title: Neutrophil elastase inhibitor sivelestat ameliorates gefitinib-naphthalene-induced acute pneumonitis in mice.
abstract: 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.
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Mikumo
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: yanagiha@kokyu.med.kyushu-u.ac.jp.
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Yanagihara
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hamada
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Harada
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Saiko
authors.initials: S
authors.lastname: Ogata-Suetsugu
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Ikeda-Harada
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Arimura-Omori
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Testuya
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakanishi
mesh_terms: D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D005260:Female; D000077156:Gefitinib; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D053208:Kaplan-Meier Estimate; D007958:Leukocyte Count; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D009281:Naphthalenes; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000517:prevention & control*; D011799:Quinazolines; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D009281:Naphthalenes; D011799:Quinazolines; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C031721:naphthalene; C069195:sivelestat; D019272:Leukocyte Elastase; D000077156:Gefitinib; D005998:Glycine
keywords: Acute pneumonitis; Gefitinib; Neutrophil elastase