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: Akira Inoue, Hong Xin, Takuji Suzuki, Masahiko Kanehira, Yoshio Kuroki, Tatsuro Fukuhara, Toshiaki Kikuchi, Makoto Maemondo, Toshihiro Nukiwa, Yasuo Saijo
• Journal: Cancer science (Cancer Sci) Vol. 99 Issue 8 Pg. 1679-84 (Aug 2008) ISSN: 1349-7006 [Electronic] England
• PMID: 18754883 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides
• Protein Kinase Inhibitors
• Pulmonary Surfactant-Associated Protein A
• Quinazolines
• Gefitinib

Topics

• Adenocarcinoma (drug therapy)
• Animals
• Gefitinib
• Gene Expression (drug effects)
• Humans
• In Vitro Techniques
• Lipopolysaccharides
• Lung Diseases, Interstitial (chemically induced)
• Mice
• Pneumonia (chemically induced)
• Protein Kinase Inhibitors (pharmacology)
• Pulmonary Surfactant-Associated Protein A (metabolism)
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)