title: Suppression of surfactant protein A by an epidermal growth factor receptor tyrosine kinase inhibitor exacerbates lung inflammation.
abstract: Interstitial lung disease (ILD) is reported as a serious adverse event in lung cancer patients treated with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). However, the mechanisms of ILD associated with gefitinib remain unknown. To address the molecular mechanisms of ILD-associated gefitinib, we determined the effect of gefitinib treatment on surfactant protein expression in vitro and in vivo. Gefitinib treatment suppressed surfactant protein (SP)-A expression in H441 human lung adenocarcinoma cells expressing SP-A, -B, -C and -D by inhibiting epidermal growth factor signal. Next, gefitinib (200 mg/kg) was given p.o. to the mice daily for 1 week. Daily administration of gefitinib gradually reduced SP-A level in the bronchoalveolar lavage fluid. When lipopolysaccharide (LPS) was instilled intratracheally to the mice pretreated with gefitinib for 1 week, lung inflammation by LPS was exacerbated and prolonged. This exacerbation of lung inflammation was rescued by intranasal administration of SP-A. These results demonstrated that pretreatment with gefitinib exacerbated LPS-induced lung inflammation by reducing SP-A expression in the lung. This study suggests that epidermal growth factor receptor tyrosine kinase inhibitor may reduce SP-A expression in the lungs of lung cancer patients and thus patients treated with epidermal growth factor receptor tyrosine kinase inhibitor may be susceptible to pathogens.
authors.affiliation: Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aobaku, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Inoue
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Takuji
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kanehira
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kuroki
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Fukuhara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Makoto
authors.initials: M
authors.lastname: Maemondo
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Saijo