Anti-fibrotic role of inhaled interferon-γ in idiopathic pulmonary fibrosis

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.