Gefitinib attenuates murine pulmonary fibrosis induced by bleomycin.

Abstract

BACKGROUND:

Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is an effective treatment for epithelial tumors, including non-small cell lung cancer (NSCLC), and is generally well tolerated. However, some clinical trials revealed that gefitinib exposure caused lung fibrosis, a severe adverse reaction. This study investigated the effect of gefitinib on lung fibrosis in mice.

METHODS:

We generated a mouse model of lung fibrosis induced by bleomycin to investigate the fibrotic effect of gefitinib. C57BL/6 mice were injected intratracheally with bleomycin or saline, with intragastric administration of gefitinib or saline. Lung tissues were harvested on day 14 or 21 for histology and genetic analysis.

RESULTS:

The histological results showed that bleomycin successfully induced lung fibrosis in mice, and gefitinib prevented lung fibrosis and suppressed the proliferation of S100A4-positive fibroblast cells. In addition, Western blotting analysis revealed that gefitinib decreased the expression of phosphorylated EGFR (p-EGFR). Furthermore, quantitative real-time PCR (qRT-PCR) demonstrated that gefitinib inhibited the accumulation of collagens I and III.

CONCLUSIONS:

These results reveal that gefitinib reduces pulmonary fibrosis induced by bleomycin in mice and suggest that administration of small molecule EGFR tyrosine kinase inhibitors has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that targeting tyrosine kinase receptors might be useful for the treatment of pulmonary fibrosis in humans.

• Authors: Ping Wang, Qing Tian, Zhi-xin Liang, Zhen Yang, Shu-feng Xu, Ji-ping Sun, Liang-an Chen
• Journal: Chinese medical journal (Chin Med J (Engl)) Vol. 123 Issue 16 Pg. 2259-64 (Aug 2010) ISSN: 2542-5641 [Electronic] China
• PMID: 20819676 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen Type I
• Collagen Type III
• Protein Kinase Inhibitors
• Quinazolines
• Bleomycin
• EGFR protein, mouse
• ErbB Receptors
• Gefitinib

Topics

• Animals
• Bleomycin (toxicity)
• Blotting, Western
• Collagen Type I (genetics)
• Collagen Type III (genetics)
• ErbB Receptors (metabolism)
• Gefitinib
• Male
• Mice
• Mice, Inbred C57BL
• Protein Kinase Inhibitors (therapeutic use)
• Pulmonary Fibrosis (chemically induced, drug therapy)
• Quinazolines (therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction