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Title: Crystalline and amorphous silica differentially regulate the cyclooxygenase-prostaglandin pathway in pulmonary fibroblasts: implications for pulmonary fibrosis.

Authors: O'Reilly, Katherine M A; Phipps, Richard P; Thatcher, Thomas H; Graf, Beth A; Van Kirk, John; Sime, Patricia J

Published In Am J Physiol Lung Cell Mol Physiol, (2005 Jun)

Abstract: Inhalation of crystalline (CS) and amorphous silica (AS) results in human pulmonary inflammation. However, silicosis develops only following CS exposure, and the pathogenic mechanisms are poorly understood. This report describes the differential abilities of CS and AS to directly upregulate the early inflammatory mediator COX-2, the recently identified prostaglandin E (PGE) synthase and the downstream mediator PGE2 in primary human lung fibroblasts. Increased cyclooxygenase (COX)-2 gene transcription and protein production were demonstrated by ribonuclease protection assay, Western blot analysis, and immunocytochemistry. In each case the ability of AS to induce COX-2 exceeded that of CS. Similarly, downstream of COX-2, production of the antifibrotic prostaglandin PGE2 was induced in a dose-dependent fashion, but AS was significantly more potent (maximal production: CS = 4,710 pg/ml and AS = 7,651 pg/ml). These increases in COX-2 and PGE2 were preceded by induction of the PGE2 synthase protein, demonstrating the potential role of this novel molecule in silica-mediated inflammation. There was specificity of induction of prostaglandins, as PGF2alpha, but not PGD2, was induced. Using specific COX-2 inhibitors, we showed increased PG production to be dependent on the COX-2 enzyme. Furthermore, stimulation of fibroblasts was particle specific, as silica but not carbon black resulted in fibroblast activation. These results demonstrate that silica can directly stimulate human lung fibroblasts to produce key inflammatory enzymes and prostaglandins. Moreover, they suggest a mechanism to explain the differing fibrogenic potential of CS and AS. The molecules COX-2, PGE synthase, and PGE2 are identified as effectors in silicosis.

PubMed ID: 15665045 Exiting the NIEHS site

MeSH Terms: Administration, Inhalation; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprost/metabolism; Dinoprostone/metabolism*; Fibroblasts/drug effects; Fibroblasts/metabolism; Gene Expression Regulation, Enzymologic*; Humans; Intramolecular Oxidoreductases/genetics; Intramolecular Oxidoreductases/metabolism; Lung/drug effects*; Lung/metabolism; Membrane Proteins; Prostaglandin D2/metabolism; Prostaglandin-E Synthases; Prostaglandin-Endoperoxide Synthases/genetics; Prostaglandin-Endoperoxide Synthases/metabolism*; Pulmonary Fibrosis/chemically induced; Pulmonary Fibrosis/metabolism; Signal Transduction*; Silicon Dioxide/toxicity*

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