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

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 PGE 2 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 PGE 2 was induced in a dose-dependent fashion, but AS was significantly more potent (maximal production: CS ϭ 4,710 pg/ml and AS ϭ 7,651 pg/ml). These increases in COX-2 and PGE 2 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 PGF 2␣, 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 PGE 2 are identified as effectors in silicosis.

Metabolomics in Lung Inflammation:A High-Resolution1H NMR Study of Mice Exposedto Silica Dust

“…In these experiments, primary human lung fibroblasts were treated with silica for 24 h, and Cox-2 expression was evaluated by Western blot and immunocytochemistry. We found that crystalline silica induced Cox-2 expression in a dose-dependent manner (O'Reilly et al 2005), and the arachidonic acid metabolism pathway was altered. Since both PGs and leukotrienes are relatively small molecules, a metabolomics study would yield valuable information on this pathway, which will be a focus of our future investigations.…”

Cross-Sectional Study on Nonmalignant Respiratory Morbidity due to Exposure to Synthetic Amorphous Silica

“…[43][44][45] This study lends support to a relevant role of solubility and (non-)biopersistence in nonmalignant respiratory morbidity due to SAS, although it cannot be excluded that differences in particle size, shape, surface area, and direct or indirect cytotoxicity to target cells add to lower toxicity. 1,44,46 …”

Different course of silicosis in four brothers of one family

“…There are two distinct types of silica found in nature, crys� talline and amorphous. The differential ability of amor� phous and crystalline silica to induce fibrosis is probably related to the physical and inflammatory properties of the silicas [16]. Several possibilities exist how silica induces fibrotic changes in the lungs.…”

“…However, silica dust may evoke the production of mediators which potentially cause fibroblast proliferation and increased matrix production even in the absence of inflammatory cells. Fibrosis leads to distortion of the normal lung ar� chitecture and disruption of the normal physiological pro� cesses of the lung [16,17]. Amorphous silica is more soluble and is more easily cleared from the lungs.…”

“…Crystalline silica particles are far larger and less easily removed from the lung, the epithe� lial damage they cause is more persistent, whereas mac� rophages that ingest crystalline silica are activated and damaged. This persistent irritation could allow the estab� lishment of a profibrogenic milieu [16]. Usually, accumuUsually, accumu� lation and deposition of respirable silica mineral contain� ing particles within the lung produce a chronic lung dis� ease characterized by granulomatous and fibrotic lesions [18].…”