Published ahead of print on June 1, 2006, doi:10.1164/rccm.200509-1534OC Am. J. Respir. Crit. Care Med., Volume 174, Number 5, September 2006, 550-556 A more recent version of this article appeared on September 1, 2006
Submitted on September 30, 2005 Gefitinib Prevents Bleomycin-induced Lung Fibrosis in MiceYoshiki Ishii1*,1 Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan * To whom correspondence should be addressed. E-mail: ishiiysk{at}dokkyomed.ac.jp.
Rationale: Transforming growth factor- Key words: epidermal growth factor, EGF receptor tyrosine kinase inhihitor, molecular targeted drug, interstitial lung disease, fibroblasts
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and epidermal growth factor, the ligands for epidermal growth factor 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-TKI may have a protective effect on lung fibrosis induced by bleomycin. Since these molecular targeted drugs may have differing effects depending on species and individuals, a cautious interpretation is warranted.
