Suppression of surfactant protein A by an epidermal growth factor receptor tyrosine kinase inhibitor exacerbates lung inflammation.
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.
Inoue
Akira
A
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Aobaku, Sendai, Japan.
Xin
Hong
H
Suzuki
Takuji
T
Kanehira
Masahiko
M
Kuroki
Yoshio
Y
Fukuhara
Tatsuro
T
Kikuchi
Toshiaki
T
Maemondo
Makoto
M
Nukiwa
Toshihiro
T
Saijo
Yasuo
Y