Interferon-γ and Idiopathic Pulmonary Fibrosis: Why Pulmonary Targeting May be an Answer
Smaldone GC, Condos R.
Respiratory Drug Delivery 2012. Volume 1, 2012: 39-50.
Tuberculosis, chronic obstructive lung disease (COPD) and idiopathic pulmonary fibrosis (IPF) are different diseases but manifest as progressive scarring of lung parenchyma or airways. Proposed mechanistic pathways of pathophysiology involve pro-fibrotic cytokines unresponsive to usual anti-inflammatory agents (e.g., steroids). Interferon-γ is a cytokine that can stimulate macrophage function and inhibit fibrotic pathways and therefore has been tried as therapy in tuberculosis and IPF. Unfortunately, for IPF, in several major clinical trials, parenteral interferon-γ failed to stem disease progression. Dosing in systemic therapy is limited by side effects. In recent studies, our group has approached this problem using inhaled interferon-γ targeted directly to the lung. In a controlled clinical trial, inhaled interferon-γ aerosol (aINF-γ) was effective in tuberculosis while parenteral interferon-γ was not, indicating that macrophages can be effectively immune- stimulated by aerosol therapy. We are taking a similar approach in IPF. In our first trial, we evaluated safety and delivery of aIFN-γ (100μg 3 times/wk; M,W,F) in 10 IPF patients. In an attempt to facilitate parenchymal deposition, we used the I-neb (Philips Respironics, Parsippany, NJ). In vivo deposition was measured via gamma camera. Pulmonary function tests (PFTs) were measured at baseline, and every 12 14 weeks for 80 weeks. Bronchoalveolar lavage (BAL) of the middle lobe was performed at baseline and 28 weeks. BAL and plasma samples were analyzed for chemokines and cytokines, including INF-γ. Patients tolerated 80 weeks of aIFN-γ well, with no systemic side effects. BAL IFN-γ increased 60-fold and profibrotic cytokines (FGP-2, Flt-3 ligand, IL-5) were significantly decreased; IFN-γ plasma levels were unchanged. PFTs showed minimal change in FVC. Post-hoc analysis indicated that the slope of decline in TLC and DLCO reversed after beginning therapy. Inhaled IFN-γ is safe in IPF and can be effectively delivered to lung parenchyma. The pre-therapy decline in PFTs appeared to reverse following treatment. We speculate that the same fibrotic pathways active in lung parenchyma may be at fault in the airways of COPD. These concepts suggest that clinical trials of inhaled interferon-γ are warranted.
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