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Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9035-40. doi: 10.1073/pnas.0803933105. Epub 2008 Jun 24.

The Nalp3 inflammasome is essential for the development of silicosis.

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1
Division of Allergy and Immunology, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.

Abstract

Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1beta and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.

PMID:
18577586
PMCID:
PMC2449360
DOI:
10.1073/pnas.0803933105
[Indexed for MEDLINE]
Free PMC Article

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