Systemic Inhibition of NF-κB Activation Protects from Silicosis

Abstract

BackgroundSilicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFα) plays a central role in the pathogenesis of silicosis. TNFα signaling is mediated by the transcription factor, Nuclear Factor (NF)-κB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-κB activation represents a potential therapeutic strategy for silicosis.Methods/FindingsIn the present work we evaluated the lung transplant database (May 1986–July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFα expressing macrophage and NF-κB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16–7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8–15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22–0.9 yr) following lung transplantation (2.4 yr; CI:1.5–3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-κB activation with a pharmacologic inhibitor (BAY 11-7085) of IκBα phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IκBα mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica.ConclusionsAlthough limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-κB protects from silica-induced lung injury, epithelial cell specific NF-κB inhibition appears to aggravate the outcome of experimental silicosis.