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Systemic inhibition of NF-κB activation protects from silicosis

di Giuseppe, M and Gambelli, F and Hoyle, GW and Lungarella, G and Studer, SM and Richards, T and Yousem, S and McCurry, K and Dauber, J and Kaminski, N and Leikauf, G and Ortiz, LA (2009) Systemic inhibition of NF-κB activation protects from silicosis. PLoS ONE, 4 (5).

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Abstract

Background: Silicosis 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/Findings: In 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. Conclusions: Although 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. © 2009 Di Giuseppe et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
di Giuseppe, M
Gambelli, F
Hoyle, GW
Lungarella, G
Studer, SM
Richards, T
Yousem, Syousem@pitt.eduYOUSEM
McCurry, K
Dauber, J
Kaminski, N
Leikauf, Ggleikauf@pitt.eduGLEIKAUF
Ortiz, LAlao1@pitt.eduLAO1
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorBarnes, Peter J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 25 May 2009
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 4
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0005689
Schools and Programs: Graduate School of Public Health > Occupational Medicine
Refereed: Yes
PubMed Central ID: PMC2682759
PubMed ID: 19479048
Date Deposited: 25 Jul 2012 14:20
Last Modified: 04 Feb 2019 15:58
URI: http://d-scholarship.pitt.edu/id/eprint/13143

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