New anti-fibrotic mechanisms of n-acetyl-seryl-aspartyl-lysyl-proline in silicon dioxide-induced silicosis

Life Sci. 2010 Aug 14;87(7-8):232-9. doi: 10.1016/j.lfs.2010.06.016. Epub 2010 Jul 16.


Aims: We previously reported that tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibited pulmonary inflammation and fibrosis in SiO(2)-induced silicosis. This study aimed to explore the precise mechanism involved.

Main methods: Rats were divided into 3 groups: 1) sham (saline), 2) silicosis+vehicle, and 3) silicosis+Ac-SDKP [800 microg/(kgd)]. SiO(2) particles or saline were administered by tracheal instillation and Ac-SDKP or vehicle (saline) via a mini-osmotic pump planted into the abdominal cavity 48 h before instillation. Animals were observed for 4 weeks. Silicotic nodule fraction (SNF) and macrophage infiltration (ED-1 positive cells) were measured by hematoxylin and eosin (H.E.) and immunohistochemical staining respectively. Collagen I and III, transforming growth factor-beta1 (TGF-beta1) proteins and monocyte chemotactic protein-1 (MCP-1) mRNA were detected by Western Blot (WB) and real-time RT-PCR respectively. In vitro, pulmonary fibroblasts were stimulated by TGF-beta1 (5 microg/ml) with or without Ac-SDKP. Phosphorylated c-Jun N-terminal Kinase (p-JNK) was detected by WB and p-JNK nuclear translocation by confocal analysis.

Key findings: SiO(2) significantly increased the SNF, collagen I and III proteins, TGF-beta1, MCP-1 mRNA and macrophage infiltration. All these pathological changes were inhibited by Ac-SDKP. TGF-beta1 resulted in fibroblast proliferation, increased expression of collagen I and III proteins, p-JNK and its subsequent nuclear translocation. Addition of Ac-SDKP markedly suppressed these changes.

Significance: These data indicate that the anti-fibrotic effect of Ac-SDKP in silicosis is mediated by inhibiting chronic inflammation, TGF-beta1 production, and TGF-beta1-induced pulmonary fibroblast proliferation and collagen synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Migration Inhibition
  • Cell Proliferation / drug effects
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Collagen / immunology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / immunology
  • Fibrosis
  • Gene Expression Regulation / drug effects
  • JNK Mitogen-Activated Protein Kinases / immunology
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Male
  • Oligopeptides / therapeutic use*
  • Protein Transport
  • Rats
  • Rats, Wistar
  • Silicon Dioxide
  • Silicosis / drug therapy*
  • Silicosis / immunology
  • Silicosis / pathology*
  • Transforming Growth Factor beta1 / immunology


  • Chemokine CCL2
  • Oligopeptides
  • Transforming Growth Factor beta1
  • Silicon Dioxide
  • Collagen
  • JNK Mitogen-Activated Protein Kinases
  • goralatide