Neutrophil elastase inhibitor sivelestat ameliorates gefitinib, naphthalene-induced acute pneumonitis in mice

Abstract

Neutrophil elastase inhibitor sivelestat ameliorates gefitinib, naphthalene-induced acute pneumonitis in mice. I ntroduction: Gefitinib, one of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI), is an effective therapeutic agent for non-small cell lung cancer with EGFR mutations. It is well known that gefitinib can cause severe acute pneumonitis in some patients. We previously demonstrated that mice with naphthalene-induced airway epithelial injury developed severe gefitinib-induced pneumonitis and that neutrophil plays important roles in the development of the disease. (Harada C et al . Am J Respir Crit Care Med . 2011). Aims and objectives: The aim of this study is to investigate the effects of neutrophil elastase inhibitor sivelestat (ONO-5046) on gefitinib-induced pneumonitis in mice. Methods: C57BL/6J mice received naphthalene (200 mg/kg) intraperitonially on day 0. Gefitinib (250 or 300 mg/kg) was orally given to mice from day 1 until 13. Sivelestat (150 mg/kg) was given intraperitoneally from day 1 until 13. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained on day14. Results: Sivelestat treatment significantly reduced the protein level , neutrophil count , inflammatory cytokine, and neutrophil elastase in BALF, and severity of histopathologic findings on day 14 of mice given 250 mg/kg of gefitinib. Moreover, sivelestat treatment significantly improved survival of mice given 300 mg/kg of gefitinib. Conclusions: The present results indicate that sivelestat may be one of the promising therapeutic agents for severe acute pneumonitis caused by gefitinib.