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

Mikumo, Hironori

doi:10.15017/1866270

Bibliographic Information

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

Other Title

好中球エラスターゼ阻害薬であるシベレスタットはゲフィチニブ、ナフタレンが引き起こすマウスの急性肺障害を軽減する

Author: Mikumo, Hironori

Alias Name

三雲, 大功
ミクモ, ヒロノリ

University: Kyushu University

Types of degree: 博士（医学）

Grant ID: 17102甲第13689号

Degree year: 2017-09-25

Description

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. 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. 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. These results indicate that sivelestat is a promising therapeutic agent for severe acute pneumonitis caused by gefitinib.