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Systemic inhibition of NF-kappaB activation protects from silicosis.

Di Giuseppe M, Gambelli F, Hoyle GW, Lungarella G, Studer SM, Richards T, Yousem S, McCurry K, Dauber J, Kaminski N, Leikauf G, Ortiz LA - PLoS ONE (2009)

Bottom Line: 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 TNFalpha expressing macrophage and NF-kappaB activation in epithelial cells.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-kappaB activation with a pharmacologic inhibitor (BAY 11-7085) of IkappaB alpha phosphorylation decreased silica-induced inflammation and collagen deposition.In contrast, transgenic mice expressing a dominant negative IkappaB alpha mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica.

View Article: PubMed Central - PubMed

Affiliation: Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

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 (TNFalpha) plays a central role in the pathogenesis of silicosis. TNFalpha signaling is mediated by the transcription factor, Nuclear Factor (NF)-kappaB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-kappaB 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 TNFalpha expressing macrophage and NF-kappaB 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-kappaB activation with a pharmacologic inhibitor (BAY 11-7085) of IkappaB alpha phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IkappaB alpha 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-kappaB protects from silica-induced lung injury, epithelial cell specific NF-kappaB inhibition appears to aggravate the outcome of experimental silicosis.

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TNFα expression in silicotic lung is predominantly identified in macrophages.Panel A show low photomicrograph (×200) of lung tissue isolated from a silica exposed subject at the time of lung transplantation. Lung parenchyma is replaced by silicotic nodule characterized by a dense palisade of fibroblast surrounding a central fibrinous core that is devoided of cells and abuts the distal airway. Alveolar macrophages accumulate in relatively normal alveolar areas adjacent to the silicotic nodule (circle). Panel B show high (×400) magnification of the area identified in panel A, illustrating immunochemistry signal with anti-TNFα antibody that is confined to cells with macrophage morphology.
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pone-0005689-g002: TNFα expression in silicotic lung is predominantly identified in macrophages.Panel A show low photomicrograph (×200) of lung tissue isolated from a silica exposed subject at the time of lung transplantation. Lung parenchyma is replaced by silicotic nodule characterized by a dense palisade of fibroblast surrounding a central fibrinous core that is devoided of cells and abuts the distal airway. Alveolar macrophages accumulate in relatively normal alveolar areas adjacent to the silicotic nodule (circle). Panel B show high (×400) magnification of the area identified in panel A, illustrating immunochemistry signal with anti-TNFα antibody that is confined to cells with macrophage morphology.

Mentions: TNFα expression and NF-κB activation was determined by performing immune staining in paraffin embedded sections of lung tissues isolated from the lungs of subjects afflicted with silicosis at the time of lung transplantation. In all 11 silicosis patients, large areas of the lung parenchyma were replaced by coalescence of silicotic nodules (Figure 2A). These nodules contain fibrinous material, had few cells, and did not demonstrate TNFα immunostaining (Figure 2A). In contrast, TNFα immunostaining was evident in preserved regions of the lung parenchyma adjacent to the silicotic nodules, which was confined to primarily to macrophages (Figure 2B), and was particularly strong in macrophages that exhibit excessive silica particles in phagosomes (Figure S1). Immunostaining for NF-κB activation was predominantly detected in the nuclei of epithelial cells adjacent to TNFα immunostaining macrophages (Figure S2).


Systemic inhibition of NF-kappaB activation protects from silicosis.

Di Giuseppe M, Gambelli F, Hoyle GW, Lungarella G, Studer SM, Richards T, Yousem S, McCurry K, Dauber J, Kaminski N, Leikauf G, Ortiz LA - PLoS ONE (2009)

TNFα expression in silicotic lung is predominantly identified in macrophages.Panel A show low photomicrograph (×200) of lung tissue isolated from a silica exposed subject at the time of lung transplantation. Lung parenchyma is replaced by silicotic nodule characterized by a dense palisade of fibroblast surrounding a central fibrinous core that is devoided of cells and abuts the distal airway. Alveolar macrophages accumulate in relatively normal alveolar areas adjacent to the silicotic nodule (circle). Panel B show high (×400) magnification of the area identified in panel A, illustrating immunochemistry signal with anti-TNFα antibody that is confined to cells with macrophage morphology.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682759&req=5

pone-0005689-g002: TNFα expression in silicotic lung is predominantly identified in macrophages.Panel A show low photomicrograph (×200) of lung tissue isolated from a silica exposed subject at the time of lung transplantation. Lung parenchyma is replaced by silicotic nodule characterized by a dense palisade of fibroblast surrounding a central fibrinous core that is devoided of cells and abuts the distal airway. Alveolar macrophages accumulate in relatively normal alveolar areas adjacent to the silicotic nodule (circle). Panel B show high (×400) magnification of the area identified in panel A, illustrating immunochemistry signal with anti-TNFα antibody that is confined to cells with macrophage morphology.
Mentions: TNFα expression and NF-κB activation was determined by performing immune staining in paraffin embedded sections of lung tissues isolated from the lungs of subjects afflicted with silicosis at the time of lung transplantation. In all 11 silicosis patients, large areas of the lung parenchyma were replaced by coalescence of silicotic nodules (Figure 2A). These nodules contain fibrinous material, had few cells, and did not demonstrate TNFα immunostaining (Figure 2A). In contrast, TNFα immunostaining was evident in preserved regions of the lung parenchyma adjacent to the silicotic nodules, which was confined to primarily to macrophages (Figure 2B), and was particularly strong in macrophages that exhibit excessive silica particles in phagosomes (Figure S1). Immunostaining for NF-κB activation was predominantly detected in the nuclei of epithelial cells adjacent to TNFα immunostaining macrophages (Figure S2).

Bottom Line: 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 TNFalpha expressing macrophage and NF-kappaB activation in epithelial cells.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-kappaB activation with a pharmacologic inhibitor (BAY 11-7085) of IkappaB alpha phosphorylation decreased silica-induced inflammation and collagen deposition.In contrast, transgenic mice expressing a dominant negative IkappaB alpha mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica.

View Article: PubMed Central - PubMed

Affiliation: Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

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 (TNFalpha) plays a central role in the pathogenesis of silicosis. TNFalpha signaling is mediated by the transcription factor, Nuclear Factor (NF)-kappaB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-kappaB 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 TNFalpha expressing macrophage and NF-kappaB 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-kappaB activation with a pharmacologic inhibitor (BAY 11-7085) of IkappaB alpha phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IkappaB alpha 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-kappaB protects from silica-induced lung injury, epithelial cell specific NF-kappaB inhibition appears to aggravate the outcome of experimental silicosis.

Show MeSH
Related in: MedlinePlus