Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats
Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats
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DOI：
10.2152/jmi.59.174
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发表时间：
2012-02-01
影响因子：
0.7
通讯作者：
Sone, Saburo
中科院分区：
文献类型：
--
作者：
Miyake, Keiko;Tani, Kenji;Sone, Saburo
背景：吉非替尼是一种表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，据报道与间质性肺疾病有关，其高发病率和死亡率已成为人们高度关注的问题，特别是在日本。在这项研究中，我们在实验模型中研究了吉非替尼对辐射引起的肺部疾病不同阶段的影响。方法：第1天对Wistar大鼠进行胸部单次X射线剂量20 Gy照射，第1至14天口服吉非替尼（50 mg/kg/天）。第15和57天收获大鼠肺并进行支气管肺泡灌洗（BAL）。结果：第 15 天和第 57 天，吉非替尼治疗增加了受辐射大鼠肺部炎症细胞的浸润，产生更多促炎细胞因子（IL-6、IL-1β），而吉非替尼治疗降低了受辐射大鼠肺部的胶原含量，并降低了第 57 天受辐射大鼠肺成纤维细胞的增殖和 EGFR 表达。 结论：在受辐射大鼠中，吉非替尼治疗加剧了肺部炎症，包括炎症细胞浸润和促炎细胞因子表达，而吉非替尼治疗由于抑制肺成纤维细胞增殖而减弱了纤维化肺重塑。
Background : Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been reported to be associated with interstitial lung disorders, and their high incidence and mortality have become a matter of great concern, especially in Japan. In this study, we investigated the effect of gefitinib on different phases of radiation-induced lung disorders in an experimental model. Methods : The thoraxes of Wistar rats were irradiated on day 1 with a single X-ray dose of 20 Gy, and gefitinib (50 mg/kg/day) was orally administered from day 1 to 14. The rat lungs were harvested on days 15 and 57 and the bronchoalveolar lavage (BAL) was performed. Results : Gefitinib treatment increased the infiltration of inflammatory cells, which produced more pro-inflammatory cytokines (IL-6, IL-1 beta), in the lungs of the irradiated rats on days 15 and 57, while gefitinib treatment reduced collagen content of the lungs in irradiated rats and decreased proliferation and EGFR expression in the lung fibroblasts from irradiated rats on day 57. Conclusions : In irradiated rats, gefitinib treatment augmented lung inflammation, including inflammatory cell infiltration and pro-inflammatory cytokine expression, while gefitinib treatment attenuated fibrotic lung remodeling due to the inhibition of lung fibroblast proliferation.