HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 288/6/L1010    most recent 00024.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by O'Reilly, K. M. A. Articles by Sime, P. J. Search for Related Content PubMed PubMed Citation Articles by O'Reilly, K. M. A. Articles by Sime, P. J.

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

Departments of ¹Medicine and ²Environmental Medicine, ³Lung Biology and Disease Program, and ⁴the Cancer Center, University of Rochester School of Medicine, Rochester, New York

Submitted 28 January 2004 ; accepted in final form 14 January 2005

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 PGF₂, 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.

silicosis; prostaglandin E₂; prostaglandin E synthase; inflammation