PURPOSE: To evaluate how a novel treatment for idiopathic pulmonary fibrosis (IPF) changes the cytokine profile in the bronchoalveolar lavage (BAL) fluid of IPF patients after 28 weeks of treatment with inhaled interferon-gamma (IFN-γ).
METHODS: 10 patients with a diagnosis of IPF made within one year of enrollment were treated with 100 mcg of interferon-gamma via the I-Neb AAD device three times a week for 70 weeks. Patients had blood work and a bronchoscopy with BAL of the middle lobe at enrollment and then again after 28 weeks of treatment with inhaled IFN-γ. Cytokines and chemokines were measured from BAL fluid, 24-hour cell culture supernatant and plasma samples by Luminex Beadlyte ELISA assay.
RESULTS: The mean BAL fluid level of IFN-γ corrected for protein increased from a baseline value of 5.23±3.16 to 320.0±79.5 pg/mg, P=0.002 after 24 weeks of inhaled IFN-γ. Mean 24-hour cell culture supernatant levels of IFN-γ also increased from 8.25±5.40 to 36.9±11.0 pg/ml, P=0.027. Mean 24-hour cell culture supernatant levels of FGP-2, Flt-3 ligand and IL-5 were significantly decreased (12.00±1.80 to 9.60±1.66 pg/ml, p= 0.031; 5.48±1.01 to 3.61±0.83 pg/ml, p= 0.039; 0.81±0.04 to 0.74±0.03 pg/ml, p= 0.049, respectively).
CONCLUSIONS: IFN-γ can be effectively aerosolized to the lung parenchyma achieving high concentrations in BAL fluid. In IPF, targeted therapy with inhaled IFN-γ to the lung leads to a decrease in pro-inflammatory/fibrotic cytokines in the alveolar space.
CLINICAL IMPLICATIONS: The pathogenesis of IPF is poorly understood. By studying the effect of inhaled IFN- γ on the alveolar milieu, important pathways in fibrosis may be elucidated. In murine models of pulmonary fibrosis, worsening fibrotic disease is associated with a shift in cytokine balance to a TH2 CD4+ T cell response. Inhaled IFN-γ may attenuate the fibrotic response in IPF by promoting a TH1 cytokine profile and has promise as a therapeutic agent to treat IPF.
DISCLOSURE: Gerald Smaldone: Grant monies (from industry related sources): Investigator written protocol, Philips/Respironics, Consultant fee, speaker bureau, advisory committee, etc.: Philips/Respironics
Rany Condos: Grant monies (from industry related sources): Investigator written protocol, Philips/Respironics
The following authors have nothing to disclose: Stephanie Lau, Keith Diaz
The only FDA approved indications for subcutaneous IFN-g are osteopetrosis and chronic granulomatous disease. Based on our experience with inhaled IFN-g in the treatment of tuberculosis, we are using inhaled IFN-g in the targeted treatment of IPF.