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Therapies targeting inflammation reveal inconsistent results in idiopathic pulmonary fibrosis (IPF). Aerosolised interferon (IFN)-γ has been proposed as a novel therapy. Changes in the host airway microbiome are associated with the inflammatory milieu and may be associated with disease progression. Here, we evaluate whether treatment with aerosolised IFN-γ in IPF impacts either the lower airway microbiome or the host immune phenotype. Patients with IPF who enrolled in an aerosolised IFN-γ trial underwent bronchoscopy at baseline and after 6 months. 16S rRNA sequencing of bronchoalveolar lavage fluid (BALF) was used to evaluate the lung microbiome. Biomarkers were measured by Luminex assay in plasma, BALF and BAL cell supernatant. The compPLS framework was used to evaluate associations between taxa and biomarkers. IFN-γ treatment did not change α or β diversity of the lung microbiome and few taxonomic changes occurred. While none of the biomarkers changed in plasma, there was an increase in IFN-γ and a decrease in Fit-3 ligand, IFN-α2 and interleukin-5 in BAL cell supernatant, and a decrease in tumour necrosis factor-β in BALF. Multiple correlations between microbial taxa common to the oral mucosa and host inflammatory biomarkers were found. These data suggest that the lung microbiome is independently associated with the host immune tone and may have a potential mechanistic role in IPF., Lower airway microbiome and immunological tone are associated in IPF, an effect independent of IFN-γ treatment http://ow.ly/cTDo30bsJiN

Background: Previous trials of systemic interferon-γ (IFN- γ) treatment in patients with idiopathic pulmonary fibrosis (IPF) were discouraging. Recently, we demonstrated that inhaled IFN-γ is safe with no systemic side effects in IPF patients. Inhaled IFN-γ was associated with significant improvement in DLCO. Objective: To study the mechanism of local anti-fibrotic effects of inhaled IFN-γ by examining bronchoalveolar lavage fluid (BALF) for gene and protein expression before and after inhaled IFN-γ treatment. Methods: Ten patients with IPF received inhaled IFN-γ three times a week for 80 weeks. BAL was performed before and during therapy. Gene expression was measured on RNA samples from BALF cellular component using DNA microaray study utilizing Affymetrix human U133Av2 chips. Protein expression was also studied in BALF using zymography, western blot and Luminex assay. BALF soluble collagen content was measured using Sircol collagen assay. Results: Microarray gene expression demonstrated that IFN-γ treatment down regulated multiple signal pathways involved in T cell and B cell immunity, actin cytoskeleton, VEGF signaling pathway, apoptosis, PI3 signaling and chemokine C-X-C motif ligands. BALF zymography and western blot study showed that IFN-γ inhibited MMP-9, TIMP-1 and Osteopontin. IFN-γ treatment resulted in a marked decrease in BALF collagen content. Conclusion: Inhaled INF-γ has potent anti-fibrotic effects via multiple signaling pathways, immune modulatory effects and MMP inhibition. Inhaled IFN- γ has potential as a novel therapy for IPF.