title: Silica and its antagonistic effects on transforming growth factor-beta in lung fibroblast extracellular matrix production.
abstract: BACKGROUND
  Silicosis, a pneumoconiosis marked by interstitial pulmonary fibrosis, is caused by inhalation of free crystalline silica particles. When silica particles are injected into the lower lung, they are translocated across the epithelium into the interstitial space, where macrophage-derived growth factors affect lung fibroblast proliferation and collagen deposition. We hypothesized that silica may act directly on pulmonary fibroblasts modifying extracellular matrix (ECM) synthesis and that the effects of silica may be mediated by transforming growth factor-beta (TGFbeta) overproduction.
  
  
  METHODS
  To test this hypothesis, we studied a human lung fibroblast cell line (WI-1003) exposed to silica in vitro. We investigated cell morphology by electron microscopic procedure, cell growth, collagen production, and glycosaminoglycans (GAG) composition by radiolabeled precursors. Cytokine and growth factor synthesis were evaluated by specific enzyme-linked immunoadsorbent assay kits and Northern blotting analysis.
  
  
  RESULTS
  Pulmonary fibroblasts internalized silica particles without detectable cell damage. Silica directly stimulated collagen synthesis and decreased the amount of 3H-glucosamine-labeled GAG. Silica-treated fibroblasts secreted less TGFbeta than untreated controls, antagonized the stimulatory effect of TGFbeta on ECM synthesis, and reversed TGFbeta-induced inhibition of cell proliferation. Northern blotting analysis showed increased interleukin-1alpha (IL-1alpha) mRNA after silica treatment. IL-1alpha had no influence on collagen synthesis but increased the number of WI-1003 fibroblasts.
  
  
  CONCLUSIONS
  These results support our hypothesis that lung fibroblasts are direct silica targets. However, contradicting our hypothesis, silica antagonized TGFbeta activities through a TGFbeta downregulation and an IL-1alpha upregulation. The complex pattern of TGFbeta and IL-1alpha regulation in pulmonary fibroblasts is imbalanced by silica exposure and might play a key role in silica-mediated pulmonary fibrosis.
authors: Histology Section, Faculty of Medicine, University of Perugia, Italy.
authors: T
authors: T
authors: Baroni
authors: M
authors: M
authors: Bodo
authors: A
authors: A
authors: D'Alessandro
authors: C
authors: C
authors: Conte
authors: M
authors: M
authors: Calvitti
authors: G
authors: G
authors: Muzi
authors: A
authors: A
authors: Lumare
authors: S
authors: S
authors: Bellocchio
authors: G
authors: G
authors: Abbritti
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D012822:Silicon Dioxide / Q000633:toxicity*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D006025:Glycosaminoglycans; D007375:Interleukin-1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D012822:Silicon Dioxide; D003094:Collagen