Gefitinib prevents bleomycin-induced lung fibrosis in mice
Y Ishii, S Fujimoto, T Fukuda - … journal of respiratory and critical care …, 2006 - atsjournals.org
Y Ishii, S Fujimoto, T Fukuda
American journal of respiratory and critical care medicine, 2006•atsjournals.orgRationale: Transforming growth factor-α 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 …
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 …
Rationale: Transforming growth factor-α 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.
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