RT Journal Article
SR Electronic
T1 Neutrophil elastase inhibitor sivelestat ameliorates gefitinib-naphthalene-induced acute pneumonitis in mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 108464
DO 10.1101/108464
A1 Hironori Mikumo
A1 Toyoshi Yanagihara
A1 Naoki Hamada
A1 Eiji Harada
A1 Saiko Ogata-Suetsugu
A1 Chika Ikeda-Harada
A1 Masako Arimura-Omori
A1 Kunihiro Suziki
A1 Tetsuya Yokoyama
A1 Yoichi Nakanishi
YR 2017
UL http://biorxiv.org/content/early/2017/02/14/108464.abstract
AB Background and objective Gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is an effective therapeutic agent for non-small cell lung cancer with EGFR mutations. It 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 neutrophils played important roles in the development of the disease. This study aimed to investigate the effects of the neutrophil elastase inhibitor sivelestat on gefitinib-induced pneumonitis in mice.Methods C57BL/6J mice received naphthalene (200 mg/kg) intraperitoneally on day 0. Gefitinib (250 or 300 mg/kg) was orally administered to mice from day −1 until day 13. Sivelestat (150 mg/kg) was administered intraperitoneally from day 1 until day 13. Bronchoalveolar lavage fluid (BALF) and lung tissues were sampled on day 14.Results Sivelestat treatment significantly reduced the protein level, neutrophil count, neutrophil elastase activity in BALF, and severity of histopathologic findings on day 14 for mice administered with 250 mg/kg of gefitinib. Moreover, sivelestat treatment significantly improved the survival of mice administered with 300 mg/kg of gefitinib. Conclusions: These results indicate that sivelestat is a promising therapeutic agent for severe acute pneumonitis caused by gefitinib.Summary statement Neutrophil elastase inhibitor sivelestat is a promising therapeutic agent for severe acute pneumonitis caused by gefitinib.