Background The sinonasal microbiome is believed to play an important role in the pathophysiology of refractory chronic rhinosinusitis CRS We evaluated changes in the microbiome following a-month course of low-dose azithromycin Assessing microbiome alterations following such a treatment may help identify underlying mechanisms of this drug Methods A total of adults with refractory CRS were enrolled in a double-blind randomized placebo-controlled trial Patients were randomized to mg of azithromycin or placebo times weekly for months During this time daily budesonide saline irrigations were continued Sinonasal swabs were collected by endoscopically-assisted method prior to treatment initiation and at the end of it and sent for S ribosomal RNA gene sequencing Highresolution ANCHOR pipeline was used to infer and annotate putative species The patient groups were compared using DESeq differential abundance analysis Results From initiation to the end of azithromycin treatment patients showed a significant difference in beta diversity analysis p = along with a significant decrease in different operational taxonomic units OTUs of Staphylococcus aureus false discovery rate FDR < obtained from the differential abundance analysis This was not observed in placebo-treated patients By the end of treatments azithromycin-treated patients had a significant decrease in different OTUs of S aureus FDR < when compared to placebo Conclusion A-month course of mg of azithromycin times weekly in patients with refractory CRS significantly decreases S aureus abundance in the sinonasal microbiome Considering the pathogenic role of S aureus in the refractory CRS population azithromycin may constitute an additional therapeutic option to help control this disease
Background IL-21 is secreted by activated T cells and modulates immune cell functions with both proinflammatory and anti-inflammatory effects. IL-21 receptor (IL-21R), homologous to IL-2Rβ and IL-4Rα, associates with the gamma common chain upon ligand binding. It was recently described that IL-21R is overexpressed in the inflamed synovial membrane and on leucocytes of rheumatoid arthritis patients. Objective Previously we have shown that blockade of the IL-21 pathway with soluble IL-21R-Fc resulted in a reduction of clinical signs of arthritis in rodent models. To understand potential mechanisms of IL-21 regulation in arthritis, we analyzed serum immunoglobulin levels, and cytokine expression in the paws, serum, and collagen-restimulated splenocytes, in response to IL-21 pathway blockade. Methods Arthritis was induced in DBA/1 male mice with bovine type II collagen. Animals were treated with either soluble mIL-21R-Fc, which neutralizes murine IL-21 bioactivity, with TNFRII-Fc or with control IgG. Spleens from each group of treated mice were cultured in vitro with collagen and assayed for cytokine secretion. Cytokines and anticollagen-specific IgG levels were also measured in the serum by ELISA. Cytokine mRNA levels in the paws were evaluated by quantitative PCR analysis. Results Treatment of mice with IL-21R-Fc or TNFRII-Fc reduced clinical and histological signs of collagen-induced arthritis. IL-6 mRNA in paws and serum IL-6 levels were decreased after IL-21R-Fc treatment. IFNγ mRNA was increased in paws of IL-21R-Fctreated mice. Collagen-specific spleen cell responses from IL-21R-Fc-treated mice exhibited increased IFNγ and IL-2, and reduced IL-6 and IL-17 levels. Serum levels of total IgG 1 were also reduced in response to IL-21R-Fc treatment. Conclusion These data demonstrate a role for IL-21 in the modulation of collagen-specific T-cell responses and the pathology of arthritis, supporting a rationale for blockade of the IL-21 pathway in rheumatoid arthritis. P2 Combined anti-inflammatory tritherapy using a novel small interfering RNA lipoplex successfully prevents and cures mice of arthritis
ObjectivePrevious in vitro transcriptomic profiling suggests azithromycin exerts its effects in patients with chronic rhinosinusitis (CRS) via modulation of type 1 inflammation and restoration of epithelial barrier function. We wished to verify these postulated effects using in vitro models of epithelial repair and in vivo transcriptional profiling.Study DesignFunctional effects of azithromycin in CRS were verified using in vitro models of wounding. The mechanism of the effect of azithromycin was assessed in vivo using transcriptomic profiling.SettingAcademic medical center.MethodsEffects of azithromycin on the speed of epithelial repair were verified in a wounding model using primary nasal epithelial cells (pNEC) from CRS patients. Nasal brushings collected pre‐and posttreatment during a placebo‐controlled trial of azithromycin for CRS patients unresponsive to surgery underwent transcriptomic profiling to identify implicated pathways.ResultsAdministration of azithromycin improved the wound healing rates in CRS pNECs and prevented the negative effect of Staphylococcus aureus on epithelial repair. In vivo, response to azithromycin was associated with downregulation in pathways of type 1 inflammation, and upregulation of pathways implicated in the restoration of the cell cycle.ConclusionRestoration of healthy epithelial function may represent a major mode of action of azithromycin in CRS. In vitro models show enhanced epithelial repair, while in vivo transcriptomics shows downregulation of pathways type 1 inflammation accompanied by upregulation of DNA repair and cell‐cycle pathways. The maximal effect in patients with high levels of type 1‐enhanced inflammation suggests that azithromycin may represent a novel therapeutic option for surgery‐unresponsive CRS patients.
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