Suppression of surfactant protein A by an epidermal growth factor receptor tyrosine kinase inhibitor exacerbates lung inflammation
Suppression of surfactant protein A by an epidermal growth factor receptor tyrosine kinase inhibitor exacerbates lung inflammation
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DOI：
10.1111/j.1349-7006.2008.00857.x
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发表时间：
2008-08-01
期刊：
影响因子：
5.7
通讯作者：
Saijo, Yasuo
中科院分区：
文献类型：
--
作者：
Inoue, Akira;Xin, Hong;Saijo, Yasuo
间质性肺疾病（ILD）被报告为接受吉非替尼（一种表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI））治疗的肺癌患者的严重不良事件。然而，与吉非替尼相关的ILD的机制仍然未知。为了阐明ILD相关的吉非替尼的分子机制，我们在体外和体内测定了吉非替尼治疗对表面活性蛋白表达的影响。吉非替尼处理通过抑制表皮生长因子信号抑制表达表面活性蛋白（SP）-A、-B、-C和-D的H441人肺腺癌细胞中SP-A的表达。接下来，经口给予吉非替尼（200 mg/kg）。每天给小鼠注射1周。每日给予吉非替尼逐渐降低支气管肺泡灌洗液中SP-A水平。当脂多糖（LPS）注入吉非替尼预处理1周的小鼠时，LPS引起的肺部炎症加重并延长。通过鼻内施用SP-A来挽救这种肺部炎症的恶化。这些结果表明，用吉非替尼预处理通过减少肺中SP-A的表达而加重LPS诱导的肺部炎症。本研究提示，表皮生长因子受体酪氨酸激酶抑制剂可降低肺癌患者肺中SP-A的表达，因此，接受表皮生长因子受体酪氨酸激酶抑制剂治疗的患者可能对病原体易感。（Cancer Sci 2008; 99：1679-1684）
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. (Cancer Sci 2008; 99: 1679-1684)