast proliferation was inhibited by treprostinil through increased expression of the Erk1/2 inhibitor DUSP1. These data suggest that proliferation control via miR17-92 and C/EBP-β is disrupted in IPF-fibroblasts. Therefore, the inhibition of early stages of signaling cascades or specific mitogen receptors might be less effective. However, the increased proliferation is sensitive to Erk1/2 inhibition by treprostinil-induced DUSP1.