Gefitinib prevents bleomycin-induced lung fibrosis in mice
Yoshiki Ishii1, Sakae Fujimoto, Takeshi Fukuda
1Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, 800 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. ishiiysk@dokkyomed.ac.jp
Rationale:
Transforming growth factor-alpha and epidermal growth factor (EGF), the ligands for EGF receptor (EGFR), stimulate fibroblast proliferation and play an important role in the pathogenesis of pulmonary fibrosis. Therefore, inhibition of the EGFR signal by an EGFR tyrosine kinase inhibitor (EGFR-TKI) may prevent pulmonary fibrosis. However, there is a possibility that blocking the EGFR signal may inhibit epithelial cell repair, thereby exaggerating lung fibrosis.
Objective:
To investigate the effect of EGFR-TK inhibition on lung fibrosis.
Methods:
We looked at the effects of the EGFR-TKIs gefitinib (20, 90, 200 mg/kg) and AG1478 (12 mg/kg) on a bleomycin-induced lung fibrosis model in mice.
Measurements And Main Results:
Gefitinib prevented lung fibrosis at all three doses. Furthermore, in those mice that did not receive bleomycin treatment, gefitinib at 200 mg/kg did not induce lung fibrosis. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited by gefitinib. AG1478 also attenuated the lung fibrosis. In vitro studies further demonstrated that the addition of gefitinib or AG1478 suppressed the EGFR ligand-induced proliferation of lung fibroblasts.
Conclusions:
These findings suggest that, in the preclinical setting, EGFR-TKIs may have a protective effect on lung fibrosis induced by bleomycin. Because these molecular targeted drugs may have differing effects depending on species and individuals, a cautious interpretation is warranted.
Insights
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib show protective effects against bleomycin-induced lung fibrosis in mice. These findings suggest EGFR-TKIs may prevent pulmonary fibrosis, but cautious interpretation is needed.
Area of Science:
- Pulmonary Medicine
- Fibrosis Research
- Molecular Biology
Background:
- Transforming growth factor-alpha and epidermal growth factor (EGF) stimulate fibroblast proliferation, contributing to pulmonary fibrosis.
- Inhibiting the epidermal growth factor receptor (EGFR) signal via EGFR tyrosine kinase inhibitors (EGFR-TKIs) may prevent pulmonary fibrosis.
- However, EGFR signal blockade could impair epithelial cell repair, potentially worsening lung fibrosis.
Purpose of the Study:
- To investigate the therapeutic potential of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in mitigating lung fibrosis.
- To evaluate the effects of specific EGFR-TKIs, gefitinib and AG1478, on a mouse model of bleomycin-induced pulmonary fibrosis.
Main Methods:
- Utilized a bleomycin-induced lung fibrosis model in mice.
- Administered EGFR-TKIs gefitinib (20, 90, 200 mg/kg) and AG1478 (12 mg/kg).
- Conducted immunohistochemistry and in vitro studies to assess EGFR phosphorylation and fibroblast proliferation.
Main Results:
- Gefitinib demonstrated a dose-dependent protective effect against bleomycin-induced lung fibrosis.
- Gefitinib did not induce fibrosis in mice without bleomycin treatment.
- Both gefitinib and AG1478 inhibited EGFR phosphorylation in lung mesenchymal cells and suppressed EGFR ligand-induced fibroblast proliferation in vitro.
Conclusions:
- EGFR-TKIs exhibit a potential protective effect against bleomycin-induced lung fibrosis in preclinical models.
- Findings suggest EGFR-TKIs could be a therapeutic strategy for pulmonary fibrosis.
- A cautious interpretation is advised due to potential species- and individual-specific variations in drug response.
